PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T1	0-68	Sentence	denotes	Apitherapy for Age-Related Skeletal Muscle Dysfunction (Sarcopenia):
T2	69-133	Sentence	denotes	A Review on the Effects of Royal Jelly, Propolis, and Bee Pollen
T3	135-143	Sentence	denotes	Abstract
T4	144-324	Sentence	denotes	The global pandemic of sarcopenia, skeletal muscle loss and weakness, which prevails in up to 50% of older adults is increasing worldwide due to the expansion of aging populations.
T5	325-468	Sentence	denotes	It is now striking young and midlife adults as well because of sedentary lifestyle and increased intake of unhealthy food (e.g., western diet).
T6	469-699	Sentence	denotes	The lockdown measures and economic turndown associated with the current outbreak of Coronavirus Disease 2019 (COVID-19) are likely to increase the prevalence of sarcopenia by promoting sedentarism and unhealthy patterns of eating.
T7	700-815	Sentence	denotes	Sarcopenia has multiple detrimental effects including falls, hospitalization, disability, and institutionalization.
T8	816-1018	Sentence	denotes	Although a few pharmacological agents (e.g., bimagrumab, sarconeos, and exercise mimetics) are being explored in different stages of trials, not a single drug has been approved for sarcopenia treatment.
T9	1019-1164	Sentence	denotes	Hence, research has focused on testing the effect of nutraceuticals, such as bee products, as safe treatments to prevent and/or treat sarcopenia.
T10	1165-1316	Sentence	denotes	Royal jelly, propolis, and bee pollen are common bee products that are rich in highly potent antioxidants such as flavonoids, phenols, and amino acids.
T11	1317-1517	Sentence	denotes	These products, in order, stimulate larval development into queen bees, promote defenses of the bee hive against microbial and environmental threats, and increase royal jelly production by nurse bees.
T12	1518-1842	Sentence	denotes	Thanks to their versatile pharmacological activities (e.g., anti-aging, anti-inflammatory, anticarcinogenic, antimicrobial, etc.), these products have been used to treat multiple chronic conditions that predispose to muscle wasting such as hypertension, diabetes mellitus, cardiovascular disorder, and cancer, to name a few.
T13	1843-1966	Sentence	denotes	They were also used in some evolving studies to treat sarcopenia in laboratory animals and, to a limited degree, in humans.
T14	1967-2100	Sentence	denotes	However, a collective understanding of the effect and mechanism of action of these products in skeletal muscle is not well-developed.
T15	2101-2291	Sentence	denotes	Therefore, this review examines the literature for possible effects of royal jelly, bee pollen, and propolis on skeletal muscle in aged experimental models, muscle cell cultures, and humans.
T16	2292-2430	Sentence	denotes	Collectively, data from reviewed studies denote varying levels of positive effects of bee products on muscle mass, strength, and function.
T17	2431-2729	Sentence	denotes	The likely underlying mechanisms include amelioration of inflammation and oxidative damages, promotion of metabolic regulation, enhancement of satellite stem cell responsiveness, improvement of muscular blood supply, inhibition of catabolic genes, and promotion of peripheral neuronal regeneration.
T18	2730-2908	Sentence	denotes	This review offers suggestions for other mechanisms to be explored and provides guidance for future trials investigating the effects of bee products among people with sarcopenia.
T19	2910-2912	Sentence	denotes	1.
T20	2913-2925	Sentence	denotes	Introduction
T21	2926-3076	Sentence	denotes	While the numbers of older adults are expanding all over the world, the pandemic of sarcopenia, skeletal muscle loss/weakness is also on the rise [1].
T22	3077-3220	Sentence	denotes	Loss of lean body mass is a direct effect of the inflammatory and oxidative conditions that develop with aging [1,2]—described as inflammaging.
T23	3221-3518	Sentence	denotes	Both inflammatory mediators and free radicals, which are highly expressed in older seniors and in patients with chronic diseases, such as type 2 diabetes mellitus, cause remarkable shrinkage of fast-twitch type II fibers promoting their transformation into the slow-twitch type I fibers [1,3,4,5].
T24	3519-3729	Sentence	denotes	Research indicates that muscle wasting may develop after adolescence (at the beginning of the third decade of life) as a result of sedentary lifestyle and improper diet (low protein/high fat/low fiber) [6,7,8].
T25	3730-4008	Sentence	denotes	These behavioral factors alter the composition of gut microbiota promoting gut dysbiosis, which allows the passage of bacterial endotoxins into the systemic circulation to induce inflammation and oxidative stress same as in immunological aging that occurs during old age [9,10].
T26	4009-4220	Sentence	denotes	Longitudinal data show that the currently-occurring global crisis, coronavirus disease 2019 (COVID-19), is likely to aggravate the development of sarcopenia in young groups by promoting unhealthy lifestyle [11].
T27	4221-4407	Sentence	denotes	On one hand, physical inactivity is increasing as a result of the lockdown measures and stay home strategies adopted by most governments to limit the spread of this infection [11,12,13].
T28	4408-4649	Sentence	denotes	On the other hand, food production has been seriously affected during the COVID-19 outbreak along with increase in food prices, which prompt people to consume unhealthy/processed foods since they are cheaper than fresh and healthy ones [14].
T29	4650-4852	Sentence	denotes	Given its high prevalence in the general population, which ranges between 5 and 40% in western countries and increases up to 50% in advanced age, sarcopenia is considered a public health problem [4,15].
T30	4853-5060	Sentence	denotes	It causes progressive decline of functional capacity, contributes to frailty, increases the risk of falls and hospitalization in old people [16,17], and leads to poor outcomes in patients with COVID-19 [18].
T31	5061-5242	Sentence	denotes	A large number of pharmacological agents are being tested as anti-sarcopenic agents such as bimagrumab (BYM338), enobasarm (GTx-024), trevogrumab (REGN1033), and sarconeos (BIO101).
T32	5243-5286	Sentence	denotes	Most trials are in phase 1 or phase 2 [19].
T33	5287-5442	Sentence	denotes	In addition, outcomes of commonly used treatments (e.g., testosterone, growth hormone, and anabolic steroids) have been rather unsatisfactory [4,20,21,22].
T34	5443-5587	Sentence	denotes	Therefore, the most appropriate strategies for preventing and treating sarcopenia are limited to physical exercise and protein-rich diet [6,21].
T35	5588-5679	Sentence	denotes	Nevertheless, old people tend to be less compliant with physical activity programs [23,24].
T36	5680-5944	Sentence	denotes	Meanwhile, problems of the gastrointestinal (GI) tract that develop during advanced age (e.g., loss of teeth, taste, smell, and decreased absorption) as well as anabolic resistance of aged muscle limit potential benefits of protein-rich food in this group [25,26].
T37	5945-6142	Sentence	denotes	Therefore, it is of importance to search for novel preventive and curative strategies for sarcopenia, which can take into account the multifactorial nature of aging-related skeletal muscle failure.
T38	6144-6146	Sentence	denotes	2.
T39	6147-6210	Sentence	denotes	Apitherapy as a Possible Complementary Treatment for Sarcopenia
T40	6211-6296	Sentence	denotes	Rock paintings from the Stone Age portray consumption of bee products by humans [27].
T41	6297-6475	Sentence	denotes	The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30].
T42	6476-6640	Sentence	denotes	Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31].
T43	6641-6860	Sentence	denotes	The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].
T44	6861-7095	Sentence	denotes	Bee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32].
T45	7096-7208	Sentence	denotes	Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive.
T46	7209-7386	Sentence	denotes	They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32].
T47	7387-7605	Sentence	denotes	Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].
T48	7606-7752	Sentence	denotes	Several lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35].
T49	7753-7827	Sentence	denotes	These three products are widely used as dietary supplements [36,37,38,39].
T50	7828-8010	Sentence	denotes	In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42].
T51	8011-8073	Sentence	denotes	Bee products represent a part of this interventional strategy.
T52	8074-8228	Sentence	denotes	However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear.
T53	8229-8399	Sentence	denotes	Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age.
T54	8400-8596	Sentence	denotes	In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects.
T55	8597-8931	Sentence	denotes	Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”.
T56	8932-9018	Sentence	denotes	Snow ball manual search using reference lists of retrieved studies was also conducted.
T57	9019-9200	Sentence	denotes	This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis.
T58	9201-9373	Sentence	denotes	Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.
T59	9375-9379	Sentence	denotes	2.1.
T60	9380-9392	Sentence	denotes	Royal Jelly:
T61	9393-9453	Sentence	denotes	Its Constituents, Biological, and Pharmacological Activities
T62	9454-9641	Sentence	denotes	Royal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43].
T63	9642-9816	Sentence	denotes	In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32].
T64	9817-10043	Sentence	denotes	However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].
T65	10044-10154	Sentence	denotes	Protein is the most copious active element in royal jelly, representing half the weight of its dry matter [2].
T66	10155-10274	Sentence	denotes	It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45].
T67	10275-10382	Sentence	denotes	MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs.
T68	10383-10566	Sentence	denotes	MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47].
T69	10567-10624	Sentence	denotes	Novel non-MRJPs proteins have been newly discovered [48].
T70	10625-10741	Sentence	denotes	Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts.
T71	10742-11122	Sentence	denotes	These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].
T72	11123-11260	Sentence	denotes	Carbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49].
T73	11261-11466	Sentence	denotes	Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades.
T74	11467-11599	Sentence	denotes	Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].
T75	11600-11654	Sentence	denotes	Lipids make up 7–18% of the dry weight of royal jelly.
T76	11655-11883	Sentence	denotes	This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28].
T77	11884-12138	Sentence	denotes	The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51].
T78	12139-12365	Sentence	denotes	10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58].
T79	12366-12509	Sentence	denotes	In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].
T80	12510-13097	Sentence	denotes	A wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61].
T81	13098-13247	Sentence	denotes	It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher.
T82	13248-13313	Sentence	denotes	Therefore, freezing is the best method to store royal jelly [62].
T83	13314-13516	Sentence	denotes	Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].
T84	13517-13673	Sentence	denotes	Royal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56].
T85	13674-13961	Sentence	denotes	Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63].
T86	13962-14200	Sentence	denotes	Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64].
T87	14201-14492	Sentence	denotes	In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].
T88	14494-14498	Sentence	denotes	2.2.
T89	14499-14508	Sentence	denotes	Propolis:
T90	14509-14569	Sentence	denotes	Its Constituents, Biological, and Pharmacological Activities
T91	14570-14779	Sentence	denotes	Propolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65].
T92	14780-14867	Sentence	denotes	It comes in green, red, brown, or black colors based on the collected local flora [66].
T93	14868-15011	Sentence	denotes	The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”.
T94	15012-15106	Sentence	denotes	Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].
T95	15107-15218	Sentence	denotes	Propolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68].
T96	15219-15389	Sentence	denotes	Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67].
T97	15390-15591	Sentence	denotes	Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene.
T98	15592-15658	Sentence	denotes	The last two exist in raw Italian propolis at high concentrations:
T99	15659-15712	Sentence	denotes	107.12 and 145.37 μg/g of dry propolis, respectively.
T100	15713-16132	Sentence	denotes	Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69].
T101	16133-16295	Sentence	denotes	The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70].
T102	16296-16729	Sentence	denotes	Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].
T103	16730-16888	Sentence	denotes	The attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68].
T104	16889-16973	Sentence	denotes	Flavonoids comprise the majority of mostly studies bioactive substances in propolis.
T105	16974-17131	Sentence	denotes	Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey).
T106	17132-17230	Sentence	denotes	It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72].
T107	17231-17419	Sentence	denotes	Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75].
T108	17420-17616	Sentence	denotes	Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76].
T109	17617-17677	Sentence	denotes	It exists in numerous plants (e.g., Eucalyptus and Populus).
T110	17678-17778	Sentence	denotes	It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].
T111	17779-17898	Sentence	denotes	Essential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80].
T112	17899-18023	Sentence	denotes	They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82].
T113	18024-18146	Sentence	denotes	The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79].
T114	18147-18306	Sentence	denotes	For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin.
T115	18307-18512	Sentence	denotes	They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80].
T116	18513-18660	Sentence	denotes	Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques.
T117	18661-18898	Sentence	denotes	In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79].
T118	18899-19032	Sentence	denotes	Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].
T119	19033-19289	Sentence	denotes	Thanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties.
T120	19290-19410	Sentence	denotes	In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71].
T121	19411-19562	Sentence	denotes	Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].
T122	19563-19687	Sentence	denotes	Propolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68].
T123	19688-19871	Sentence	denotes	Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68].
T124	19872-19949	Sentence	denotes	Although water may be a cheap solvent, propolis has poor solubility in water.
T125	19950-20052	Sentence	denotes	Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts.
T126	20053-20123	Sentence	denotes	In addition, they retain the strong flavor and aroma of propolis [68].
T127	20124-20316	Sentence	denotes	Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80].
T128	20317-20415	Sentence	denotes	Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.
T129	20417-20421	Sentence	denotes	2.3.
T130	20422-20433	Sentence	denotes	Bee Pollen:
T131	20434-20494	Sentence	denotes	Its Constituents, Biological, and Pharmacological Activities
T132	20495-20623	Sentence	denotes	Bee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body.
T133	20624-20696	Sentence	denotes	Bee workers mix these floral pollens with honey, nectar, and bee saliva.
T134	20697-20836	Sentence	denotes	The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84].
T135	20837-20962	Sentence	denotes	Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].
T136	20963-21137	Sentence	denotes	In addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds.
T137	21138-21229	Sentence	denotes	Like other bee products, its composition varies considerably according to botanical origin.
T138	21230-21401	Sentence	denotes	Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%).
T139	21402-21706	Sentence	denotes	Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86].
T140	21707-21884	Sentence	denotes	In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86].
T141	21885-22089	Sentence	denotes	Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin.
T142	22090-22168	Sentence	denotes	Bee pollen contains other elements that still need to be explored (2–5%) [83].
T143	22169-22240	Sentence	denotes	Therefore, bee pollen represents a perfect whole health-promoting food.
T144	22241-22450	Sentence	denotes	In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].
T145	22451-22638	Sentence	denotes	Bee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87].
T146	22639-22919	Sentence	denotes	Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).
T147	22920-23154	Sentence	denotes	The composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84].
T148	23155-23242	Sentence	denotes	Storage conditions are of great importance were it to retain its biological activities.
T149	23243-23301	Sentence	denotes	Bee pollen should be consumed fresh soon after collection.
T150	23302-23415	Sentence	denotes	Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C.
T151	23416-23572	Sentence	denotes	Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].
T152	23573-23707	Sentence	denotes	Dry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89].
T153	23708-23911	Sentence	denotes	However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet.
T154	23912-24052	Sentence	denotes	Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut.
T155	24053-24178	Sentence	denotes	However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90].
T156	24179-24441	Sentence	denotes	Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].
T157	24443-24447	Sentence	denotes	2.4.
T158	24448-24503	Sentence	denotes	Safety Profile of Royal Jelly, Propolis, and Bee Pollen
T159	24504-24777	Sentence	denotes	Propolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67].
T160	24778-24909	Sentence	denotes	In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39].
T161	24910-25018	Sentence	denotes	Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66].
T162	25019-25175	Sentence	denotes	The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91].
T163	25176-25264	Sentence	denotes	The safety profile of bee pollen (both crude and processed) has been empirically tested.
T164	25265-25501	Sentence	denotes	Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90].
T165	25502-25599	Sentence	denotes	In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].
T166	25600-25687	Sentence	denotes	Several lines of evidence support the anti-allergic effect of propolis and royal jelly.
T167	25688-25924	Sentence	denotes	This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92].
T168	25925-26033	Sentence	denotes	Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature.
T169	26034-26083	Sentence	denotes	They are most frequent in small children [80,93].
T170	26084-26291	Sentence	denotes	Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80].
T171	26292-26438	Sentence	denotes	Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61].
T172	26439-26514	Sentence	denotes	In addition, bee products can be safely consumed after adequate processing.
T173	26515-26669	Sentence	denotes	Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94].
T174	26671-26673	Sentence	denotes	3.
T175	26674-26763	Sentence	denotes	Evidence of Anti-Sarcopenia Effects of Bee Products from Preclinical and Clinical Studies
T176	26764-27062	Sentence	denotes	Though few animal models were used to examine the effect of bee products on sarcopenia, findings indicate that royal jelly, propolis, and bee pollen can induce both structural and symptomatic improvements and reduce behavioral dysfunctions associated with sarcopenia in rodents (Figure 1, Panel C).
T177	27063-27492	Sentence	denotes	Both crude and protease-treated royal jelly (pRJ) significantly delayed age-related impairment of motor functions in d-galactose induced mouse model of aging [95], naturally aged sarcopenic mice [96], and in genetically heterogeneous head tilt (HET) mice—which exhibit vestibular dysfunction, imbalanced position, and inability to swim—by improving performance on grip strength, wire hang, horizontal bar, and rotarod tests [97].
T178	27493-27689	Sentence	denotes	Similarly, royal jelly improved physical performance in aged rodents—it significantly increased the number of crossings and swimming speed and prolonged swimming distance in water maze [96,98,99].
T179	27690-28106	Sentence	denotes	In addition, royal jelly decreased lipid accumulation in skeletal muscle [100], positively improved the size of muscle fibers, lowered age-related reduction of skeletal muscle weight [95,96,97,100], increased the differentiation and proliferation rate of muscle satellite cell, improved the regenerative capacity of injured muscle, and suppressed catabolic genes in aged mice with sarcopenia and in HET mice [96,97].
T180	28107-28241	Sentence	denotes	The muscle mass-accelerating effects of 10-HDA, a key fatty acid in royal jelly, were more pronounced in male animals than in females.
T181	28242-28323	Sentence	denotes	However, 10-HDA mitigated the accumulation of adipose tissue in female mice [54].
T182	28324-28448	Sentence	denotes	It is note-worthy that pRJ had no effect on muscle strength and physical performance in humans aged 70 years and above [59].
T183	28449-28519	Sentence	denotes	The effects of other bee products on muscle mass were mostly positive.
T184	28520-28655	Sentence	denotes	Bee pollen promoted body weight regain and increased the relative weight of the gastrocnemius muscle in eccentric exercising rats [90].
T185	28656-28764	Sentence	denotes	It also increased the absolute weights of plantaris and gastrocnemius muscles in malnourished old rats [36].
T186	28765-28888	Sentence	denotes	CAPE restored gastrocnemius muscle mass in rats on exhaustive exercise and in rats with ischemia reperfusion [101,102,103].
T187	28889-29026	Sentence	denotes	A study reported no effect of propolis ethanolic extracts (4% of diet) on the size of muscle or their level of myostatin in Nile tilapia.
T188	29027-29299	Sentence	denotes	However, another interesting study reported significant increases in body protein deposition and body condition factor—an estimate of future growth, survival, and reproductive potential—in Nile tilapia post-larvae and fingerlings receiving 2.6 g propolis/kg of feed [104].
T189	29300-29353	Sentence	denotes	Nonetheless, these findings seem to be bound to fish.
T190	29354-29641	Sentence	denotes	Interestingly, supplementing obese rats on high fat diet (HFD) with milk naturally enriched with long-chain polyunsaturated fatty acids (PUFA) and polyphenols from propolis significantly increased gastrocnemius muscle mass compared with whole milk and milk enriched with PUFA only [105].
T191	29642-29703	Sentence	denotes	Several molecular changes were associated with these effects.
T192	29704-29747	Sentence	denotes	We elaborate on these changes in Section 4.
T193	29748-29851	Sentence	denotes	Table 1 presents more details on treatments with bee products and key findings of the relevant studies.
T194	29853-29855	Sentence	denotes	4.
T195	29856-29931	Sentence	denotes	Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia
T196	29932-30068	Sentence	denotes	Relatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia.
T197	30069-30529	Sentence	denotes	In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D).
T198	30530-30598	Sentence	denotes	These mechanisms are exclusively described in the coming paragraphs.
T199	30600-30604	Sentence	denotes	4.1.
T200	30605-30657	Sentence	denotes	Modulating Inflammatory Responses in Skeletal Muscle
T201	30658-30741	Sentence	denotes	The role that inflammation plays in skeletal muscle is not quite clear as it looks.
T202	30742-30806	Sentence	denotes	Inflammatory mediators behave in a dual fashion in muscle cells.
T203	30807-30957	Sentence	denotes	During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108].
T204	30958-31117	Sentence	denotes	Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α.
T205	31118-31392	Sentence	denotes	On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114].
T206	31393-31585	Sentence	denotes	It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108].
T207	31586-31989	Sentence	denotes	In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds).
T208	31990-32075	Sentence	denotes	Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation.
T209	32076-32253	Sentence	denotes	These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment.
T210	32254-32429	Sentence	denotes	Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively.
T211	32430-32481	Sentence	denotes	Propolis also enhanced the expression of MAIL/IκBζ.
T212	32482-32614	Sentence	denotes	This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].
T213	32615-32899	Sentence	denotes	Chronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115].
T214	32900-33139	Sentence	denotes	CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102].
T215	33140-33254	Sentence	denotes	This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102].
T216	33255-33562	Sentence	denotes	As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101].
T217	33563-33701	Sentence	denotes	The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101].
T218	33702-34000	Sentence	denotes	As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].
T219	34001-34145	Sentence	denotes	Royal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100].
T220	34146-34363	Sentence	denotes	TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107].
T221	34364-34642	Sentence	denotes	Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight.
T222	34643-34908	Sentence	denotes	Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].
T223	34910-34914	Sentence	denotes	4.2.
T224	34915-34964	Sentence	denotes	Counteracting Oxidative Stress in Skeletal Muscle
T225	34965-35188	Sentence	denotes	High production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101].
T226	35189-35517	Sentence	denotes	Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118].
T227	35518-35736	Sentence	denotes	Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101].
T228	35737-36032	Sentence	denotes	ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].
T229	36033-36169	Sentence	denotes	Royal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95].
T230	36170-36385	Sentence	denotes	Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110].
T231	36386-36735	Sentence	denotes	Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109].
T232	36736-37026	Sentence	denotes	In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].
T233	37027-37128	Sentence	denotes	Bee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes.
T234	37129-37305	Sentence	denotes	Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106].
T235	37306-37539	Sentence	denotes	Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90].
T236	37540-37830	Sentence	denotes	It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2].
T237	37831-38029	Sentence	denotes	Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities.
T238	38030-38190	Sentence	denotes	For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119].
T239	38191-38351	Sentence	denotes	Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels.
T240	38352-38578	Sentence	denotes	PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120].
T241	38579-38861	Sentence	denotes	Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].
T242	38862-39147	Sentence	denotes	The antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123].
T243	39148-39253	Sentence	denotes	Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122].
T244	39254-39446	Sentence	denotes	In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101].
T245	39447-39704	Sentence	denotes	Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103].
T246	39705-39910	Sentence	denotes	In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase.
T247	39911-40082	Sentence	denotes	Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102].
T248	40083-40252	Sentence	denotes	Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].
T249	40253-40605	Sentence	denotes	In summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].
T250	40607-40611	Sentence	denotes	4.3.
T251	40612-40632	Sentence	denotes	Metabolic Regulation
T252	40633-40709	Sentence	denotes	Skeletal muscle is the main tissue that utilizes insulin for glucose uptake.
T253	40710-41008	Sentence	denotes	Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake.
T254	41009-41200	Sentence	denotes	This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126].
T255	41201-41286	Sentence	denotes	Insulin resistance and glucose intolerance increase with old age evoking muscle loss.
T256	41287-41460	Sentence	denotes	In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].
T257	41461-41636	Sentence	denotes	AMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism.
T258	41637-41806	Sentence	denotes	It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase.
T259	41807-42037	Sentence	denotes	Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111].
T260	42038-42315	Sentence	denotes	In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].
T261	42316-42546	Sentence	denotes	The molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle.
T262	42547-42745	Sentence	denotes	Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129].
T263	42746-42859	Sentence	denotes	Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100].
T264	42860-43041	Sentence	denotes	In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96].
T265	43042-43275	Sentence	denotes	In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1.
T266	43276-43404	Sentence	denotes	This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].
T267	43405-43576	Sentence	denotes	Japanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training.
T268	43577-43851	Sentence	denotes	These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway.
T269	43852-43954	Sentence	denotes	Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106].
T270	43955-44075	Sentence	denotes	It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific.
T271	44076-44384	Sentence	denotes	In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%).
T272	44385-44506	Sentence	denotes	On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training.
T273	44507-44811	Sentence	denotes	Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106].
T274	44812-44900	Sentence	denotes	Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit.
T275	44901-45140	Sentence	denotes	This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].
T276	45141-45277	Sentence	denotes	Several lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111].
T277	45278-45420	Sentence	denotes	This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109].
T278	45421-45622	Sentence	denotes	Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111].
T279	45623-45939	Sentence	denotes	Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts.
T280	45940-46098	Sentence	denotes	The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].
T281	46099-46271	Sentence	denotes	Similar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK.
T282	46272-46393	Sentence	denotes	These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator.
T283	46394-46566	Sentence	denotes	In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111].
T284	46567-46990	Sentence	denotes	Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111].
T285	46991-47222	Sentence	denotes	It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].
T286	47224-47228	Sentence	denotes	4.4.
T287	47229-47268	Sentence	denotes	Enhancement of Muscle Protein Synthesis
T288	47269-47561	Sentence	denotes	Imbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers.
T289	47562-47929	Sentence	denotes	Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17].
T290	47930-48532	Sentence	denotes	Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].
T291	48533-48800	Sentence	denotes	Research indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways.
T292	48801-49109	Sentence	denotes	Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism.
T293	49110-49277	Sentence	denotes	It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136].
T294	49278-49386	Sentence	denotes	Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1.
T295	49387-49460	Sentence	denotes	Even more, amino acids on their own can adequately activate mTORC1 [136].
T296	49461-49807	Sentence	denotes	Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase.
T297	49808-50159	Sentence	denotes	Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].
T298	50160-50307	Sentence	denotes	As shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99].
T299	50308-50637	Sentence	denotes	In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36].
T300	50638-50788	Sentence	denotes	Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen.
T301	50789-50869	Sentence	denotes	However, it fostered muscle protein deposition in post-larva Nile tilapia [104].
T302	50870-51130	Sentence	denotes	Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105].
T303	51131-51284	Sentence	denotes	Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth.
T304	51285-51462	Sentence	denotes	Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].
T305	51464-51468	Sentence	denotes	4.5.
T306	51469-51521	Sentence	denotes	Suppression of Catabolic Activity in Skeletal Muscle
T307	51522-51626	Sentence	denotes	Skeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein).
T308	51627-51747	Sentence	denotes	Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124].
T309	51748-51831	Sentence	denotes	Muscle protein metabolism is regulated by the interaction of a wide range of genes.
T310	51832-51981	Sentence	denotes	Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx).
T311	51982-52055	Sentence	denotes	These genes heighten the occurrence of age-related muscular atrophy [97].
T312	52056-52216	Sentence	denotes	Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice.
T313	52217-52414	Sentence	denotes	In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97].
T314	52415-52717	Sentence	denotes	Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103].
T315	52718-52961	Sentence	denotes	Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].
T316	52962-53117	Sentence	denotes	The molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways.
T317	53118-53243	Sentence	denotes	Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96].
T318	53244-53515	Sentence	denotes	Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70].
T319	53516-53667	Sentence	denotes	AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family.
T320	53668-53991	Sentence	denotes	Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140].
T321	53992-54331	Sentence	denotes	In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140].
T322	54332-54484	Sentence	denotes	In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141].
T323	54485-54666	Sentence	denotes	FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation.
T324	54667-54885	Sentence	denotes	In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].
T325	54887-54891	Sentence	denotes	4.6.
T326	54892-54925	Sentence	denotes	Enhancement of Stem Cell Function
T327	54926-55097	Sentence	denotes	Reduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96].
T328	55098-55277	Sentence	denotes	Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143].
T329	55278-55538	Sentence	denotes	On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97].
T330	55539-55640	Sentence	denotes	AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1.
T331	55641-55934	Sentence	denotes	IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96].
T332	55935-56169	Sentence	denotes	Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss.
T333	56170-56279	Sentence	denotes	AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].
T334	56281-56285	Sentence	denotes	4.7.
T335	56286-56316	Sentence	denotes	Counteracting Glycation Stress
T336	56317-56581	Sentence	denotes	Oxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145].
T337	56582-56763	Sentence	denotes	AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113].
T338	56764-56878	Sentence	denotes	Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions.
T339	56879-57075	Sentence	denotes	On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs.
T340	57076-57300	Sentence	denotes	On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146].
T341	57301-57438	Sentence	denotes	Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147].
T342	57439-57523	Sentence	denotes	However, its anti-glycation effect has not been investigated in skeletal muscle yet.
T343	57524-57666	Sentence	denotes	Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors.
T344	57667-57771	Sentence	denotes	Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37].
T345	57772-58026	Sentence	denotes	Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38].
T346	58027-58231	Sentence	denotes	CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103].
T347	58232-58399	Sentence	denotes	The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148].
T348	58400-58576	Sentence	denotes	However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass.
T349	58577-58720	Sentence	denotes	This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers.
T350	58721-58923	Sentence	denotes	It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].
T351	58925-58929	Sentence	denotes	4.8.
T352	58930-58951	Sentence	denotes	Neuronal Regeneration
T353	58952-59098	Sentence	denotes	Neuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149].
T354	59099-59256	Sentence	denotes	Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150].
T355	59257-59400	Sentence	denotes	Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion.
T356	59401-59605	Sentence	denotes	Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113].
T357	59606-59832	Sentence	denotes	Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151].
T358	59833-59990	Sentence	denotes	Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69].
T359	59991-60246	Sentence	denotes	Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway:
T360	60247-60275	Sentence	denotes	MuRF1 and Atrogin-1 [1,152].
T361	60276-60446	Sentence	denotes	Propolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve.
T362	60447-60647	Sentence	denotes	Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells.
T363	60648-60901	Sentence	denotes	Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113].
T364	60902-60988	Sentence	denotes	Neuroprotective effects of propolis in motor neurons are documented in the literature.
T365	60989-61251	Sentence	denotes	Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65].
T366	61252-61688	Sentence	denotes	In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].
T367	61689-61919	Sentence	denotes	The release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size.
T368	61920-62048	Sentence	denotes	However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153].
T369	62049-62141	Sentence	denotes	On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154].
T370	62142-62267	Sentence	denotes	Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60].
T371	62268-62508	Sentence	denotes	In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103].
T372	62509-62815	Sentence	denotes	In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115].
T373	62816-62907	Sentence	denotes	However, investigations of the action of bee products on neurotransmission are very scarce.
T374	62909-62913	Sentence	denotes	4.9.
T375	62914-62945	Sentence	denotes	Improving Muscular Blood Supply
T376	62946-63150	Sentence	denotes	Aging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155].
T377	63151-63438	Sentence	denotes	Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110].
T378	63439-63569	Sentence	denotes	Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle.
T379	63570-63720	Sentence	denotes	Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157].
T380	63721-63872	Sentence	denotes	In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues.
T381	63873-64060	Sentence	denotes	Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102].
T382	64061-64195	Sentence	denotes	Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.
T383	64196-64440	Sentence	denotes	Mitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old).
T384	64441-64577	Sentence	denotes	They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity.
T385	64578-64746	Sentence	denotes	Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157].
T386	64747-64947	Sentence	denotes	Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155].
T387	64948-65132	Sentence	denotes	In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor.
T388	65133-65485	Sentence	denotes	The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155].
T389	65486-65916	Sentence	denotes	In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF).
T390	65917-66158	Sentence	denotes	The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110].
T391	66159-66325	Sentence	denotes	Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90].
T392	66326-66415	Sentence	denotes	Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108].
T393	66416-66579	Sentence	denotes	VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks.
T394	66580-66685	Sentence	denotes	VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110].
T395	66686-66832	Sentence	denotes	Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK.
T396	66833-66939	Sentence	denotes	It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158].
T397	66940-67092	Sentence	denotes	Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.
T398	67094-67099	Sentence	denotes	4.10.
T399	67100-67143	Sentence	denotes	Improving the Composition of Gut Microbiome
T400	67144-67304	Sentence	denotes	Bee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66].
T401	67305-67376	Sentence	denotes	Most bee products investigated in this review were administered orally.
T402	67377-67607	Sentence	denotes	Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152].
T403	67608-67738	Sentence	denotes	In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks.
T404	67739-67879	Sentence	denotes	HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers.
T405	67880-68027	Sentence	denotes	DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal.
T406	68028-68261	Sentence	denotes	Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].
T407	68262-68345	Sentence	denotes	Lactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84].
T408	68346-68477	Sentence	denotes	Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160].
T409	68478-68562	Sentence	denotes	Moreover, oligosaccharides have been chemically isolated from bee products [32,161].
T410	68563-68726	Sentence	denotes	These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161].
T411	68727-68885	Sentence	denotes	Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162].
T412	68886-68978	Sentence	denotes	On the other side, microbiome of the gut can affect the biological activity of bee products.
T413	68979-69193	Sentence	denotes	The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163].
T414	69194-69418	Sentence	denotes	Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes.
T415	69420-69422	Sentence	denotes	5.
T416	69423-69433	Sentence	denotes	Discussion
T417	69434-69593	Sentence	denotes	Age-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia.
T418	69594-69778	Sentence	denotes	Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21].
T419	69779-70052	Sentence	denotes	Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action.
T420	70053-70270	Sentence	denotes	Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes.
T421	70271-70695	Sentence	denotes	These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].
T422	70696-70848	Sentence	denotes	One of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164].
T423	70849-71070	Sentence	denotes	Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111].
T424	71071-71248	Sentence	denotes	In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36].
T425	71249-71362	Sentence	denotes	Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111].
T426	71363-71490	Sentence	denotes	Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake.
T427	71491-71602	Sentence	denotes	In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106].
T428	71603-71744	Sentence	denotes	AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22].
T429	71745-71941	Sentence	denotes	Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes.
T430	71942-72057	Sentence	denotes	However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.
T431	72058-72217	Sentence	denotes	The activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136].
T432	72218-72528	Sentence	denotes	Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136].
T433	72529-72768	Sentence	denotes	Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137].
T434	72769-72866	Sentence	denotes	Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis.
T435	72867-73127	Sentence	denotes	Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152].
T436	73128-73309	Sentence	denotes	Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].
T437	73310-73603	Sentence	denotes	According to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle.
T438	73604-73911	Sentence	denotes	The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117].
T439	73912-74402	Sentence	denotes	However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38].
T440	74403-74550	Sentence	denotes	These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy.
T441	74551-74763	Sentence	denotes	In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].
T442	74764-75005	Sentence	denotes	As for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population.
T443	75006-75198	Sentence	denotes	This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59].
T444	75199-75337	Sentence	denotes	Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality.
T445	75338-75606	Sentence	denotes	In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].
T446	75607-75737	Sentence	denotes	The relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed.
T447	75738-75829	Sentence	denotes	Existing knowledge indicates that muscle strength may be intact in people with muscle loss.
T448	75830-75922	Sentence	denotes	Likewise, decreased muscle strength may not necessarily alter physical performance [21,170].
T449	75923-76179	Sentence	denotes	Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss.
T450	76180-76477	Sentence	denotes	More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21].
T451	76478-76750	Sentence	denotes	In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry.
T452	76751-77033	Sentence	denotes	This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171].
T453	77034-77087	Sentence	denotes	Animal studies lend further support to those reports.
T454	77088-77342	Sentence	denotes	For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs.
T455	77343-77578	Sentence	denotes	On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97].
T456	77579-77742	Sentence	denotes	Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97].
T457	77743-77842	Sentence	denotes	Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59].
T458	77843-78058	Sentence	denotes	Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.
T459	78059-78152	Sentence	denotes	Multifactorial conditions such as sarcopenia should be addressed by multimodal interventions.
T460	78153-78308	Sentence	denotes	Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21].
T461	78309-78647	Sentence	denotes	Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106].
T462	78648-78823	Sentence	denotes	Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172].
T463	78824-79023	Sentence	denotes	In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle.
T464	79024-79127	Sentence	denotes	It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein.
T465	79128-79270	Sentence	denotes	These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105].
T466	79271-79411	Sentence	denotes	On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173].
T467	79412-79583	Sentence	denotes	Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108].
T468	79584-79739	Sentence	denotes	This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114].
T469	79740-80096	Sentence	denotes	Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106].
T470	80097-80363	Sentence	denotes	Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].
T471	80364-80435	Sentence	denotes	In most studies, whole royal jelly, bee pollen, and propolis were used.
T472	80436-80661	Sentence	denotes	However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly.
T473	80662-80776	Sentence	denotes	Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly.
T474	80777-81040	Sentence	denotes	In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69].
T475	81041-81119	Sentence	denotes	10-HDA was the only element in royal jelly that was tested in skeletal muscle.
T476	81120-81178	Sentence	denotes	It enhanced glucose uptake via AMPK phosphorylation [106].
T477	81179-81339	Sentence	denotes	It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54].
T478	81340-81579	Sentence	denotes	CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103].
T479	81580-81727	Sentence	denotes	The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111].
T480	81728-81979	Sentence	denotes	More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene.
T481	81980-82154	Sentence	denotes	Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells.
T482	82155-82322	Sentence	denotes	Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].
T483	82323-82463	Sentence	denotes	Matters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia.
T484	82464-82586	Sentence	denotes	In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation.
T485	82587-82746	Sentence	denotes	For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47].
T486	82747-82879	Sentence	denotes	In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132].
T487	82880-82959	Sentence	denotes	Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.
T488	82960-83041	Sentence	denotes	Despite the details illustrated in this review, many questions remain unanswered.
T489	83042-83213	Sentence	denotes	The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances?
T490	83214-83506	Sentence	denotes	Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21].
T491	83507-83763	Sentence	denotes	The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function).
T492	83765-83767	Sentence	denotes	6.
T493	83768-83779	Sentence	denotes	Conclusions
T494	83780-83998	Sentence	denotes	All animal studies discussed above indicate that royal jelly, propolis, and bee pollen as well as their key ingredients such as 10-HDA and CAPE might counteract age-related muscular decline, especially in early stages.
T495	83999-84151	Sentence	denotes	These products operate by modulating most mechanisms that contribute to sarcopenia such as metabolic dysregulation, inflammation, oxidative stress, etc.
T496	84152-84342	Sentence	denotes	However, more studies are needed to examine the specific cellular and molecular mechanisms of these products and other major ingredients that were not explored, such as MRJPs in royal jelly.
T497	84343-84495	Sentence	denotes	Among all bee products, royal jelly has been used to improve muscular performance in humans, though at a small scale, without any reported side effects.
T498	84496-84747	Sentence	denotes	Future RCTs that examine the effect of bee products on sarcopenia should consider individual variations (e.g., gender, general health, activity level, diet, etc.) and combine functional and subjective outcome measures with sound predictive biomarkers.
T499	84749-84769	Sentence	denotes	Author Contributions
T500	84770-85008	Sentence	denotes	Conceptualization, A.M.A.; methodology, A.M.A.; software, A.M.A.; validation, A.M.A.; writing—original draft preparation, A.M.A.; writing—review and editing, H.K.; supervision, H.K.; project administration, H.K.; funding acquisition, H.K.

T1

0-68

Sentence

denotes

Apitherapy for Age-Related Skeletal Muscle Dysfunction (Sarcopenia):

T2

69-133

Sentence

denotes

A Review on the Effects of Royal Jelly, Propolis, and Bee Pollen

T3

135-143

Sentence

denotes

Abstract

T4

144-324

Sentence

denotes

The global pandemic of sarcopenia, skeletal muscle loss and weakness, which prevails in up to 50% of older adults is increasing worldwide due to the expansion of aging populations.

T5

325-468

Sentence

denotes

It is now striking young and midlife adults as well because of sedentary lifestyle and increased intake of unhealthy food (e.g., western diet).

T6

469-699

Sentence

denotes

The lockdown measures and economic turndown associated with the current outbreak of Coronavirus Disease 2019 (COVID-19) are likely to increase the prevalence of sarcopenia by promoting sedentarism and unhealthy patterns of eating.

T7

700-815

Sentence

denotes

Sarcopenia has multiple detrimental effects including falls, hospitalization, disability, and institutionalization.

T8

816-1018

Sentence

denotes

Although a few pharmacological agents (e.g., bimagrumab, sarconeos, and exercise mimetics) are being explored in different stages of trials, not a single drug has been approved for sarcopenia treatment.

T9

1019-1164

Sentence

denotes

Hence, research has focused on testing the effect of nutraceuticals, such as bee products, as safe treatments to prevent and/or treat sarcopenia.

T10

1165-1316

Sentence

denotes

Royal jelly, propolis, and bee pollen are common bee products that are rich in highly potent antioxidants such as flavonoids, phenols, and amino acids.

T11

1317-1517

Sentence

denotes

These products, in order, stimulate larval development into queen bees, promote defenses of the bee hive against microbial and environmental threats, and increase royal jelly production by nurse bees.

T12

1518-1842

Sentence

denotes

Thanks to their versatile pharmacological activities (e.g., anti-aging, anti-inflammatory, anticarcinogenic, antimicrobial, etc.), these products have been used to treat multiple chronic conditions that predispose to muscle wasting such as hypertension, diabetes mellitus, cardiovascular disorder, and cancer, to name a few.

T13

1843-1966

Sentence

denotes

They were also used in some evolving studies to treat sarcopenia in laboratory animals and, to a limited degree, in humans.

T14

1967-2100

Sentence

denotes

However, a collective understanding of the effect and mechanism of action of these products in skeletal muscle is not well-developed.

T15

2101-2291

Sentence

denotes

Therefore, this review examines the literature for possible effects of royal jelly, bee pollen, and propolis on skeletal muscle in aged experimental models, muscle cell cultures, and humans.

T16

2292-2430

Sentence

denotes

Collectively, data from reviewed studies denote varying levels of positive effects of bee products on muscle mass, strength, and function.

T17

2431-2729

Sentence

denotes

The likely underlying mechanisms include amelioration of inflammation and oxidative damages, promotion of metabolic regulation, enhancement of satellite stem cell responsiveness, improvement of muscular blood supply, inhibition of catabolic genes, and promotion of peripheral neuronal regeneration.

T18

2730-2908

Sentence

denotes

This review offers suggestions for other mechanisms to be explored and provides guidance for future trials investigating the effects of bee products among people with sarcopenia.

T19

2910-2912

Sentence

denotes

1.

T20

2913-2925

Sentence

denotes

Introduction

T21

2926-3076

Sentence

denotes

While the numbers of older adults are expanding all over the world, the pandemic of sarcopenia, skeletal muscle loss/weakness is also on the rise [1].

T22

3077-3220

Sentence

denotes

Loss of lean body mass is a direct effect of the inflammatory and oxidative conditions that develop with aging [1,2]—described as inflammaging.

T23

3221-3518

Sentence

denotes

Both inflammatory mediators and free radicals, which are highly expressed in older seniors and in patients with chronic diseases, such as type 2 diabetes mellitus, cause remarkable shrinkage of fast-twitch type II fibers promoting their transformation into the slow-twitch type I fibers [1,3,4,5].

T24

3519-3729

Sentence

denotes

Research indicates that muscle wasting may develop after adolescence (at the beginning of the third decade of life) as a result of sedentary lifestyle and improper diet (low protein/high fat/low fiber) [6,7,8].

T25

3730-4008

Sentence

denotes

These behavioral factors alter the composition of gut microbiota promoting gut dysbiosis, which allows the passage of bacterial endotoxins into the systemic circulation to induce inflammation and oxidative stress same as in immunological aging that occurs during old age [9,10].

T26

4009-4220

Sentence

denotes

Longitudinal data show that the currently-occurring global crisis, coronavirus disease 2019 (COVID-19), is likely to aggravate the development of sarcopenia in young groups by promoting unhealthy lifestyle [11].

T27

4221-4407

Sentence

denotes

On one hand, physical inactivity is increasing as a result of the lockdown measures and stay home strategies adopted by most governments to limit the spread of this infection [11,12,13].

T28

4408-4649

Sentence

denotes

On the other hand, food production has been seriously affected during the COVID-19 outbreak along with increase in food prices, which prompt people to consume unhealthy/processed foods since they are cheaper than fresh and healthy ones [14].

T29

4650-4852

Sentence

denotes

Given its high prevalence in the general population, which ranges between 5 and 40% in western countries and increases up to 50% in advanced age, sarcopenia is considered a public health problem [4,15].

T30

4853-5060

Sentence

denotes

It causes progressive decline of functional capacity, contributes to frailty, increases the risk of falls and hospitalization in old people [16,17], and leads to poor outcomes in patients with COVID-19 [18].

T31

5061-5242

Sentence

denotes

A large number of pharmacological agents are being tested as anti-sarcopenic agents such as bimagrumab (BYM338), enobasarm (GTx-024), trevogrumab (REGN1033), and sarconeos (BIO101).

T32

5243-5286

Sentence

denotes

Most trials are in phase 1 or phase 2 [19].

T33

5287-5442

Sentence

denotes

In addition, outcomes of commonly used treatments (e.g., testosterone, growth hormone, and anabolic steroids) have been rather unsatisfactory [4,20,21,22].

T34

5443-5587

Sentence

denotes

Therefore, the most appropriate strategies for preventing and treating sarcopenia are limited to physical exercise and protein-rich diet [6,21].

T35

5588-5679

Sentence

denotes

Nevertheless, old people tend to be less compliant with physical activity programs [23,24].

T36

5680-5944

Sentence

denotes

Meanwhile, problems of the gastrointestinal (GI) tract that develop during advanced age (e.g., loss of teeth, taste, smell, and decreased absorption) as well as anabolic resistance of aged muscle limit potential benefits of protein-rich food in this group [25,26].

T37

5945-6142

Sentence

denotes

Therefore, it is of importance to search for novel preventive and curative strategies for sarcopenia, which can take into account the multifactorial nature of aging-related skeletal muscle failure.

T38

6144-6146

Sentence

denotes

2.

T39

6147-6210

Sentence

denotes

Apitherapy as a Possible Complementary Treatment for Sarcopenia

T40

6211-6296

Sentence

denotes

Rock paintings from the Stone Age portray consumption of bee products by humans [27].

T41

6297-6475

Sentence

denotes

The first evidence of human usage of bee products for therapeutic and cosmetic purposes dates back 6000 years in ancient Egypt and later in China, Greece, and Rome [27,28,29,30].

T42

6476-6640

Sentence

denotes

Current research interest is directed toward the use of natural substances, including bee products, as potential pharmaceuticals to modify disease progression [31].

T43

6641-6860

Sentence

denotes

The term “apitherapy” describes a category of complementary and alternative medicine that comprises therapeutic use of various bee products including apilarnil (atomized drone larva) to prevent and treat illnesses [30].

T44

6861-7095

Sentence

denotes

Bee workers of either Apis mellifera or Apis cerana species—the former is common in Europe, Asia, Africa, and America while the latter exists only in southern and southeastern Asia—produce and store multiple bioactive substances [32].

T45

7096-7208

Sentence

denotes

Royal jelly, propolis, bee pollen, honey, bee venom, bee bread, and bee wax are common products of the bee hive.

T46

7209-7386

Sentence

denotes

They all (to a varying degree) possess multiple health promoting properties due to their high content of natural antioxidants such as flavonoids, phenols, or terpenoids [28,32].

T47

7387-7605

Sentence

denotes

Research documents variability in contents and effects of every single bee product, mainly due to the influence of bee species, botanical origin, geographic location, season, extraction, and handling procedures [2,28].

T48

7606-7752

Sentence

denotes

Several lines of evidence describe anti-aging effects of royal jelly, bee pollen, and propolis both in humans and laboratory animals [2,33,34,35].

T49

7753-7827

Sentence

denotes

These three products are widely used as dietary supplements [36,37,38,39].

T50

7828-8010

Sentence

denotes

In the meantime, the literature gives examples of numerous dietary supplements that could successfully prevent or alleviate the progression of muscle mass loss in old age [40,41,42].

T51

8011-8073

Sentence

denotes

Bee products represent a part of this interventional strategy.

T52

8074-8228

Sentence

denotes

However, the extent to which bee products can affect sarcopenia as well as understanding of their underlying mechanism of action are far from being clear.

T53

8229-8399

Sentence

denotes

Therefore, we conducted this review with the aim of investigating the anti-aging properties of these products with a focus on skeletal muscle functioning in advanced age.

T54

8400-8596

Sentence

denotes

In this respect, we reviewed animal and human studies investigating effects of the aforementioned products on skeletal muscle aging and elaborated on different mechanisms underlying these effects.

T55

8597-8931

Sentence

denotes

Studies included in this review were retrieved by searching PubMed and Google scholar using a combination of terminologies of “sarcopenia, muscle wasting, muscle mass, lean body mass, skeletal muscle, motor” with “royal jelly, honey, bee pollen, propolis, bee venom, bee bread, bee wax, chrysin, apamin, caffeic acid phenethyl ester”.

T56

8932-9018

Sentence

denotes

Snow ball manual search using reference lists of retrieved studies was also conducted.

T57

9019-9200

Sentence

denotes

This search resulted in a number of studies, which addressed muscle wasting and related dynamics through the use of three bee products, namely royal jelly, bee pollen, and propolis.

T58

9201-9373

Sentence

denotes

Figure 1, Panel A and Panel B, summarizes the chemical composition and biological properties of these bee products while this section elaborates on these products in depth.

T59

9375-9379

Sentence

denotes

2.1.

T60

9380-9392

Sentence

denotes

Royal Jelly:

T61

9393-9453

Sentence

denotes

Its Constituents, Biological, and Pharmacological Activities

T62

9454-9641

Sentence

denotes

Royal jelly is a thick, milky, white-yellowish, acidic colloid substance secreted from the hypopharyngeal and mandibular salivary glands of young nurse honey bees (5–15 days old) [32,43].

T63

9642-9816

Sentence

denotes

In general, fresh royal jelly mostly consists of water (67% w/w) in addition to carbohydrates (16%), proteins and amino acids (12.5%), fat (5%), and many other elements [32].

T64

9817-10043

Sentence

denotes

However, royal jelly content of these substances noticeably varies depending on numerous factors like botanical source, bee species, bee artificial feeding, weather, season, location, method of processing, and the like [2,44].

T65

10044-10154

Sentence

denotes

Protein is the most copious active element in royal jelly, representing half the weight of its dry matter [2].

T66

10155-10274

Sentence

denotes

It vastly comprises nine 49–87 kDa water-insoluble proteins, known as major royal jelly proteins 1–9 (MRJPs1-9) [2,45].

T67

10275-10382

Sentence

denotes

MRJPs constitute more than 80% of royal jelly protein content, and MRJPs1–5 constitute 82–90% of all MRJPs.

T68

10383-10566

Sentence

denotes

MRJPs contain 400–578 amino acids that contribute to the antioxidant effect of royal jelly as well as its role in cell proliferation, cell adhesion, cell growth, and immunity [46,47].

T69

10567-10624

Sentence

denotes

Novel non-MRJPs proteins have been newly discovered [48].

T70

10625-10741

Sentence

denotes

Royalisin, jelleines, and aspimin are examples of other proteins that exist in royal jelly, albeit in small amounts.

T71

10742-11122

Sentence

denotes

These proteins as well as MRJPs demonstrate strong antimicrobial and bactericidal activities even against the most drug-resistant bacterial strains such as methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, vancomycin-resistant Enterococci, as well as extended-spectrum β-lactamase-producing Proteus mirabilis and Escherichia coli [28,29].

T72

11123-11260

Sentence

denotes

Carbohydrates (e.g., fructose, glucose maltose, trehalose, melibiose, ribose, and erlose) constitute 7.5–16% or royal jelly content [49].

T73

11261-11466

Sentence

denotes

Reducing sugars in royal jelly are thought to contribute to its epigenetic effect through the activation of insulin-like growth factor 1 (IGF-1) and mammalian target of rapamycin (mTOR) signaling cascades.

T74

11467-11599

Sentence

denotes

Thus, they stimulate caste differentiation of Apis mellifera larvae into queens by increasing intake of food and key nutrients [50].

T75

11600-11654

Sentence

denotes

Lipids make up 7–18% of the dry weight of royal jelly.

T76

11655-11883

Sentence

denotes

This fraction largely comprises a group of unique and rare saturated or monounsaturated short and medium chain fatty acids that are terminally or internally hydroxylated with terminal mono- or dicarboxylic acid functions [2,28].

T77

11884-12138

Sentence

denotes

The vast majority of royal jelly fat content (80–85%) consists of short hydroxyl fatty acids such as trans-10-hydroxy-2-decenoic acid (10-HDA), which exists only in royal jelly; and therefore, it is known as royal jelly acid or queen bee acid [28,49,51].

T78

12139-12365

Sentence

denotes

10-HDA is one of the most potent bioactive elements in royal jelly expressing strong anti-aging, neuroprotective, antiproliferative, antimicrobial, antioxidant, anti-inflammatory, and epigenetic effects [52,53,54,55,56,57,58].

T79

12366-12509

Sentence

denotes

In addition, the lipid fraction of royal jelly contains phenolic acids (4–10%), wax (5–6%), steroids (3–4%), and phospholipids (0.4–0.8%) [49].

T80

12510-13097

Sentence

denotes

A wide range of minor constituents and bioactive compounds exist profusely in royal jelly such as acetylcholine, nucleotides (adenosine, guanosine, adenosine tri-phosphate (ATP), adenosine monophosphate (AMP)), minerals (iron, sodium, calcium, potassium, zinc, magnesium, manganese, and copper), amino acids (8 out of 9 essential amino acids Val, Leu, Ile, Thr, Met, Phe, Lys, and Trp), vitamins (retinol (A), ascorbic acid (C), tocopherol (E), riboflavin (B2), niacin (B3), and other B vitamins), esters, aldehydes, ketones, alcohol, and minor heterocyclic compounds [2,28,49,59,60,61].

T81

13098-13247

Sentence

denotes

It is worth noting that royal jelly loses most of its bioactive ingredients and biological properties when stored at a temperature of 5 °C or higher.

T82

13248-13313

Sentence

denotes

Therefore, freezing is the best method to store royal jelly [62].

T83

13314-13516

Sentence

denotes

Enzymatic treatment of royal jelly removes allergen proteins and enhances its nutrient content in addition to improving its digestibility and absorption in the gut without altering its freshness [2,59].

T84

13517-13673

Sentence

denotes

Royal jelly has been historically used as a beautifying agent by famous queens such as Cleopatra, and it is still involved in the cosmetic industry [29,56].

T85

13674-13961

Sentence

denotes

Its rich content of bioactive compounds grants it a plethora of diverse health benefits such as antioxidant, anti-inflammatory, neurotrophic, hypotensive, antidiabetic, antilipidemic, antirheumatic, anticarcinogenic, anti-fatigue, antiadipogenic, and antimicrobial activities [43,45,63].

T86

13962-14200

Sentence

denotes

Therefore, it is widely used to treat multiple serious conditions including diabetes, hypertension, hyperlipidemia, cancer, skin diseases, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease [2,43,46,59,64].

T87

14201-14492

Sentence

denotes

In addition, bee queens (which enjoy long lifespan as well as super fertility and physical qualities) consume royal jelly throughout their entire lives, and royal jelly is considered a promising anti-aging nutraceutical that can positively enhance fertility and improve body composition [2].

T88

14494-14498

Sentence

denotes

2.2.

T89

14499-14508

Sentence

denotes

Propolis:

T90

14509-14569

Sentence

denotes

Its Constituents, Biological, and Pharmacological Activities

T91

14570-14779

Sentence

denotes

Propolis, also known as bee glue, is a sticky wax-like substance that constitutes a mixture of bee salivary secretions, bee wax, and resinous sap occurring in the bark and leaf-buds of specific plants [37,65].

T92

14780-14867

Sentence

denotes

It comes in green, red, brown, or black colors based on the collected local flora [66].

T93

14868-15011

Sentence

denotes

The word propolis comprises two Greek words “pro” and “polis”, which in order mean “in front of or at the entrance to” and “community or city”.

T94

15012-15106

Sentence

denotes

Propolis is a hive-defensive substance, which bees use to protect and repair their hives [67].

T95

15107-15218

Sentence

denotes

Propolis is a unique product of a complex composition that comprises more than 420 chemical substances [37,68].

T96

15219-15389

Sentence

denotes

Nonetheless, its composition and biological activities vary considerably depending on its botanical and geographical origins as well as the time of harvesting [38,65,67].

T97

15390-15591

Sentence

denotes

Propolis is rich in oxyprenylated phenylpropanoids—secondary metabolites from plants, fungi, and bacteria [69]—such as 7-isopentenyloxucoumarin, boropinic acid, 4-geranyloxyferulic acid, and auraptene.

T98

15592-15658

Sentence

denotes

The last two exist in raw Italian propolis at high concentrations:

T99

15659-15712

Sentence

denotes

107.12 and 145.37 μg/g of dry propolis, respectively.

T100

15713-16132

Sentence

denotes

Flavonoids, a large group of phenolic compounds, are abundant in Italian propolis, and they are differentiated into several groups including flavanones (e.g., naringenine, 4.4 mg/g), flavones (e.g., apigenine, 1.7 mg/g), flavonols (e.g., galaning, 0.9 mg/g), tannins (e.g., gallic acid 8.4 mg/g), catechins (expressed as (+)-catechin 0.4 mg/g, and caffeic acid and its esters (expressed as caffeic acid, 9.2 mg/g) [69].

T101

16133-16295

Sentence

denotes

The most profuse flavonoids in ethanolic extracts of Brazilian propolis are artepillin C (38.6 mg/g), coumaric acid (10.6 mg/g), and kaempferide (12.6 mg/g) [70].

T102

16296-16729

Sentence

denotes

Key other constituents of propolis include polyphenol (e.g., phenolic acids and aromatic esters), phenolic aldehydes, terpenoids, ketones, enzymes (e.g., α- and β-amylase), vitamins (e.g., thiamin (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid (C), tocopherol (E)), minerals (e.g., calcium, potassium, magnesium, iron, sodium, barium) essential oils, alcohol, fatty acids, β-steroids, and many other elements [37,38,67,68,71].

T103

16730-16888

Sentence

denotes

The attention of several drug targeting studies has recently been focused on the therapeutic activities of individual bioactive compounds in propolis [65,68].

T104

16889-16973

Sentence

denotes

Flavonoids comprise the majority of mostly studies bioactive substances in propolis.

T105

16974-17131

Sentence

denotes

Chrysin (5,7-dihydroxyflavone) is a flavonoid that exists in certain mushrooms, flowers (e.g., blue passion flower), and in other bee products (e.g., honey).

T106

17132-17230

Sentence

denotes

It expresses anti-inflammatory, antioxidant, anti-proliferative, and neuroprotective effects [72].

T107

17231-17419

Sentence

denotes

Caffeic acid phenethyl ester (CAPE), a derivative of hydroxycinnamic acid, expresses anti-oxidant, immunomodulatory, anti-inflammatory, antiviral, and ant-neoplastic properties [73,74,75].

T108

17420-17616

Sentence

denotes

Pinocembrin (5,7-dihydroxyflavanone) is the most copious flavonoid in propolis—1 g of balsam/an ethanolic extract from poplar propolis found in Spain contains up to 606–701 mg of pinocembrin [76].

T109

17617-17677

Sentence

denotes

It exists in numerous plants (e.g., Eucalyptus and Populus).

T110

17678-17778

Sentence

denotes

It exhibits anti-inflammatory, antioxidant, antimicrobial, and antiproliferative activities [77,78].

T111

17779-17898

Sentence

denotes

Essential/volatile oils are major bioactive constituents of propolis, and they contribute to its special aroma [79,80].

T112

17899-18023

Sentence

denotes

They also, partially, contribute to the strong antimicrobial, antioxidant, and anticancer activities of propolis [79,81,82].

T113

18024-18146

Sentence

denotes

The volatile fraction of propolis varies in each sample even within a single country due to plant source and climate [79].

T114

18147-18306

Sentence

denotes

For instance, cumulative knowledge shows that volatile oils in propolis found in countries surrounding the Mediterranean depend mainly on the botanical origin.

T115

18307-18512

Sentence

denotes

They primarily comprise poplar-derived compounds (e.g., benzoic acid and its esters and oxygenated sesquiterpene β-eudesmol) and conifer-derived compounds such as the hydrocarbon monoterpene α-pinene [80].

T116

18513-18660

Sentence

denotes

Interestingly, the number of volatile compounds derived from a single type of propolis is also reported to vary according to extraction techniques.

T117

18661-18898

Sentence

denotes

In this regard, reports from China show that traditional hydrodistillation, steam-distillation extraction, and dynamic headspace sampling could characterize around 12, 40 and 70 type of volatile components of propolis, respectively [79].

T118

18899-19032

Sentence

denotes

Moreover, the level of antimicrobial activity of volatile compounds of propolis greatly depends on their extent of purification [82].

T119

19033-19289

Sentence

denotes

Thanks to its countless bioactive elements, propolis enjoys a range of versatile biological and pharmacological properties including antimicrobial, antiviral, antifungal, antioxidant, anti-inflammatory, antineoplastic, antiaging, and cytostatic properties.

T120

19290-19410

Sentence

denotes

In addition, it is considered a perfect natural food preservative due to its antimicrobial activity [35,38,65,66,68,71].

T121

19411-19562

Sentence

denotes

Because of its enormous health-promoting activities, propolis is widely used as a dietary supplement in many countries, especially in Japan [37,38,39].

T122

19563-19687

Sentence

denotes

Propolis is not suitable for use in its crude state since it may contact harmful materials e.g., asphalt from the road [68].

T123

19688-19871

Sentence

denotes

Using solvents like ethanol, glycerol, chloroform, ether and acetone or water is necessary to get rid of hazardous substances and to increase its yield of bioactive compounds [67,68].

T124

19872-19949

Sentence

denotes

Although water may be a cheap solvent, propolis has poor solubility in water.

T125

19950-20052

Sentence

denotes

Therefore, propolis water extracts are 10-fold lower in their phenolic contents than ethanol extracts.

T126

20053-20123

Sentence

denotes

In addition, they retain the strong flavor and aroma of propolis [68].

T127

20124-20316

Sentence

denotes

Moreover, propolis contains allergenic components: caffeic acids derivates (e.g., 3-methyl-2-butenyl caffeate and phenylethyl caffeate), as well as benzyl salicylate and benzyl cinnamate [80].

T128

20317-20415

Sentence

denotes

Therefore, propolis use/consumption should be contraindicated in individuals with known allergies.

T129

20417-20421

Sentence

denotes

2.3.

T130

20422-20433

Sentence

denotes

Bee Pollen:

T131

20434-20494

Sentence

denotes

Its Constituents, Biological, and Pharmacological Activities

T132

20495-20623

Sentence

denotes

Bee pollen is an api-material that originally comprises male gametophytes or spermatophytes of flowers, which stick to bee body.

T133

20624-20696

Sentence

denotes

Bee workers mix these floral pollens with honey, nectar, and bee saliva.

T134

20697-20836

Sentence

denotes

The latter is rich in various enzymes e.g., amylase, catalase, as well as lactic acid bacteria, which cause pollen fermentation [36,83,84].

T135

20837-20962

Sentence

denotes

Hence, the tiny wind pollen grains collected by bees aggregate together to form granules or pellets of 1.4–4 mm in size [84].

T136

20963-21137

Sentence

denotes

In addition to water, which in order constitutes 20–30% and 6–8% of the content of recently collected and dried bee pollen, bee pollen contains around 200 chemical compounds.

T137

21138-21229

Sentence

denotes

Like other bee products, its composition varies considerably according to botanical origin.

T138

21230-21401

Sentence

denotes

Carbohydrates account for the most abundant ingredient (18.50–84.25%), and reducing sugars such as glucose, fructose, and sucrose constitute the vastest majority (13–55%).

T139

21402-21706

Sentence

denotes

Other major elements include proteins and essential amino acids (5–60%), unsaturated and saturated fatty acids (0.15–31.26%), crude fiber (0.3–20%), nucleic acids (especially RNA), and various minerals (e.g., potassium, phosphorus, calcium, magnesium, zinc, copper, manganese, and iron) [36,83,84,85,86].

T140

21707-21884

Sentence

denotes

In addition, its average total phenolic content is 30.59 mg gallic acid equivalents (GAE)/g, but again it varies considerably based on floral origin (0.69–213.20 mg GAE/g) [86].

T141

21885-22089

Sentence

denotes

Moreover, bee pollen is abundant in both water- and fat-soluble vitamins e.g., β-carotene (vitamin A precursor), ascorbic acid (C), tocopherol (E), folic acid (B9), and other vitamin B, especially niacin.

T142

22090-22168

Sentence

denotes

Bee pollen contains other elements that still need to be explored (2–5%) [83].

T143

22169-22240

Sentence

denotes

Therefore, bee pollen represents a perfect whole health-promoting food.

T144

22241-22450

Sentence

denotes

In fact, comparisons of the percentages of nutrients in bee pollen with daily required intake of an adult individual revealed that few grams of bee pollen can meet daily human nutritional requirements [83,84].

T145

22451-22638

Sentence

denotes

Bee pollen demonstrates various biological properties and therapeutic activities e.g., antioxidant, anti-inflammatory, anti-lipidemic, anticancer, antiallergic, and antimicrobial [36,87].

T146

22639-22919

Sentence

denotes

Existing knowledge emphasizes its antiaging effects: it reduced the production of age-related pigment known as lipofuscin (induced by oral peroxidized corn oil or intravenous alloxan injection) in cardiac muscle, brain, liver, and suprarenal gland in aged mice (reviewed in [34]).

T147

22920-23154

Sentence

denotes

The composition of bee pollens depends primarily on its botanical source since nutrient contents (e.g., polyphenols) of pollen grains, which support their survival and fusion with female gametes, vary between different plants [83,84].

T148

23155-23242

Sentence

denotes

Storage conditions are of great importance were it to retain its biological activities.

T149

23243-23301

Sentence

denotes

Bee pollen should be consumed fresh soon after collection.

T150

23302-23415

Sentence

denotes

Most of its major elements (reducing sugars, total proteins, vitamin C, and provitamin A) are destroyed at 40 °C.

T151

23416-23572

Sentence

denotes

Lyophilization damages its vitamin content while freezing is recommended for the storage of bee pollen since it does not affect its chemical structure [83].

T152

23573-23707

Sentence

denotes

Dry pollen pellets resist decay due to their tough outer coat, which comprises two layers made of cellulose and sporopollenin [88,89].

T153

23708-23911

Sentence

denotes

However, ingestion of bee pollen by humans may not yield its optimal nutritional value because the hard sporopollenin shell hinders access of digestive secretions to the nutrient-rich core of the pellet.

T154

23912-24052

Sentence

denotes

Biological, chemical, and mechanical techniques are used to break bee pollen microcapsules in order to enhance its digestibility in the gut.

T155

24053-24178

Sentence

denotes

However, these methods may be expensive or ineffective i.e., they degrade important nutrients via enzymatic activity [88,90].

T156

24179-24441

Sentence

denotes

Ultraviolet spectroscopy and high performance liquid chromatography-photo diode array show that processing bee pollen through the use of an edible lipid-surfactant mixture (Captex 355 and Tween 80) increases its yield of polyphenols and flavonoid aglycones [90].

T157

24443-24447

Sentence

denotes

2.4.

T158

24448-24503

Sentence

denotes

Safety Profile of Royal Jelly, Propolis, and Bee Pollen

T159

24504-24777

Sentence

denotes

Propolis exists in a plethora of commercial products that are directly consumed or used by humans e.g., lozenges, soap, toothpastes and mouth wash, creams, gels, cough syrups, wines, cakes, chewing gums, candies, shampoo, chocolate, skin lotions, processed meat, etc. [67].

T160

24778-24909

Sentence

denotes

In addition, royal jelly, bee pollen, and propolis are widely used as dietary supplements in many parts of the world [36,37,38,39].

T161

24910-25018

Sentence

denotes

Existing knowledge denotes no adverse effects from their consumption either in rodents or in humans [39,66].

T162

25019-25175

Sentence

denotes

The safety of pinocembrin, a flavonoid available in propolis and an approved drug in China, is documented since its elimination from the body is rapid [91].

T163

25176-25264

Sentence

denotes

The safety profile of bee pollen (both crude and processed) has been empirically tested.

T164

25265-25501

Sentence

denotes

Oral consumption of bee pollen (up to 2 g/kg body weight) expressed no allergic reactions in mice including behavioral changes, salivation, diarrhea, respiratory or autonomic responses, restlessness, convulsions, tremors, or death [90].

T165

25502-25599

Sentence

denotes

In fact, the German Federal Board of Health acknowledges bee pollen as an official medicine [36].

T166

25600-25687

Sentence

denotes

Several lines of evidence support the anti-allergic effect of propolis and royal jelly.

T167

25688-25924

Sentence

denotes

This effect involves inhibiting mast cell degranulation, suppressing cysteinyl-leukotriene release, as well as reducing serum histamine, IgG, and IgE levels in various allergic conditions by suppressing histamine H1 receptor [37,39,92].

T168

25925-26033

Sentence

denotes

Nevertheless, rare allergic reactions to bee products other than bee venom are documented in the literature.

T169

26034-26083

Sentence

denotes

They are most frequent in small children [80,93].

T170

26084-26291

Sentence

denotes

Examples of such reactions comprise contact dermatitis in beekeepers following the handling of propolis, as well as contact stomatitis and oral mucositis after the usage of lozenges containing propolis [80].

T171

26292-26438

Sentence

denotes

Hence, bee products should be used with caution, especially in people with known allergies, pregnant and lactating women, and small children [61].

T172

26439-26514

Sentence

denotes

In addition, bee products can be safely consumed after adequate processing.

T173

26515-26669

Sentence

denotes

Processing involves removal of known allergens such as enzyme treatment of royal jelly and filtration of bee venom by stepped-gradient open column [2,94].

T174

26671-26673

Sentence

denotes

3.

T175

26674-26763

Sentence

denotes

Evidence of Anti-Sarcopenia Effects of Bee Products from Preclinical and Clinical Studies

T176

26764-27062

Sentence

denotes

Though few animal models were used to examine the effect of bee products on sarcopenia, findings indicate that royal jelly, propolis, and bee pollen can induce both structural and symptomatic improvements and reduce behavioral dysfunctions associated with sarcopenia in rodents (Figure 1, Panel C).

T177

27063-27492

Sentence

denotes

Both crude and protease-treated royal jelly (pRJ) significantly delayed age-related impairment of motor functions in d-galactose induced mouse model of aging [95], naturally aged sarcopenic mice [96], and in genetically heterogeneous head tilt (HET) mice—which exhibit vestibular dysfunction, imbalanced position, and inability to swim—by improving performance on grip strength, wire hang, horizontal bar, and rotarod tests [97].

T178

27493-27689

Sentence

denotes

Similarly, royal jelly improved physical performance in aged rodents—it significantly increased the number of crossings and swimming speed and prolonged swimming distance in water maze [96,98,99].

T179

27690-28106

Sentence

denotes

In addition, royal jelly decreased lipid accumulation in skeletal muscle [100], positively improved the size of muscle fibers, lowered age-related reduction of skeletal muscle weight [95,96,97,100], increased the differentiation and proliferation rate of muscle satellite cell, improved the regenerative capacity of injured muscle, and suppressed catabolic genes in aged mice with sarcopenia and in HET mice [96,97].

T180

28107-28241

Sentence

denotes

The muscle mass-accelerating effects of 10-HDA, a key fatty acid in royal jelly, were more pronounced in male animals than in females.

T181

28242-28323

Sentence

denotes

However, 10-HDA mitigated the accumulation of adipose tissue in female mice [54].

T182

28324-28448

Sentence

denotes

It is note-worthy that pRJ had no effect on muscle strength and physical performance in humans aged 70 years and above [59].

T183

28449-28519

Sentence

denotes

The effects of other bee products on muscle mass were mostly positive.

T184

28520-28655

Sentence

denotes

Bee pollen promoted body weight regain and increased the relative weight of the gastrocnemius muscle in eccentric exercising rats [90].

T185

28656-28764

Sentence

denotes

It also increased the absolute weights of plantaris and gastrocnemius muscles in malnourished old rats [36].

T186

28765-28888

Sentence

denotes

CAPE restored gastrocnemius muscle mass in rats on exhaustive exercise and in rats with ischemia reperfusion [101,102,103].

T187

28889-29026

Sentence

denotes

A study reported no effect of propolis ethanolic extracts (4% of diet) on the size of muscle or their level of myostatin in Nile tilapia.

T188

29027-29299

Sentence

denotes

However, another interesting study reported significant increases in body protein deposition and body condition factor—an estimate of future growth, survival, and reproductive potential—in Nile tilapia post-larvae and fingerlings receiving 2.6 g propolis/kg of feed [104].

T189

29300-29353

Sentence

denotes

Nonetheless, these findings seem to be bound to fish.

T190

29354-29641

Sentence

denotes

Interestingly, supplementing obese rats on high fat diet (HFD) with milk naturally enriched with long-chain polyunsaturated fatty acids (PUFA) and polyphenols from propolis significantly increased gastrocnemius muscle mass compared with whole milk and milk enriched with PUFA only [105].

T191

29642-29703

Sentence

denotes

Several molecular changes were associated with these effects.

T192

29704-29747

Sentence

denotes

We elaborate on these changes in Section 4.

T193

29748-29851

Sentence

denotes

Table 1 presents more details on treatments with bee products and key findings of the relevant studies.

T194

29853-29855

Sentence

denotes

4.

T195

29856-29931

Sentence

denotes

Mechanisms of Action of Royal Jelly, Bee Pollen, and Propolis in Sarcopenia

T196

29932-30068

Sentence

denotes

Relatively few studies have explored the mechanism through which royal jelly, bee pollen, and propolis may be beneficial for sarcopenia.

T197

30069-30529

Sentence

denotes

In vivo and in vitro studies included in this review uncovered a number of inter-related cellular and molecular events that underlie the effect of these bee products on skeletal muscle including suppression of catabolic genes, counteracting metabolic abnormalities, inflammation, and oxidative damages as well as enhancement of motor neuronal regeneration, promotion of stem cell function, and correction of the structure of gut microbiome (Figure 1, Panel D).

T198

30530-30598

Sentence

denotes

These mechanisms are exclusively described in the coming paragraphs.

T199

30600-30604

Sentence

denotes

4.1.

T200

30605-30657

Sentence

denotes

Modulating Inflammatory Responses in Skeletal Muscle

T201

30658-30741

Sentence

denotes

The role that inflammation plays in skeletal muscle is not quite clear as it looks.

T202

30742-30806

Sentence

denotes

Inflammatory mediators behave in a dual fashion in muscle cells.

T203

30807-30957

Sentence

denotes

During injury, cytokines and chemokines stimulate muscle repair and regeneration via activation of myoblasts, a core event in muscle remodeling [108].

T204

30958-31117

Sentence

denotes

Similarly, serum and muscle levels of IL-6 temporarily increase following physical exercise, and IL-6 blocks the activity of catabolic cytokines such as TNF-α.

T205

31118-31392

Sentence

denotes

On the other hand, chronic inflammation in muscle cells, which correlates with persistent mitochondrial dysfunction and metabolic dysregulation, pathologically activates muscle fiber transformation and atrophy, eventually resulting in the development of sarcopenia [23,114].

T206

31393-31585

Sentence

denotes

It seems that bee products also act dually in skeletal muscle: they support the activity of cytokines that promote muscle remodeling [108] and suppress muscle-consuming cytokines [38,101,108].

T207

31586-31989

Sentence

denotes

In this regard, treating undifferentiated C2C12 myoblasts with ethanolic extracts of Brazilian propolis (100 μg/mL for 8 h) triggered the migration of RAW264 macrophage and increased their production of angiogenic factors (e.g., vascular endothelial growth factor A (VEGF-A) and metalloproteinase-12 (MMP-12)), chemokines (e.g., CCL-2 and CCL-5), and cytokines (e.g., IL-6, which increased by 40-folds).

T208

31990-32075

Sentence

denotes

Propolis inhibited the expression of IL-1β and TNF-α at 4, 8, and 12 h of incubation.

T209

32076-32253

Sentence

denotes

These effects were nuclear factor kappa B (NF-κB)-dependent given that propolis simultaneously increased nuclear translocation of p65 and p50 NF-κB proteins 3 h after treatment.

T210

32254-32429

Sentence

denotes

Meanwhile, inhibiting IκB kinase (IKK) by BMS-345541 profoundly hindered the effect of propolis on the expression of CCL-2, CCL-5, and IL-6 by 66%, 81%, and 69%, respectively.

T211

32430-32481

Sentence

denotes

Propolis also enhanced the expression of MAIL/IκBζ.

T212

32482-32614

Sentence

denotes

This molecule modulates chromatin and selectively induces the production of IL-6, leukemia inhibitory factor (LIF), and CCL-2 [108].

T213

32615-32899

Sentence

denotes

Chronic muscle tissue infiltration by inflammatory cells (e.g., leukocytes, neutrophils, and monocytes) activates oxidative and inflammatory signaling cascades that degrade cellular structures and promote necrosis such as inducible nitric oxide synthase (iNOS) and NF-kB [90,101,115].

T214

32900-33139

Sentence

denotes

CAPE and high levels (200 and 300 mg/kg) of crude and processed bee pollen reduced inflammatory cell infiltration into the gastrocnemius muscle of rats with muscle injury induced by eccentric exercise and ischemia reperfusion [90,101,102].

T215

33140-33254

Sentence

denotes

This effect was revealed by lower activity of myeloperoxidase, an indicator of neutrophil sequestration [101,102].

T216

33255-33562

Sentence

denotes

As such, CAPE and bee pollen not only suppressed lipid peroxidation (lower levels of malondialdehyde, MDA) but also inhibited the activity of myostatin and the production of muscle depleting cytokines and chemokines such as IL-1β, α2-macroglobulin, and monocyte chemotactic protein 1 (MCP-1) [36,38,90,101].

T217

33563-33701

Sentence

denotes

The underlying mechanism entailed downregulation of nuclear p65NF-κB and blockage of its consensus binding sites in skeletal muscle [101].

T218

33702-34000

Sentence

denotes

As a result, bee products increased muscle mass both in sarcopenic obese rat and malnourished old rats [36] and restored the structure of myofibers (despite the persistence of necrosis) compared with untreated eccentric exercising animals, which demonstrated necrotic and fragmented myofibers [90].

T219

34001-34145

Sentence

denotes

Royal jelly downregulated the activity of tumor necrosis factor receptor 1 (TNFR1) in the adipose tissue of aged obese rats receiving HFD [100].

T220

34146-34363

Sentence

denotes

TNFR1 interacts with TNFR2 to negatively regulate toll-like receptors (TLR) and Nod-like receptor signaling and stimulate excessive release of cytokines via activation of key inflammatory pathways such as NF-κB [107].

T221

34364-34642

Sentence

denotes

Mitigation of TNFR1 was associated with a significant increase of the weight of hind limb muscle and reductions in insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), serum lipids, muscle triglyceride levels, body weight gain, and abdominal fat weight.

T222

34643-34908

Sentence

denotes

Therefore, royal jelly may protect against muscle loss in conditions involving impairment of the adipokine profile mainly through suppression of inflammatory responses associated with high fat mass, which is followed by correction of metabolic irregularities [100].

T223

34910-34914

Sentence

denotes

4.2.

T224

34915-34964

Sentence

denotes

Counteracting Oxidative Stress in Skeletal Muscle

T225

34965-35188

Sentence

denotes

High production of reactive oxygen species (ROS) in skeletal muscle tissues has serious destructive effects, which alter the integrity of skeletal muscle resulting into fatigue, muscle wasting, and muscle weakness [90,101].

T226

35189-35517

Sentence

denotes

Sources of intramuscular ROS are numerous including mitochondrial dysfunction (e.g., alteration of mitochondrial enzymes in the respiratory chain as well as enzymes responsible for β-oxidation), neutrophil infiltration, and the activity of cytokines and major muscle degrading molecules such as myostatin [21,36,38,101,102,118].

T227

35518-35736

Sentence

denotes

Oxidative and nitrosative damages in skeletal muscle tissues are mediated by the activity of numerous pro-oxidant enzymes that are associated with inflammatory processes such as cyclooxygenase-2 (COX-2) and iNOS [101].

T228

35737-36032

Sentence

denotes

ROS triggers the activity of corrosive molecules such as poly (ADP-ribose) polymerase (PARP), xanthine oxidase, and adenosine deaminase, which contribute to DNA damage, lipid peroxidation (e.g., increased MDA), and protein nitrotyrosylation as well as ATP catabolism in muscle tissues [101,102].

T229

36033-36169

Sentence

denotes

Royal jelly enhanced the activity of antioxidant enzymes and suppressed lipid peroxidation in a d-galactose induced model of aging [95].

T230

36170-36385

Sentence

denotes

Two weeks of propolis treatment in rats undergoing hind limb unloading significantly reduced nuclear ROS levels and numbers of apoptotic endothelial cells in the soleus muscle to levels similar to normal rats [110].

T231

36386-36735

Sentence

denotes

Moreover, propolis significantly suppressed MDA activity in skeletal muscle and increased liver levels of SOD as well as gastrocnemius muscle levels of SOD, glutathione peroxidase and catalase in rats on eccentric exercise training (70% VO2max treadmill running exercise for 60 min) compared with rats receiving exercise alone or no treatment [109].

T232

36736-37026

Sentence

denotes

In addition, intraperitoneal pre-administration of CAPE (60 min before induction of ischemia reperfusion) significantly ameliorated the effects associated with high ROS levels, which accompany acute ischemia such as protein peroxidation and ATP catabolism in the gastrocnemius muscle [102].

T233

37027-37128

Sentence

denotes

Bee products probably reduced ROS production via regulation of the activity of mitochondrial enzymes.

T234

37129-37305

Sentence

denotes

Royal jelly increased the maximal activity of citrate synthase (CS) and β-hydroxyacyl coenzyme A dehydrogenase (β-HAD) in the soleus muscle of rats on endurance training [106].

T235

37306-37539

Sentence

denotes

Bee pollen restored mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal, increased SOD and glutathione, and reduced MDA, NO, and total protein content in the gastrocnemius muscle of rats on exhaustive exercise [90].

T236

37540-37830

Sentence

denotes

It also increased the activity of CS and complex IV in malnourished old rats via a mechanism that involved activation of mTOR [36]. mTOR is a major signaling pathway that regulates various signaling cascades involved in metabolism and autophagy such nuclear respiratory factor 2 (NRF2) [2].

T237

37831-38029

Sentence

denotes

Therefore, it is possible that the antioxidant activity demonstrated by bee products, particularly that expressed in the mitochondria, is associated with their metabolic and hypoglycemic activities.

T238

38030-38190

Sentence

denotes

For instance, 10-HDA increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle of diabetic mice [112,119].

T239

38191-38351

Sentence

denotes

Similarly, aged mice treated with amino acids similar to those found in royal jelly demonstrated improved size of muscle fiber by increasing PGC-1α mRNA levels.

T240

38352-38578

Sentence

denotes

PGC-1α functions as a key regulator of sirtuin 1, which limits ROS production through stimulation of mitochondrial biogenesis and ROS defense system, thus protecting metabolically active tissues against oxidative damage [120].

T241

38579-38861

Sentence

denotes

Mechanistically, when PGC-1α gets activated, it interacts with other bioactive molecules such as muscle-specific transcription factors to stimulate the expression of genes that induce mitochondrial oxidative metabolism in brown fat and fiber-type switching in skeletal muscle [121].

T242

38862-39147

Sentence

denotes

The antioxidant activity of royal jelly and CAPE might be related to their strong capacity to activate the master redox-active NRF2 signaling pathway [73,122], which stimulates the production of internal antioxidants such as heme oxygenase-1 (HO-1), which scavenge free radicals [123].

T243

39148-39253

Sentence

denotes

Meanwhile, NRF2 and HO-1 block ROS production indirectly via suppression of inflammatory reactions [122].

T244

39254-39446

Sentence

denotes

In this context, CAPE reduced degenerative myopathy in rats on eccentric exercise via a complex mechanism that involved inhibition of NF-κB and its downstream pro-oxidant COX-2 and iNOS [101].

T245

39447-39704

Sentence

denotes

Correspondingly, CAPE decreased markers of oxidative cellular damages (protein carbonyl, protein nitrosylation, xanthine oxidase, and adenosine deaminase) associated with ischemia reperfusion and eccentric exercise in the gastrocnemius muscle [101,102,103].

T246

39705-39910

Sentence

denotes

In this regard, CAPE operated via a mechanism that involved inhibition of neutrophil and leukocyte infiltration into the gastrocnemius muscle, which was associated with decreased levels of myeloperoxidase.

T247

39911-40082

Sentence

denotes

Myeloperoxidase contributes to excessive production of ROS and oxidative organ damage through a mechanism that embroils increased synthesis of hypochlorous acid [101,102].

T248

40083-40252

Sentence

denotes

Furthermore, CAPE accelerated purine salvage for ATP synthesis and inhibited ROS-induced lipid peroxidation via attenuation of the activity of adenosine deaminase [102].

T249

40253-40605

Sentence

denotes

In summary, the reported antioxidant effects of bee products were multifaceted involving increased production of antioxidant enzymes [90,95,109,110], and decreased ROS production [90,101,102,103,110] (secondary to reduction of inflammatory cell infiltration into skeletal muscle) [90,101,102,103], and restoration of mitochondrial activity [36,90,106].

T250

40607-40611

Sentence

denotes

4.3.

T251

40612-40632

Sentence

denotes

Metabolic Regulation

T252

40633-40709

Sentence

denotes

Skeletal muscle is the main tissue that utilizes insulin for glucose uptake.

T253

40710-41008

Sentence

denotes

Insulin regulates mitochondrial oxidative phosphorylation of proteins in human skeletal muscle and contributes to calcium mobilization from the sarcoplasmic-endoplasmic reticulum to mitochondria to stimulate the translocation of glucose transporter 4 (GLUT4) to the cell surface for glucose uptake.

T254

41009-41200

Sentence

denotes

This process improves muscle protein synthesis in healthy people when the delivery of amino acids to skeletal muscle is increased, eventually leading to increased muscular mass [124,125,126].

T255

41201-41286

Sentence

denotes

Insulin resistance and glucose intolerance increase with old age evoking muscle loss.

T256

41287-41460

Sentence

denotes

In this respect, hypoglycemic agents such as metformin can improve skeletal muscle metabolism via activation of adenosine monophosphate activated protein kinase (AMPK) [21].

T257

41461-41636

Sentence

denotes

AMPK, a heterotrimeric complex that consists of a catalytic subunit and two regulatory subunits, is an intracellular energy sensor that regulates glucose and lipid metabolism.

T258

41637-41806

Sentence

denotes

It gets activated when cellular energy is depleted through allosteric binding of AMP or phosphorylation by AMPK kinase at Thr172 of the catalytic subunit by AMPK kinase.

T259

41807-42037

Sentence

denotes

Upregulated AMPK activates signaling pathways that generate ATP from glucose and fatty acid oxidation, and it simultaneously blocks signaling that contributes to the synthesis of cholesterol, fatty acid, and triacylglycerol [111].

T260

42038-42315

Sentence

denotes

In addition, AMPK masters numerous signaling cascades such as Forkhead Box O transcription factor (FOXO) and AKT/mTOR, which regulate the expression of genes associated with inflammation, oxidative stress, mitochondrial function, autophagy, metabolism, and apoptosis [127,128].

T261

42316-42546

Sentence

denotes

The molecular events involved in the effect of bee products on catabolic genes and anabolic resistance in skeletal muscle could be much related to their hypoglycemic effects, which positively affect the quality of skeletal muscle.

T262

42547-42745

Sentence

denotes

Evidence signifies a positive effect of royal jelly acid (10-HDA) on inflammation and autophagy via upregulation of AMPK, which subsequently alters NF-κB and NLRP3 inflammasome-IL1β signaling [129].

T263

42746-42859

Sentence

denotes

Positive effects of whole royal jelly on skeletal muscle are associated with improved insulin signaling [96,100].

T264

42860-43041

Sentence

denotes

In one study, royal jelly improved serum IGF-1 levels in aged rats and increased AKT signaling in satellite cells extracted from aged rats in a separate in vitro investigation [96].

T265

43042-43275

Sentence

denotes

In another study, royal jelly decreased fat mass and improved anabolic resistance in the skeletal muscle of old obese rats on HFD via downregulation of inflammatory responses in adipose tissue as indicated by downregulation of TNFR1.

T266

43276-43404

Sentence

denotes

This effect was associated with enhanced sensitivity to insulin—portrayed by reduction of serum insulin level and HOMA-IR [100].

T267

43405-43576

Sentence

denotes

Japanese researchers proved that oral consumption of royal jelly and 10-HDA induced mitochondrial adaptation in the soleus muscle when accompanied with endurance training.

T268

43577-43851

Sentence

denotes

These compounds also enhanced glucose uptake in skeletal muscle by inducing the phosphorylation of AMPK [106,112], an effect that was mediated by the upstream kinase Ca²⁺/calmodulin-dependent kinaseβ—independently of changes in AMP:ATP ratio and the liver kinase B1 pathway.

T269

43852-43954

Sentence

denotes

Activation of AMPK was followed by translocation of GLUT4 to the plasma membrane of L6 myotubes [106].

T270

43955-44075

Sentence

denotes

It is note-worthy that effects of royal jelly on mitochondrial biogenesis under endurance training were muscle-specific.

T271

44076-44384

Sentence

denotes

In this respect, neither endurance training nor royal jelly alone had an effect on the maximal activities of CS and β-HAD—the enzyme that catalyzes the rate-limiting step of β-oxidation of long-chain fatty acids—in the soleus muscle, which comprises type I fiber (around 35–45%) and type IIa (around 35–50%).

T272

44385-44506

Sentence

denotes

On the other hand, royal jelly enhanced the activity of these enzymes in the soleus muscle of mice on endurance training.

T273

44507-44811

Sentence

denotes

Of interest, endurance training increased the activity of CS and β-HAD in the plantaris and tibialis anterior muscles (which are mainly type II fiber with a total percentage of type IIb and type IIx fiber types of 90%) while royal jelly failed to exert an effect on these muscles in sedentary mice [106].

T274

44812-44900

Sentence

denotes

Nonetheless, the observed effects of royal jelly in the soleus muscle represent a merit.

T275

44901-45140

Sentence

denotes

This is mainly because the oxidative type I fibers (e.g., soleus muscle) naturally undergo higher protein turnover (especially degradation), which makes them unable to grow in size or respond properly to insufficient nutrient intake [130].

T276

45141-45277

Sentence

denotes

Several lines of evidence indicate that propolis may affect muscle quality through the regulation of glucose metabolism [69,70,109,111].

T277

45278-45420

Sentence

denotes

This effect was vividly depicted in vivo by increased glycogen level in skeletal muscle and reduced serum levels of glucose and insulin [109].

T278

45421-45622

Sentence

denotes

Same as insulin, ethanolic extracts of propolis and CAPE induced glucose uptake [69,70,111] and potentiated insulin-mediated AKT activation and glucose uptake in differentiated L6 myoblast cells [111].

T279

45623-45939

Sentence

denotes

Likewise, Italian propolis at concentrations of 0.1 and 1 mg/mL as well as 4-geranyloxyferulic acid and auraptene (2 oxyprenylated phenylpropanoids, which are abundant in propolis) remarkably increased GLUT4 translocation to the plasma membrane and accelerated GLUT4-mediated glucose uptake in L6 skeletal myoblasts.

T280

45940-46098

Sentence

denotes

The effect of propolis at a concentration of 11 mg/mL was significantly superior to the effect of insulin (0.1 μM), which was used as a positive control [69].

T281

46099-46271

Sentence

denotes

Similar to royal jelly, the effects of propolis (1 μg/mL), CAPE (10 μM), artepillin C, coumaric acid, and kaempferide on glucose metabolism occurred via activation of AMPK.

T282

46272-46393

Sentence

denotes

These effects were comparable to those of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a potent AMPK activator.

T283

46394-46566

Sentence

denotes

In the meantime, co-treatment with inhibitors of AMPK (e.g., compound C) and of phosphatidylinositol 3-kinase (PI3K) (e.g., LY-294002) blocked the effects of CAPE [70,111].

T284

46567-46990

Sentence

denotes

Phosphorylation of AMPK results in activation of the insulin receptor (IR) and subsequent phosphorylation of PI3K followed by activation of AKT and protein kinase C (PKC) leading to GLUT4 translocation and subsequent activation of several molecules that modulate insulin-stimulated glucose transport, eventually leading to glucose influx into cells of several tissues such as skeletal muscle and adipose tissue [69,70,111].

T285

46991-47222

Sentence

denotes

It is worth noting that the effects of CAPE on AMPK and AKT were quick (within 1 h and 3 min, respectively), and they vanished quickly (both molecules returned back to their basal levels within 12 h and 30 min, respectively) [111].

T286

47224-47228

Sentence

denotes

4.4.

T287

47229-47268

Sentence

denotes

Enhancement of Muscle Protein Synthesis

T288

47269-47561

Sentence

denotes

Imbalance between muscle protein synthesis and degradation is associated with low protein intake and altered efficiency of the GI tract in old age, which triggers skeletal muscle loss and poor physical performance [36,40], given that proteins are the main building blocks of muscle myofibers.

T289

47562-47929

Sentence

denotes

Moreover, transmembrane proteins and micro-peptides (e.g., myomixer and myomaker/Tmem8c) contribute to the formation of myofibers by promoting myoblast fusion via a mechanism that involves appropriate localization of Tmem8c at the plasma membrane of myoblasts allowing trafficking related to palmitoylation of C-terminal cysteine residues and C-terminal leucine [17].

T290

47930-48532

Sentence

denotes

Amino acid supplements (e.g., leucine, a master dietary regulator of muscle protein turnover, and its metabolite β-hydroxy β-methylbutyrate) and early refeeding with high protein diet (especially fast digestive proteins) can preserve muscle mass and function, revert sarcopenia, and enhance mobility and quality of life (QoL) by correcting age-related nutritional deficiencies, muscle protein turnover, and immune dysregulation—these effects are even greater when combined with other nutrients like vitamin D or omega 3 fatty acids as well as with physical exercise [6,131,132,133,134,135,136,137,138].

T291

48533-48800

Sentence

denotes

Research indicates that age-related skeletal muscle wasting results mainly from insufficient delivery of amino acids to skeletal muscle due to dysregulations in the activity of mTORC1- and activating transcription factor-4 (ATF4)-mediated amino acid sensing pathways.

T292

48801-49109

Sentence

denotes

Meanwhile, interventions that ameliorate age-related damages in skeletal muscle operate primarily by reversing alterations in the delivery of amino acids to skeletal muscle via upregulation of mTORC1 and/or ATF4 [139]. mTORC1 is a nutrient sensing protein that acts as a core regulator of protein metabolism.

T293

49110-49277

Sentence

denotes

It is sensitive to amino acids, energy status (ATP), stress (e.g., oxidative stress), and growth factors (e.g., insulin), which all can regulate its signaling [2,136].

T294

49278-49386

Sentence

denotes

Nevertheless, bioavailability of amino acids is necessary for growth factors to effectively activate mTORC1.

T295

49387-49460

Sentence

denotes

Even more, amino acids on their own can adequately activate mTORC1 [136].

T296

49461-49807

Sentence

denotes

Evidence from preclinical and human studies confirms that ingestion of essential amino acids (similar to those found in royal jelly and bee pollen such as valine) increases cellular bioavailability of amino acids, which is associated with activation of the endothelial nitric oxide synthase (eNOs) pathway. eNOs further upregulates mTORC1 kinase.

T297

49808-50159

Sentence

denotes

Translocation of mTORC1 from the cytosol to the surface of lysosomes is associated with improved mitochondrial biogenesis and cellular oxidative capacity in skeletal muscle due to activation of its substrates: P70 ribosomal proteins S6 kinase (S6K) and eukaryotic translation initiation 4E-binding protein 1 (eIF4E, also known as 4eBP1) [120,135,136].

T298

50160-50307

Sentence

denotes

As shown in Table 1, royal jelly and 10-HDA significantly increased muscle mass [54,96,100] and improved motor performance in aged rats [95,98,99].

T299

50308-50637

Sentence

denotes

In addition, dietary supplementation with monofloral bee pollen significantly improved the rate of muscle protein synthesis and restored muscle mass in emaciated old rats via upregulation of mTOR and two related downstream controllers of protein translation: p70S6k and 4eBP1, which were suppressed in malnourished old rats [36].

T300

50638-50788

Sentence

denotes

Although propolis improved various muscle-related parameters, its effect on muscle mass in rodents was limited—relative to royal jelly and bee pollen.

T301

50789-50869

Sentence

denotes

However, it fostered muscle protein deposition in post-larva Nile tilapia [104].

T302

50870-51130

Sentence

denotes

Moreover, milk naturally enriched with PUFA and polyphenols from propolis remarkably increased the weight of the gastrocnemius muscle of growing obese rats while whole milk and milk enriched with PUFA only could not express any effect on skeletal muscle [105].

T303

51131-51284

Sentence

denotes

Therefore, this finding denotes that propolis could have enhanced the delivery of amino acids available in milk to skeletal muscle leading to its growth.

T304

51285-51462

Sentence

denotes

Altogether, it is likely that the observed anabolic effects of royal jelly and bee pollen are associated with their high content of proteins and amino acids [32,36,83,84,85,86].

T305

51464-51468

Sentence

denotes

4.5.

T306

51469-51521

Sentence

denotes

Suppression of Catabolic Activity in Skeletal Muscle

T307

51522-51626

Sentence

denotes

Skeletal muscle tissues represent the largest protein store in the human body (30–45% of total protein).

T308

51627-51747

Sentence

denotes

Muscular mass, strength, and functions are greatly governed by the rates of muscle protein synthesis and turnover [124].

T309

51748-51831

Sentence

denotes

Muscle protein metabolism is regulated by the interaction of a wide range of genes.

T310

51832-51981

Sentence

denotes

Aging is associated with various stresses, which increase the expression of catabolic genes such as E3 ubiquitin ligases MuRF1 and atrogin-1 (MAFbx).

T311

51982-52055

Sentence

denotes

These genes heighten the occurrence of age-related muscular atrophy [97].

T312

52056-52216

Sentence

denotes

Oral consumption of royal jelly by aged HET mice resulted in lower levels of catabolic genes (e.g., MuRF1 and MAFbx), which were similar to those in young mice.

T313

52217-52414

Sentence

denotes

In the meantime, the expression of these genes in the control mice was high indicating that royal jelly can delay age-related muscular apoptosis by suppressing the activity of catabolic genes [97].

T314

52415-52717

Sentence

denotes

Two other studies reported that CAPE suppressed catabolism that contributed to degenerative myopathy in the gastrocnemius muscle of rats undergoing eccentric exercising or femoral artery ligation as reflected by decreased serum levels of creatine kinase, a marker of muscular proteolysis [101,102,103].

T315

52718-52961

Sentence

denotes

Apart from skeletal muscle, CAPE was reported to protect heart muscle against age-related deteriorations such as accumulation of lipofuscin, nuclear irregularity, mitochondrial degeneration, and myofilament disorganization and disruption [33].

T316

52962-53117

Sentence

denotes

The molecular mechanism underling blockage of muscle proteolysis by bee products in sarcopenic rodents involves an interplay of various signaling pathways.

T317

53118-53243

Sentence

denotes

Royal jelly and bee pollen activated mTOR and its substrate AKT, which are suggested to inhibit muscular proteolysis [36,96].

T318

53244-53515

Sentence

denotes

Similar to the effect of royal jelly on catabolic genes in HET mice, treating both L6 myoblasts and rats with propolis, CAPE, and kaempferide resulted in potent activation of AKT in a PI3K-dependent manner [111], in addition to phosphorylation of IR, PI3K, and AMPK [70].

T319

53516-53667

Sentence

denotes

AKT, a key substrate of mTORC2, is a conserved serine/threonine nutrient sensing protein kinase that belongs to the PI3k-related protein kinase family.

T320

53668-53991

Sentence

denotes

Upon presence of growth factors, PI3k gets activated by IR substrate resulting in stimulation of a series of signaling cascades that involve activation of AKT, which leads to further activation of mTORC1. mTORC1 activates the phosphorylation of two main regulators of cap-dependent protein synthesis: S6K and eIF4E [2,140].

T321

53992-54331

Sentence

denotes

In addition, mTORC1 contributes to autophagy—a turnover process that involves clearance of dysfunctional organelles and long-lived protein aggregations with provision of energy and macromolecular precursors in return—by binding with AMPK resulting in phosphorylation of autophagy genes such as Unc51-like kinase 1 at different sites [140].

T322

54332-54484

Sentence

denotes

In fact, royal jelly is reported to fine-tune the transcriptional activity of the FOXO through modulating the activity of insulin/IGF-1 signaling [141].

T323

54485-54666

Sentence

denotes

FOXO plays a major role in the activation of AKT pathway, which implicates regulation of multiple stress–response pathways such as ROS detoxification and DNA repair and translation.

T324

54667-54885

Sentence

denotes

In addition, the FOXOs family exerts a direct effect on certain muscle atrophy genes such as MUSA1 and a formerly uncharacterized ligase known as Specific of Muscle Atrophy and Regulated by Transcription (SMART) [142].

T325

54887-54891

Sentence

denotes

4.6.

T326

54892-54925

Sentence

denotes

Enhancement of Stem Cell Function

T327

54926-55097

Sentence

denotes

Reduction of the number and functional capacity of the muscle satellite cells is considered a core contributor to the development of age-related muscular dysfunction [96].

T328

55098-55277

Sentence

denotes

Induction of myogenesis via in vivo reprogramming of muscle satellite cells is a currently studied strategy that has not been successfully used for sarcopenia treatment yet [143].

T329

55278-55538

Sentence

denotes

On the other hand, treating sarcopenic rats with both royal jelly and pRJ was reported to increase the number of Pax7-positive satellite cells in vivo and in vitro (pRJ only). pRJ induced self-renewal of satellite cells via activation of AKT signaling [96,97].

T330

55539-55640

Sentence

denotes

AKT activity was associated with activation of IGF-1 as indicated by increased serum levels of IGF-1.

T331

55641-55934

Sentence

denotes

IGF-1 plays a crucial rule in the activation of various signaling pathways; it is believed to be a major mediator of muscle growth and repair that functions by stimulating the proliferation and differentiation of satellite cells into myotubes, albeit the exact mechanism is not clear yet [96].

T332

55935-56169

Sentence

denotes

Similarly, pRJ activated AKT-signaling pathway in satellite cells culture, which was associated with increased proliferation of myosatellite cells and their differentiation into myotubes—an effect that is contradictory to muscle loss.

T333

56170-56279

Sentence

denotes

AKT is thought to contribute to the synthesis of muscular proteins and inhibition of muscle proteolysis [96].

T334

56281-56285

Sentence

denotes

4.7.

T335

56286-56316

Sentence

denotes

Counteracting Glycation Stress

T336

56317-56581

Sentence

denotes

Oxidative stress, inflammation, and insensitivity to insulin, which accompany advanced age, contribute to the production of advanced glycation end products (AGEs) via enhancement of the activity of the Receptor for Advanced Glycation End products (RAGE) [144,145].

T337

56582-56763

Sentence

denotes

AGEs destroy the protein and lipid ingredients of muscle tissues by promoting the production of destructive molecules such as free radicals and inflammatory cytokines [101,102,113].

T338

56764-56878

Sentence

denotes

Thanks to their potent antioxidant properties, polyphenolic compounds exert multifaceted anti-glycation functions.

T339

56879-57075

Sentence

denotes

On one hand, they scavenge free-radicals and chelate transition metals that are involved in the synthesis of dicarbonyl intermediates subsequently resulting in inhibition of the formation of AGEs.

T340

57076-57300

Sentence

denotes

On the other hand, polyphenolic compounds antagonize AGE receptors, mainly RAGE, and facilitate the removal of already formed a,b-dicarbonyl intermediates such as methylglyoxal, promoting the degradation of AGEs [37,38,146].

T341

57301-57438

Sentence

denotes

Royal jelly is reported to downregulate the activity of RAGE, the main receptor for AGEs, in an aged model of cognitive impairment [147].

T342

57439-57523

Sentence

denotes

However, its anti-glycation effect has not been investigated in skeletal muscle yet.

T343

57524-57666

Sentence

denotes

Propolis exhibits strong anti-AGE properties, which are superior to those of quercetin or chlorogenic acid, well-known natural AGE inhibitors.

T344

57667-57771

Sentence

denotes

Its flavonoid fraction potently impedes the synthesis of AGEs by trapping dicarbonyl intermediates [37].

T345

57772-58026

Sentence

denotes

Table 1 shows that propolis accelerated AGEs clearance in a model of muscle aging induced by administration of a precursor of AGEs (methylglyoxal) via activation of glyoxalase 1, an enzyme that eliminates dicarbonyl compounds (key elements of AGEs) [38].

T346

58027-58231

Sentence

denotes

CAPE inhibited the production of AGEs-related molecules such as protein carbonyl in the gastrocnemius muscle of rats via blockage of the activity of xanthine oxidase and adenosine deaminase [101,102,103].

T347

58232-58399

Sentence

denotes

The latter negatively affects insulin signaling and promotes the development of hyperglycemia, which represents a favorable condition for the production of AGEs [148].

T348

58400-58576

Sentence

denotes

However, propolis could not counteract the wasting effects of AGEs that already occurred in the extensor digitorum longus muscle though it tended to restore soleus muscle mass.

T349

58577-58720

Sentence

denotes

This finding denotes that different muscle tissues respond differently to treatment, probably based on their ratio of type I to type II fibers.

T350

58721-58923

Sentence

denotes

It also signifies the importance of early use of bee products (e.g., propolis) for the prevention of AGEs formation in skeletal muscle in people with high risk for AGEs formation such as diabetics [38].

T351

58925-58929

Sentence

denotes

4.8.

T352

58930-58951

Sentence

denotes

Neuronal Regeneration

T353

58952-59098

Sentence

denotes

Neuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149].

T354

59099-59256

Sentence

denotes

Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150].

T355

59257-59400

Sentence

denotes

Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion.

T356

59401-59605

Sentence

denotes

Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113].

T357

59606-59832

Sentence

denotes

Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151].

T358

59833-59990

Sentence

denotes

Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69].

T359

59991-60246

Sentence

denotes

Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway:

T360

60247-60275

Sentence

denotes

MuRF1 and Atrogin-1 [1,152].

T361

60276-60446

Sentence

denotes

Propolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve.

T362

60447-60647

Sentence

denotes

Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells.

T363

60648-60901

Sentence

denotes

Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113].

T364

60902-60988

Sentence

denotes

Neuroprotective effects of propolis in motor neurons are documented in the literature.

T365

60989-61251

Sentence

denotes

Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65].

T366

61252-61688

Sentence

denotes

In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].

T367

61689-61919

Sentence

denotes

The release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size.

T368

61920-62048

Sentence

denotes

However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153].

T369

62049-62141

Sentence

denotes

On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154].

T370

62142-62267

Sentence

denotes

Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60].

T371

62268-62508

Sentence

denotes

In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103].

T372

62509-62815

Sentence

denotes

In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115].

T373

62816-62907

Sentence

denotes

However, investigations of the action of bee products on neurotransmission are very scarce.

T374

62909-62913

Sentence

denotes

4.9.

T375

62914-62945

Sentence

denotes

Improving Muscular Blood Supply

T376

62946-63150

Sentence

denotes

Aging is associated with higher onset of atherosclerosis and restenosis, which involve vascular and microvascular damages that result from hyperproliferation of vascular smooth muscle cells (VSMCs) [155].

T377

63151-63438

Sentence

denotes

Muscle unloading (e.g., in sedentary lifestyle) involves chronic neuromuscular inactivity, which results in reductions in capillary number, luminal diameter, and capillary volume as well as heightened production of anti-angiogenic factors, such as p53 and TSP-1 in skeletal muscle [110].

T378

63439-63569

Sentence

denotes

Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle.

T379

63570-63720

Sentence

denotes

Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157].

T380

63721-63872

Sentence

denotes

In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues.

T381

63873-64060

Sentence

denotes

Free radicals alter cellular structure and function by attacking lipid and protein biomolecules that exist in the structure of biological membranes, enzymes, and transport proteins [102].

T382

64061-64195

Sentence

denotes

Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.

T383

64196-64440

Sentence

denotes

Mitchell and colleagues examined changes in microvascular blood volume, microvascular flow velocity, and microvascular blood flow in the quadriceps muscle following treatment with 15 g of amino acids in young and old subjects (20–70 years old).

T384

64441-64577

Sentence

denotes

They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity.

T385

64578-64746

Sentence

denotes

Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157].

T386

64747-64947

Sentence

denotes

Bee products such as bee pollen and propolis have a potential to boost microcirculation and correct pathologies that contribute to vascular dysfunction such as hyperglycemia and dyslipidemia [36,155].

T387

64948-65132

Sentence

denotes

In this context, CAPE, one of the basic constituents of propolis, was reported to combat vascular damages by counteracting the proliferative activity of platelet-derived growth factor.

T388

65133-65485

Sentence

denotes

The molecular mechanism involved inducing cell-cycle arrest in VSMCs via activation of p38mitogen-activated protein kinase (MAPK), which was associated with accumulation of hypoxia-inducible factor (HIF)-1α—mainly due to inhibition of HIF prolylhydroxylase, a key contributor to proteasomal degradation of HIF-1α—and subsequent induction of HO-1 [155].

T389

65486-65916

Sentence

denotes

In the same regard, supplementing rats undergoing capillary regression (resulting from two weeks of hind limb unloading) in the soleus muscle with two daily intragastric doses of propolis for two weeks restored capillary number, capillary structure, capillary volume, and capillary to muscle fiber ratio through a mechanism that involves inhibition of anti-angiogenic factors and activation of pro-angiogenic factors (e.g., VEGF).

T390

65917-66158

Sentence

denotes

The relative muscle-to-body weight in treated animals was higher than in the unloaded control animals, and the number of TUNEL-positive apoptotic endothelial cells in the soleus muscle was similar to that in the normal control animals [110].

T391

66159-66325

Sentence

denotes

Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90].

T392

66326-66415

Sentence

denotes

Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108].

T393

66416-66579

Sentence

denotes

VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks.

T394

66580-66685

Sentence

denotes

VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110].

T395

66686-66832

Sentence

denotes

Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK.

T396

66833-66939

Sentence

denotes

It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158].

T397

66940-67092

Sentence

denotes

Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.

T398

67094-67099

Sentence

denotes

4.10.

T399

67100-67143

Sentence

denotes

Improving the Composition of Gut Microbiome

T400

67144-67304

Sentence

denotes

Bee products such as royal jelly and propolis display potent antifungal, bactericidal, microbicidal, anti-inflammatory, antioxidant, and healing effects [2,66].

T401

67305-67376

Sentence

denotes

Most bee products investigated in this review were administered orally.

T402

67377-67607

Sentence

denotes

Therefore, it is likely that their therapeutic effects may start locally within the GI tract, which frequently undergoes propagation of harmful endobacteria, inflammation, aberrations, and permeability in advanced age [10,24,152].

T403

67608-67738

Sentence

denotes

In this respect, Roquetto and colleagues [116] supplemented C57BL/6 mice on HFD with crude propolis (0.2%) for two and five weeks.

T404

67739-67879

Sentence

denotes

HFD increased the proportion of the phylum Firmicutes as well as levels of circulating lipopolysaccharide (LPS) and inflammatory biomarkers.

T405

67880-68027

Sentence

denotes

DNA sequencing for the 16S rRNA of the gut microbiota revealed that five weeks of propolis treatment rendered the microbiota profile almost normal.

T406

68028-68261

Sentence

denotes

Compared with untreated mice, propolis-supplemented animals demonstrated lower levels of serum triacylglycerols, glucose, and circulating LPS, along with reduced expression of TLR4 and inflammatory cytokines in skeletal muscle [116].

T407

68262-68345

Sentence

denotes

Lactic acid bacteria profusely exist in bee saliva and all bee products [36,83,84].

T408

68346-68477

Sentence

denotes

Various species of lactic acid bacteria have been experimentally used to correct GI dysbiosis and related muscle wasting [159,160].

T409

68478-68562

Sentence

denotes

Moreover, oligosaccharides have been chemically isolated from bee products [32,161].

T410

68563-68726

Sentence

denotes

These api-materials are classified as prebiotics, fermented non-digestible compounds that promote the proliferative activity of health-promoting bacteria [24,161].

T411

68727-68885

Sentence

denotes

Supplementing frail old adults with fructooligosaccharides expressed positive effects on skeletal muscle strength (handgrip) and endurance (exhaustion) [162].

T412

68886-68978

Sentence

denotes

On the other side, microbiome of the gut can affect the biological activity of bee products.

T413

68979-69193

Sentence

denotes

The literature shows that certain endobacteria transform dietary polyphenols into phenolic acids, which can easily access the circulation and then cross the blood brain barrier to produce therapeutic effects [163].

T414

69194-69418

Sentence

denotes

Hence, it is important that future investigations of bee products among sarcopenic subjects examine the effect of these products on the composition of GI microbial population and its association with muscle-related outcomes.

T415

69420-69422

Sentence

denotes

5.

T416

69423-69433

Sentence

denotes

Discussion

T417

69434-69593

Sentence

denotes

Age-related deteriorations in skeletal muscle are multifactorial in nature, which contributes to the high failure rates of drugs designed to target sarcopenia.

T418

69594-69778

Sentence

denotes

Thus, there is a strong need for new therapeutic agents that express multidimensional effects in order to provide physically frail elders a chance to restore their health and QoL [21].

T419

69779-70052

Sentence

denotes

Given the scarcity of human trials using bee products among physically frail and sarcopenic subjects, cell culture and animal studies may provide useful information about the effect of bee products on skeletal muscle and help identifying their probable mechanism of action.

T420

70053-70270

Sentence

denotes

Both in vivo and in vitro studies indicate that substances produced by honey bees such as royal jelly, bee pollen, and propolis can positively modulate basic cellular functions of myoblasts as well as mature myocytes.

T421

70271-70695

Sentence

denotes

These products seem to be promising anti-sarcopenic agents because they can promote muscle protein synthesis [36,104], decrease mitochondrial oxidative stress [36,90,106], mitigate inflammation [38,90,101,108,115], improve muscular blood supply [102,110], enhance peripheral motor conduction [113], accelerate the removal of AGEs [38], counteract catabolism, and decrease markers of skeletal muscle atrophy [97,101,102,103].

T422

70696-70848

Sentence

denotes

One of the major pathologies underlying age-related skeletal muscle failure is insulin resistance, which alters glucose metabolism [3,4,21,118,130,164].

T423

70849-71070

Sentence

denotes

Numerous studies signify that bee products may protect against muscle wasting by correcting metabolic dysregulations in skeletal muscle via activation of some of the key nutrient sensing molecules [69,96,100,106,109,111].

T424

71071-71248

Sentence

denotes

In this respect, bee pollen permitted mTORC1 to mitigate anabolic resistance through the regulation of muscle protein and muscle growth in malnourished sarcopenic old rats [36].

T425

71249-71362

Sentence

denotes

Royal jelly and CAPE restored muscle mass and metabolism through activation of AKT, a substrate of mTOR [96,111].

T426

71363-71490

Sentence

denotes

Polyphenols in propolis [70], CAPE [111], and 10-HDA [106] activated AMPK resulting in enhanced skeletal muscle glucose uptake.

T427

71491-71602

Sentence

denotes

In the meantime, royal jelly improved mitochondrial biogenesis in skeletal muscle via activation of AMPK [106].

T428

71603-71744

Sentence

denotes

AMPK and mTOR are master regulators of metabolism and autophagy [2,165]; they keep muscle integrity by stimulating protein synthesis [21,22].

T429

71745-71941

Sentence

denotes

Accordingly, all these findings denote that bee products represent a promising nutritional strategy that can tackle skeletal muscle wasting in old age by correcting its underling metabolic causes.

T430

71942-72057

Sentence

denotes

However, the detailed physiological processes involved still need to be deeply unraveled in further investigations.

T431

72058-72217

Sentence

denotes

The activity of mTOR depends mainly on the bioavailability of essential amino acids in addition to many other molecules in the cellular microenvironment [136].

T432

72218-72528

Sentence

denotes

Evidence from preclinical and human studies confirms that ingestion of essential amino acids increases their cellular bioavailability, which is associated with upregulation of the activity of the nutrient sensing mTORC1 kinase following its translocation from the cytosol to the surface of lysosomes [135,136].

T433

72529-72768

Sentence

denotes

Research shows that ingestion of small amounts of essential amino acids (6.8 g) by healthy older adults could stimulate muscle protein synthesis by activating mTORC1 signaling even without involvement in resistance exercise training [137].

T434

72769-72866

Sentence

denotes

Other factors affect the capacity of essential amino acids to stimulate muscle protein synthesis.

T435

72867-73127

Sentence

denotes

Amino acid bioavailability depends to a great extent on the bacterial strains of resident gut microbiome, which can either promote amino acid loss by degrading them or substantially contribute to their availability by producing some of them e.g., lysine [152].

T436

73128-73309

Sentence

denotes

Furthermore, amino acid supplements in old age do not enhance muscle protein metabolism, combat anabolic resistance, or improve muscle condition under sedentary conditions [25,166].

T437

73310-73603

Sentence

denotes

According to Table 1, different models of skeletal muscle injury (e.g., natural aging [96], sarcopenic obesity [54], AGE-induced muscle wasting [38], malnutrition-related muscle loss [36], exhaustive exercise [90,109], etc.) were used to evaluate the effect of bee products on skeletal muscle.

T438

73604-73911

Sentence

denotes

The effects of bee products on muscle mass varied considerably: some studies reported that bee products increased muscle mass [36,54,90,96,100,105,113] and improved physical performance [95,96,97,98,99] while others could not or did not depict any significant change in muscle mass [38,102,103,104,110,117].

T439

73912-74402

Sentence

denotes

However, the latter revealed major beneficial effects related to the biology of skeletal muscle aging such as improved muscle protein deposition [104], enhanced activity of mitochondrial enzymes [106], decreased muscle infiltration by inflammatory cells, decreased muscle proteolysis, lowered lipid peroxidation and protein carbonylation [102,103], increased microvascular blood supply, heightened production of antioxidants [110], and increased clearance of AGEs from skeletal muscle [38].

T440

74403-74550

Sentence

denotes

These findings suggest that bee products may prevent the development of sarcopenia if supplemented earlier before the occurrence of muscle atrophy.

T441

74551-74763

Sentence

denotes

In this regard, supplementing young football players with royal jelly for two months resulted in a significant increase in muscle and bone mass compared with control players who did not receive royal jelly [167].

T442

74764-75005

Sentence

denotes

As for the effect of bee products on sarcopenia in humans, we could locate only one randomized control trial (RCT), which examined the effect of pRJ (1.2 g/d or 4.8 g/d over 1 year) on muscle strength among institutionalized aged population.

T443

75006-75198

Sentence

denotes

This study revealed no significant effect of pRJ on the tested muscular functions: handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed [59].

T444

75199-75337

Sentence

denotes

Nonetheless, such outcome indexes may not be sufficient to evaluate the overall effect of royal jelly on muscular performance and quality.

T445

75338-75606

Sentence

denotes

In addition, the literature documents gut microbiome alterations-related to muscle loss in institutionalized old adults compared with older adults living in the community, which might affect the efficacy of nutritional therapies in this particular group [164,168,169].

T446

75607-75737

Sentence

denotes

The relation between muscle mass or strength and physical function in old people is not as direct or clear as originally presumed.

T447

75738-75829

Sentence

denotes

Existing knowledge indicates that muscle strength may be intact in people with muscle loss.

T448

75830-75922

Sentence

denotes

Likewise, decreased muscle strength may not necessarily alter physical performance [21,170].

T449

75923-76179

Sentence

denotes

Research notes that selection of interventions that merely increase muscle mass and/or strength entails ignoring valuable therapies that contribute to various biological processes of muscle recovery by interfering with pathologies conducive to muscle loss.

T450

76180-76477

Sentence

denotes

More, combining functional measures of muscle performance with different comprehensive biomarkers (e.g., of metabolism, inflammation, oxidative stress, etc.) in skeletal muscle and the whole body may identify therapies that can positively affect muscle qualities independent of mass increase [21].

T451

76478-76750

Sentence

denotes

In support of this argument, treating sarcopenic elderly with oral amino acids (which represent only one ingredient of royal jelly or bee pollen) significantly increased whole-body lean mass 6 and 18 months after treatment as indicated by dual-energy X-ray absorptiometry.

T452

76751-77033

Sentence

denotes

This effect was attributed to enhancement of insulin sensitivity and anabolism as portrayed by significant reductions in fasting blood glucose, serum insulin, HOMA-IR, and serum tumor necrosis factor-α (TNF-α) as well as increase of serum level of IGF-1 and IGF-1/TNF-α ratio [171].

T453

77034-77087

Sentence

denotes

Animal studies lend further support to those reports.

T454

77088-77342

Sentence

denotes

For instance, royal jelly had no effect on muscle differentiation genes (myogenic differentiation 1 (MyoD), myogenein, myostatin) in sarcopenic mice, indicating that royal jelly may not improve age-related deterioration of muscle strength—once it occurs.

T455

77343-77578

Sentence

denotes

On the other hand, royal jelly significantly reduced the progression of muscle atrophy by decreasing the expression of catabolism genes E3 ubiquitin ligases MuRF1 and atrogin-1 in old mice to levels similar to those in young mice [97].

T456

77579-77742

Sentence

denotes

Royal jelly also stimulated the differentiation of satellite stem cells both in vivo and in vitro and improved the regenerative capacity of injured muscle [96,97].

T457

77743-77842

Sentence

denotes

Therefore, royal jelly treatment might reduce the progression of age-related muscular atrophy [59].

T458

77843-78058

Sentence

denotes

Future RCTs that evaluate the effect of bee products on muscle qualities and motor performance in humans should be properly designed to include biological markers of motor functioning along with behavioral measures.

T459

78059-78152

Sentence

denotes

Multifactorial conditions such as sarcopenia should be addressed by multimodal interventions.

T460

78153-78308

Sentence

denotes

Nutrition and physical exercise are key strategies that can preserve muscle mass and function in older adults both in clinical and community settings [21].

T461

78309-78647

Sentence

denotes

Thus, it might be helpful to compare the effect of combining bee products with other conventional treatments such as other dietary elements and exercise given that factors such as physical activity and diet can interfere with or promote the effect of bee products on muscle qualities and disorders that underlie muscle weakness [105,106].

T462

78648-78823

Sentence

denotes

Fat mass increases with age, especially after age-related hormonal decline (e.g., after menopause), and it activates inflammatory processes that disturb body physiology [172].

T463

78824-79023

Sentence

denotes

In this regard, supplementing obese rats with milk naturally enriched with PUFA and polyphenols from propolis increased gastrocnemius muscle mass and tended to increase the mass of the soleus muscle.

T464

79024-79127

Sentence

denotes

It decreased the diameter of adipocytes and tended to decrease serum levels of low-density lipoprotein.

T465

79128-79270

Sentence

denotes

These findings suggest a role of propolis-enriched milk in the mitigation of sarcopenic obesity, albeit it had no effect on body weight [105].

T466

79271-79411

Sentence

denotes

On the other side, many studies show that exercise has significantly improved muscle mass and strength in sarcopenic seniors [4,42,132,173].

T467

79412-79583

Sentence

denotes

Propolis treatment of undifferentiated L6 myoblast selectively stimulated IL-6 production and inhibited pathological cytokines such as interleukin (IL)-1β and TNF-α [108].

T468

79584-79739

Sentence

denotes

This interesting in vitro investigation indicates that propolis can mimic the mechanism through which exercise induces skeletal muscle remodeling [23,114].

T469

79740-80096

Sentence

denotes

Evidence from preclinical studies shows that concurrent treatment of rats on endurance training with royal jelly enhanced mitochondrial adaptation in muscles that combine both type I and type II fibers such as the soleus muscle whereas neither royal jelly alone nor exercise alone could influence the activity of mitochondrial enzymes in that muscle [106].

T470

80097-80363

Sentence

denotes

Moreover, bee pollen and propolis treatment of rats on exhaustive exercise increased the production of antioxidant enzymes, blocked the production of free radicals, promoted glycogen use in the skeletal muscle and liver, and restored muscle fiber structure [90,109].

T471

80364-80435

Sentence

denotes

In most studies, whole royal jelly, bee pollen, and propolis were used.

T472

80436-80661

Sentence

denotes

However, these products appeared in different forms e.g., neat vs processed bee pollen [90], water [109] vs ethanolic extracts [110] of propolis, lyophilized [98,99] and crude [97] vs enzyme-treated [59,95,96,97] royal jelly.

T473

80662-80776

Sentence

denotes

Both processed bee pollen [36] and pRJ [97,106] had better effects compared with crude bee pollen and royal jelly.

T474

80777-81040

Sentence

denotes

In addition, a large group of constituents of royal jelly and propolis were used such as 10-HDA [54,106], CAPE [69,101,102,103], artepillin C, coumaric acid, kaempferide [70], boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene [69].

T475

81041-81119

Sentence

denotes

10-HDA was the only element in royal jelly that was tested in skeletal muscle.

T476

81120-81178

Sentence

denotes

It enhanced glucose uptake via AMPK phosphorylation [106].

T477

81179-81339

Sentence

denotes

It also restored body weight, restored skeletal muscle mass (only in males), and reduced fat mass (only in females) in aged rats undergoing chronic stress [54].

T478

81340-81579

Sentence

denotes

CAPE is one of the most investigated compounds in propolis: it enhanced skeletal muscle glucose uptake [111], inhibited cytokine and ROS production, prevented protein carbonylation, lipid peroxidation, and muscle proteolysis [101,102,103].

T479

81580-81727

Sentence

denotes

The effects of whole ethanolic extracts of propolis and CAPE on glucose uptake in skeletal muscle were comparable to those of insulin [69,109,111].

T480

81728-81979

Sentence

denotes

More, investigations of the effect of flavonoids and oxyprenylated phenylpropanoids abundant in ethanolic extracts of propolis on glucose uptake in skeletal muscle revealed superior effects of kaempferide [70], 4-geranyloxyferulic acid, and auraptene.

T481

81980-82154

Sentence

denotes

Among 5 oxyprenylated phenylpropanoids derived from propolis, auraptene most potently activated GLUT4 translocation and accelerated glucose influx into skeletal muscle cells.

T482

82155-82322

Sentence

denotes

Measurement of the incorporated amounts of these compounds into myotubes indicated that auraptene had the highest bioavailability among other effective compounds [69].

T483

82323-82463

Sentence

denotes

Matters concerning dosage and duration of treatment remain issues of concern should these compounds be used to prevent and treat sarcopenia.

T484

82464-82586

Sentence

denotes

In addition, the effect of other active ingredients of bee products on skeletal muscle pathologies is worth investigation.

T485

82587-82746

Sentence

denotes

For instance, MRJPs are reported to contribute to most therapeutic properties of royal jelly due to their rich amino acid content (up to 578 amino acids) [47].

T486

82747-82879

Sentence

denotes

In the meantime, the literature documents a potent regulatory effect of amino acids on skeletal muscle protein turnover [6,131,132].

T487

82880-82959

Sentence

denotes

Nonetheless, the effect of MRJPs on skeletal muscle were not studied until now.

T488

82960-83041

Sentence

denotes

Despite the details illustrated in this review, many questions remain unanswered.

T489

83042-83213

Sentence

denotes

The most important question among all is which bee product or bee component can produce the best benefits against skeletal muscle senescence and under which circumstances?

T490

83214-83506

Sentence

denotes

Sarcopenia is the result of several interrelated factors such as neuromuscular dysfunction, oxidative stress, metabolic alterations, poor blood supply, hormonal deficiencies (e.g., sex hormones), chronic inflammation, and lifestyle choices (e.g., physical inactivity and unhealthy diet) [21].

T491

83507-83763

Sentence

denotes

The effect of bee products on some of these factors are underaddressed (e.g., neuromuscular dysfunction, muscle blood supply, and gut microbiome) while some other have not been explored yet (e.g., sex steroids and their association with muscular function).

T492

83765-83767

Sentence

denotes

6.

T493

83768-83779

Sentence

denotes

Conclusions

T494

83780-83998

Sentence

denotes

All animal studies discussed above indicate that royal jelly, propolis, and bee pollen as well as their key ingredients such as 10-HDA and CAPE might counteract age-related muscular decline, especially in early stages.

T495

83999-84151

Sentence

denotes

These products operate by modulating most mechanisms that contribute to sarcopenia such as metabolic dysregulation, inflammation, oxidative stress, etc.

T496

84152-84342

Sentence

denotes

However, more studies are needed to examine the specific cellular and molecular mechanisms of these products and other major ingredients that were not explored, such as MRJPs in royal jelly.

T497

84343-84495

Sentence

denotes

Among all bee products, royal jelly has been used to improve muscular performance in humans, though at a small scale, without any reported side effects.

T498

84496-84747

Sentence

denotes

Future RCTs that examine the effect of bee products on sarcopenia should consider individual variations (e.g., gender, general health, activity level, diet, etc.) and combine functional and subjective outcome measures with sound predictive biomarkers.

T499

84749-84769

Sentence

denotes

Author Contributions

T500

84770-85008

Sentence

denotes

Conceptualization, A.M.A.; methodology, A.M.A.; software, A.M.A.; validation, A.M.A.; writing—original draft preparation, A.M.A.; writing—review and editing, H.K.; supervision, H.K.; project administration, H.K.; funding acquisition, H.K.

T501

85009-85085

Sentence

denotes

All authors have read and agreed to the published version of the manuscript.

T502

85087-85094

Sentence

denotes

Funding

T503

85095-85251

Sentence

denotes

This study was supported by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and development, AMED, Japan (Grant No.

T504

85252-85270

Sentence

denotes

18dm0107100h0003).

T505

85272-85293

Sentence

denotes

Conflicts of Interest

T506

85294-85338

Sentence

denotes

The authors declare no conflict of interest.

T507

85339-85352

Sentence

denotes

Abbreviations

T508

85353-85420

Sentence

denotes

4eBP1/eIF4E Eukaryotic translation initiation 4E-binding protein 1

T509

85421-85461

Sentence

denotes

10-HDA trans-10-hydroxy-2-decenoic acid

T510

85462-85499

Sentence

denotes

AGEs Advanced glycation end products

T511

85500-85555

Sentence

denotes

AKT A serine/threonine nutrient sensing protein kinase

T512

85556-85584

Sentence

denotes

AMP Adenosine monophosphate

T513

85585-85639

Sentence

denotes

AMPK Adenosine monophosphate activated protein kinase

T514

85640-85673

Sentence

denotes

ARE Antioxidant response element

T515

85674-85713

Sentence

denotes

ATF4 Activating transcription factor-4

T516

85714-85742

Sentence

denotes

ATP Adenosine tri-phosphate

T517

85743-85762

Sentence

denotes

COX Cyclooxygenase

T518

85763-85802

Sentence

denotes

eNOs Endothelial nitric oxide synthase

T519

85803-85828

Sentence

denotes

ER Endoplasmic reticulum

T520

85829-85849

Sentence

denotes

FOXO Forkhead box O

T521

85850-85870

Sentence

denotes

GI Gastrointestinal

T522

85871-85899

Sentence

denotes

GLUT4 Glucose transporter 4

T523

85900-85928

Sentence

denotes

HET Heterogeneous head tilt

T524

85929-85947

Sentence

denotes

HFD High fat diet

T525

85948-85977

Sentence

denotes

HIF Hypoxia-inducible factor

T526

85978-86000

Sentence

denotes

HO-1 Heme oxygenase 1

T527

86001-86060

Sentence

denotes

HOMA-IR Homeostatic model assessment of insulin resistance

T528

86061-86076

Sentence

denotes

IKK IκB kinase

T529

86077-86110

Sentence

denotes

IGFs Insulin-like growth factors

T530

86111-86126

Sentence

denotes

IL Interleukin

T531

86127-86164

Sentence

denotes

iNOS Inducible nitric oxide synthase

T532

86165-86185

Sentence

denotes

IR Insulin receptor

T533

86186-86228

Sentence

denotes

LESM Lower extremity skeletal muscle mass

T534

86229-86267

Sentence

denotes

MAPK Mitogen-activated protein kinase

T535

86268-86288

Sentence

denotes

MDA Malondialdehyde

T536

86289-86324

Sentence

denotes

mTOR Mammalian target of rapamycin

T537

86325-86353

Sentence

denotes

MMP-12 Metalloproteinase-12

T538

86354-86391

Sentence

denotes

MCP-1 Monocyte chemotactic protein 1

T539

86392-86425

Sentence

denotes

MRJPs Major royal jelly proteins

T540

86426-86458

Sentence

denotes

MyoD Myogenic differentiation 1

T541

86459-86488

Sentence

denotes

NF-kB Nuclear factor kappa-B

T542

86489-86550

Sentence

denotes

NRF2 Nuclear factor erythroid 2/Nuclear respiratory factor 2

T543

86551-86627

Sentence

denotes

PGC-1α Peroxisome proliferator-activated receptor gamma coactivator 1 alpha

T544

86628-86659

Sentence

denotes

PI3k Phosphoinositide-3 kinase

T545

86660-86693

Sentence

denotes

PUFA Polyunsaturated fatty acids

T546

86694-86715

Sentence

denotes

PKC Protein kinase C

T547

86716-86749

Sentence

denotes

pRJ Protease-treated royal jelly

T548

86750-86770

Sentence

denotes

QOL Quality of life

T549

86771-86821

Sentence

denotes

RAGE Receptor for Advanced Glycation End products

T550

86822-86851

Sentence

denotes

RCT Randomized control trial

T551

86852-86880

Sentence

denotes

ROS Reactive oxygen species

T552

86881-86905

Sentence

denotes

SDs Standard deviations

T553

86906-86943

Sentence

denotes

S6K P70 ribosomal proteins S6 kinase

T554

86944-87008

Sentence

denotes

SMART Specific of Muscle Atrophy and Regulated by Transcription

T555

87009-87035

Sentence

denotes

TNF Tumor necrosis factor

T556

87036-87075

Sentence

denotes

TNFR1 Tumor necrosis factor receptor 1

T557

87076-87120

Sentence

denotes

VEGF-A Vascular endothelial growth factor A

T558

87121-87156

Sentence

denotes

VSMCs Vascular smooth muscle cells

T559

87158-87499

Sentence

denotes

Figure 1 Brief summary of the chemical composition and biological activities of royal jelly, bee pollen, and propolis along with their effects on aged skeletal muscle and possible underlying mechanism. ↑ denotes increase, ↓ denotes decrease, MRJPs: major royal jelly proteins, 10-HDA: trans-10-hydroxy-2-decenoic acid, GI: gastrointestinal.

T560

87500-87609

Sentence

denotes

Panels (A,B) describe the composition and the biological properties of royal jelly, bee pollen, and propolis.

T561

87610-87934

Sentence

denotes

Thanks to their rich structure (which consists of proteins, polyphenols, vitamins, minerals, and trace elements) [2,28,37,49,59,60,61,68,80,86], these bee substances demonstrate a wide range of therapeutic activities such as counteracting inflammation and oxidative stress, in addition to many others [37,38,39,43,45,63,83].

T562

87935-88028

Sentence

denotes

Panel (C) summarizes the effects of royal jelly, bee pollen, and propolis on skeletal muscle.

T563

88029-88177

Sentence

denotes

These products increased muscle mass [36,54,95,96] and restored muscle function in old [36,38,95,96,97] and exhausted [54,90,101,106] animal models.

T564

88178-88643

Sentence

denotes

As shown in Panel (D), these effects originated from multiple molecular events that resulted in several therapeutic actions including amelioration of inflammation [36,38,90,101,107,108] and oxidative [95,106,109,110] damages, metabolic regulation [69,70,96,100,106,109,111,112], enhancements of satellite cell responsiveness [96,97], improving muscular blood supply [110], inhibition of catabolic genes [97], and promotion of peripheral neuronal regeneration [113].

T565

88644-88873

Sentence

denotes

However, future studies could examine the involvement of other possible mechanisms in the muscle-enhancing potential of these bee products such as the role of gut microbiome in the absorption of nutrient contents of bee products.

T566

88874-89056

Sentence

denotes

It is not clear if these api-materials affect muscle quality via modulation of sex steroids and signaling pathways of dietary restriction, which are known to affect muscle integrity.

T567

89057-89249

Sentence

denotes

Table 1 Characteristics of Included Pre-Clinical and Clinical Studies Examining the Effect of Royal Jelly, Propolis, Bee Pollen, and their Constituents on Skeletal Muscle (N of studies = 24).

T568

89250-89397

Sentence

denotes

Bee Products/Their Constituents Animal Model/Cell Line Experimental Design Outcome Measures Results and Possible Related Mechanisms References

T569

89398-89437

Sentence

denotes

In vitroRoyal jelly and pRJ (500 μg/mL:

T570

89438-90027

Sentence

denotes

1, 2, 3, and 5 d)In vivoDietary royal jelly and pRJ (1% and 5% for 3 months) In vitroSC isolated from aged miceIn vivo21-months old male C57BL/6 mice as a mouse model of sarcopenia In vitroEG1: royal jelly treated SCEG2: pRJ treated SCCG: untreated SCIn vivoEG1 and EG2: aged mice on 1% and 5% royal jelly, respectivelyEG3 and EG4: aged mice on 1% and 5% pRJ, respectivelyCG: untreated aged mice In vitroSC proliferation and differentiation into myotubes and AKT signaling.In vivoNo of SC, skeletal muscle weight, grip strength, regenerative capacity of injured muscle, and serum IGF-1.

T571

90029-90331

Sentence

denotes

In vitropRJ enhanced SC proliferation rate and differentiation into myotubes through activation of AKT signaling.In vivoRoyal jelly and pRJ significantly increased the number of SC, weight of skeletal muscle, grip strength, regenerative capacity of injured skeletal muscle, and IGF-1 serum level. [96]

T572

90332-90474

Sentence

denotes

Intragastric 10-HDA (1.6 mM/kg body weight) In vitroL6 myotubes obtained from Osaka biobankIn vivo7-weeks old male C57BL/6J mice In vitroEG:

T573

90475-90524

Sentence

denotes

10-HDACG1: AICAR (1 mM)CG2: DMSO (0.1%)In vivoEG:

T574

90525-90618

Sentence

denotes

10-HDA (1.6 mM)CG1: gum Arabic (5%) Glucose uptake, AMPK signaling, and Glut4 translocation.

T575

90620-90742

Sentence

denotes

10-HDA increased glucose uptake into L6 myotubes following AMPK activation and Glut4 translocation to the plasma membrane.

T576

90743-90908

Sentence

denotes

AMPK activation was induced by the upstream kinase Ca²/calmodulin-dependent kinase β, independent of changes in AMP:ATP ratio and the liver kinase B1 pathway. [106]

T577

90909-91237

Sentence

denotes

Intragastric royal jelly and pRJ (0.7 and 1.4 mg/kg body weight/d/90 d) D-galactose induced mouse model of aging EG1 and EG2: mice on 0.7 and 1.4 mg RJ, respectivelyEG3 and EG4: mice on 0.7 and 1.4 mg RJ hydrolysate, respectivelyCG: untreated mice Antioxidant enzymes, body weight, muscular performance, memory, and learning.

T578

91239-91444

Sentence

denotes

Both doses of pRJ prevented age-related locomotor decline, preserved body weight, enhanced memory and learning, increased antioxidant enzyme activity, and inhibited the production of lipid peroxides. [95]

T579

91445-91928

Sentence

denotes

Oral 10-HDA (12-60 mg/kg body weight/d/4 months) Obese old rats and stressed mice as models of sarcopenia and depression (male and female Sprague-Dawley and 2-months old male and female BALB/c) EG1 and EG2: aged obese rats on 10-HDA (12 or 24 mg/kg/d for 3.5 months)EG3 and EG4: stressed BALB/c mice on 10-HDA (30 or 60 mg/kg/d for 4 months)CG1 and CG2: untreated aged obese rats and untreated stressed BALB/c mice Body weight, weight of abdominal adipose tissue, and muscle mass.

T580

91930-92082

Sentence

denotes

10-HDA significantly increased weight gain and weight maintenance in aged rats/mice undergoing behavioral stress without any change in diet consumption.

T581

92083-92229

Sentence

denotes

It also significantly decreased adipose tissue in female animals and increased muscle mass in male rodents compared with untreated controls. [54]

T582

92230-92755

Sentence

denotes

Dietary royal jelly and pRJ + MF powder diet (0.05% or 0.5%) 6-months old male HET mouse model of severe sarcopenia (background strains: BALB/c, C57BL/6, C3H, and DBA/2) EG1 and EG2: HET mice on 0.05% and 0.5% royal jelly, respectivelyEG3 and EG4: HET mice on 0.05% and 0.5% pRJ, respectivelyCG1: untreated HET miceCG2: untreated young mice No of blood cells and Pax7 SC, albumin, AST, ALT, T-CHO, TG, expression of muscle genes (MyoD, myogenein, myostatin) and catabolic genes (E3 ubiquitin ligases MuRF1, and atrogin-1).

T583

92756-92834

Sentence

denotes

Behavioral tests: grip strength, wire hang, rotarod, and horizontal bar tests.

T584

92836-93154

Sentence

denotes

RJ and pRJ significantly delayed age-related impairment of motor functions, positively improved physical performance of treated mice in 4 types of tests (grip strength, wire hang, horizontal bar, and rotarod), lowered age-related muscular atrophy, increased No of Pax7 SC markers, and suppressed catabolic genes. [97]

T585

93155-93499

Sentence

denotes

Intragastric royal jelly (100 mg/kg body weight/d/8 weeks) 10-months old male Sprague-Dawley on HFD as a rat model of sarcopenic obesity EG1: aged rats on royal jelly and HFDEG2: aged rats on royal jellyCG1: untreated young ratsCG2: untreated aged ratsCG3: untreated old rats on HFD Serum levels of T-CHO, TG, HDL-c, LDL-c, insulin, HOMA-IR.

T586

93500-93526

Sentence

denotes

Skeletal muscle TG levels.

T587

93527-93568

Sentence

denotes

Serum and adipose tissue levels of TNFR1.

T588

93569-93667

Sentence

denotes

Percentage of weight gain of the body, abdominal fat, and tibialis anterior and hind limb muscles.

T589

93669-93961

Sentence

denotes

Royal jelly significantly decreased insulin levels, HOMA-IR, TNFR1 in serum and adipose tissue, serum lipids, muscle TG levels, body weight gain and abdominal fat weight and significantly increased the weight of hind limb muscle in aged rats on HFD compared with aged mice on HFD only. [100]

T590

93962-94304

Sentence

denotes

Oral royal jelly (1.0 mg/g body weight/d/3 weeks) 6–7 weeks old ICR mice EG: endurance exercise + royal jellyCG1: sedentary rats on royal jellyCG2: endurance exercise+ distilled waterCG3: sedentary rats on distilled water CS, β-HAD, and activities of AMPK and acetyl-CoA carboxylase in the soleus, plantaris, and tibialis anterior muscles.

T591

94306-94627

Sentence

denotes

Royal jelly increased CS and β-HAD maximal activities in the soleus muscle compared with all CGs but failed to affect these enzymes in the plantaris and tibialis anterior muscles of sedentary mice compared with CG2.Royal jelly effects in the soleus muscle were mediated by AMPK and acetyl-CoA carboxylase activity. [106]

T592

94628-94887

Sentence

denotes

Gavage/oral lyophilized royal jelly (50 and 100 mg/kg body weight/d/8 weeks) 18-months old (naturally aging) Wistar male rats as a model of aging EG1 and EG2: aged rats on royal jelly 50 and 100 mg, respectivelyCG: aged rats on gavage solution of 0.9% NaCl.

T593

94889-94958

Sentence

denotes

Learning, spatial memory, and motor performance on Morris water maze.

T594

94960-95117

Sentence

denotes

Royal jelly improved learning, spatial memory, and motor performance e.g., increased the number of crossings, swimming speed, and swimming distance. [98,99]

T595

95118-95198

Sentence

denotes

Oral pRJ (1.2 or 4.8 g/d over 1 year) Institutionalized older adults (mean age:

T596

95199-95567

Sentence

denotes

78.5 ± 7.5 years, N = 199, N males = 99, N females = 95) EG1 and EG2: pRJ (1.2 and 4.8 g/d), respectivelyCG: placebo Handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed. pRJ had no significant effect on handgrip strength, six-minute walk test, timed up and go test, and standing on one leg with eyes closed. [59]

T597

95568-95926

Sentence

denotes

Brazilian propolis extract (100 μg/mL/4-12 h) In vitroDifferentiated myoblast C2C12 cells and RAW264 macrophages isolated from mice EGs: propolis (100 μg/mL)CG1: ethanol (0.008%)CG2: DMSO (0.08%).CG3: IKK inhibitor (BMS-345541) IL-6, LIF, CCL-2, CCL-5, CXCL-10, VEGF-A, COX2, MMP-12, migration of RAW264 macrophages, and activities of MAIL/IκBζ and NF-κB.

T598

95928-96117

Sentence

denotes

Propolis (at 8h) induced RAW264 macrophage migration, activated MAIL/IκBζ and NF-κB proteins p50 and p65, and increased levels of VEGF-A, COX-2, MMP-12, CCL-2, CCL-5, CCL-10, LIF, and IL-6.

T599

96118-96178

Sentence

denotes

Propolis inhibited the production of IL-1β and TNF-α. [108]

T600

96179-96370

Sentence

denotes

CAPE (1 and 10 μM/3 min-12 h) In vitroDifferentiated L6 myoblast cells isolated from rats EGs: CAPE (1, 10 μM)CG1: insulin (100 nM)CG2: AICAR 2-Deoxyglucose uptake, AMPK and AKT signaling.

T601

96372-96492

Sentence

denotes

CAPE (10 μM/1h) increased 2-Deoxyglucose uptake (same as insulin) and activated AMPK (same as AICAR, an AMPK activator).

T602

96493-96560

Sentence

denotes

CAPE (10 μM/3 min) activated AKT in a PI3K-dependent manner. [111]

T603

96561-96973

Sentence

denotes

Boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, auraptene (0.1, 1, 10 μM), and raw Italian propolis (0.001–1 mg/mL) In vitroDifferentiated L6 myoblast cells isolated from rats EGs: boropinic acid, 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, auraptene (0.1, 1, 10 μM), and propolis (0.001–1 mg/mL)CG1: insulin (0.1 μM)CG2: DMSO GLUT4-mediated glucose uptake and GLUT4 translocation.

T604

96975-97138

Sentence

denotes

Propolis (1.0 and 1 mg/mL), 4-geranyloxyferulic acid, 7-isopentenyloxycoumarin, and auraptene significantly increased glucose uptake and GLUT4 translocation. [69]

T605

97139-97707

Sentence

denotes

In vitroA single oral dose of Brazilian propolis extract (250 mg/kg body weight)In vivoArtepillin C, coumaric acid, and kaempferide (1–104 ng/mL for 15 min) In vitroDifferentiated L6 myoblast cells isolated from ratsIn vivo5-weeks old male ICR mice EGs: artepillin C, coumaric acid, and kaempferide (1, 10 μM), and propolis (1–104 ng/mL)CG1: insulin (100 nM)CG2: AICARCG3: DMSO 2-Deoxyglucose uptake, OGTT, maltase and sucrase-isomaltase activities in epithelial cells of the small intestinal, phosphorylation of AMPK, PI3K, AKT, AS160, IR, and GLUT4 translocation.

T606

97709-98102

Sentence

denotes

Polyphenols in propolis activated PI3K and AMPK signaling pathways and promoted GLUT4 translocation in L6 myotubes though only kaempferide increased glucose uptake.Propolis extract (In vitro, 1 μg) and In vivo significantly promoted the phosphorylation of IR, PI3K, and AMPK and increased GLUT4 translocation in rat skeletal muscle and subsequently decreased postprandial blood glucose levels.

T607

98103-98189

Sentence

denotes

Propolis extract had no effect on α-glucosidase activity in the small intestine. [70]

T608

98190-98532

Sentence

denotes

Gavage CAPE (5 and 10 mg/kg/d/5 d) 6-7-weeks old male adult Wistar rats EG: CAPE + eccentric exerciseCG1: normal rats + propylene glycol in salineCG2: acute eccentric treadmill exercise Serum creatine kinase levels, IL-1β, MCP-1, COX-2, iNOS, leukocyte infiltration, and the extent of muscle fiber damage (vacuolization and fragmentation).

T609

98534-98808

Sentence

denotes

CAPE decreased serum creatine kinase, protein nitrotyrosine, PARP activity, MDA, leukocyte infiltration, skeletal muscle cell fragmentation and vacuolization, muscle levels of COX2, iNOS, IL-1β, MCP-1, and p65NF-κB activity to levels in resting CG1 compared with CG2. [101]

T610

98809-99110

Sentence

denotes

Dietary propolis (0.1% over 20 weeks) MGO-induced muscle wasting in male C57BL/6NCr mice (4-weeks old) EG: propolis + MGOCG1: MGO onlyCG2: propolis onlyCG3: untreated mice Weight of EDL and soleus muscles, soleus and EDL levels of AGEs, inflammation-related molecules, and activity of glyoxalase 1.

T611

99112-99362

Sentence

denotes

Propolis had no effect on MGO-induced loss of EDL muscle but tended to increase the weight of the soleus muscle regardless of MGO treatment.Propolis decreased muscular levels of AGEs, IL-1β, IL-6, TLR4 and enhanced the activity of glyoxalase 1. [38]

T612

99363-99674

Sentence

denotes

Dietary crude propolis (0.2% over 2 or 5 weeks) HFD-induced muscle wasting in male C57BL/6 mice (4-weeks old) EG: propolis + HFDCG1: HFD onlyCG2: untreated mice 16S rRNA of gut microbiota, serum levels of LPS, triacylglycerols and glucose, and skeletal muscle levels of inflammatory cytokine TLR4 expression.

T613

99676-99843

Sentence

denotes

Propolis (5 weeks) significantly decreased serum triacylglycerols, glucose, circulating LPS and down-regulated the expression TLR4 and inflammatory cytokine in muscle.

T614

99844-99904

Sentence

denotes

It countereacted the effect of HFD on gut microbiota. [116]

T615

99905-100213

Sentence

denotes

Oral propolis water extract (50 mg/kg body weight/d/6 weeks) 6-weeks old Sprague-Dawley rats EG: propolis + eccentric exerciseCG1: only eccentric exerciseCG2: no treatment Blood levels of glucose and insulin, MDA, SOD, GPX, and CAT in the liver and in the tissue of the liver and the gastrocnemius muscle.

T616

100215-100299

Sentence

denotes

Serum levels of glucose and insulin were significantly lower in EG and CG1 than CG2.

T617

100300-100368

Sentence

denotes

Glycogen level in skeletal muscle was higher in EG and CG1 than CG2.

T618

100369-100433

Sentence

denotes

Skeletal muscle levels of MDA were lower in EG than CG1 and CG2.

T619

100434-100543

Sentence

denotes

Liver levels of SOD as well as gastrocnemius muscle levels of SOD, GPX and CAT were higher in EG only. [109]

T620

100544-100620

Sentence

denotes

Gavage naturally-enriched milk with PUFA and propolis polyphenols (PUFA/P-M:

T621

100621-100782

Sentence

denotes

5 mL/kg body weight /85 d) 21-d old male Wistar rats EG: HFD + PUFA/P-MCG1: HFD + waterCG2: HFD + whole milkCG3: HFD + PUFA milkCG 4: standard chow + waterN.B.

T622

100783-100932

Sentence

denotes

All treatments were repeated in absence of HFD Weight gain, mass of internal organs and the soleus and gastrocnemius muscles, and glucose tolerance.

T623

100934-101110

Sentence

denotes

Among all treatments in obese rats, only PUFA/P-m increased gastrocnemius muscle mass (tended to increase soleus muscle mass) and mesenteric fat and tended to lower LDL levels.

T624

101111-101226

Sentence

denotes

It decreased the size of adipocytes compared with all groups except PUFA milk with no effect on body weight. [105]

T625

101227-101391

Sentence

denotes

Dietary propolis 4% (105 d) Nile tilapia in net cages (males only) EG: propolis rich dietCG: propolis free diet Muscle morphometry and myostatin gene expression.

T626

101393-101495

Sentence

denotes

Propolis diet had no effect on muscle growth or myostatin gene expression at 35, 70, and 105 d. [117]

T627

101496-101748

Sentence

denotes

Dietary propolis (1, 2, 3 and 4 g/kg of feed/45 d) Nile tilapia post-larvae and fingerlings in tanks EG: propolis rich dietCG: propolis free diet Final weight, total and standard body length, survival, body composition, and intestinal villus height.

T628

101750-101866

Sentence

denotes

Propolis supplementation had no effect on weight, total and standard length, survival, and intestinal villus height.

T629

101867-102011

Sentence

denotes

However, 2.6 g propolis/kg of feed significantly improved body protein deposition and body condition factor—an estimate of future growth. [104]

T630

102012-102349

Sentence

denotes

Intraperitoneal CAPE (10 μM/kg 1 h before ischemia reperfusion) Adult male Wistar rats undergoing ischemia reperfusion EG: ischemia reperfusion + CAPECG1: ischemia reperfusionCG2: sham Neutrophil infiltration, serum creatine kinase, serum and gastrocnemius muscle levels of protein carbonyl, xanthine oxidase, and adenosine deaminase.

T631

102351-102541

Sentence

denotes

CAPE reduced neutrophil infiltration and serum creatine kinase as well as protein carbonyl, xanthine oxidase, and adenosine deaminase levels in the blood and gastrocnemius muscle. [102,103]

T632

102542-102982

Sentence

denotes

Gavage propolis (1 g/kg body weight/d/2 weeks) Adult male Wistar rats with 2-week hind limb unloading (HU) EG: HU rats + propolisCG1: normal rats + propolisCG2: normal ratsCG3: untreated HU rats Soleus muscle weight, FCSA, myofiber number, apoptosis of endothelial cells, capillary to muscle fiber ratio, capillary number, luminal diameter, and capillary volume, levels of ROS, SOD-1, anti-angiogenic factors, and pro-angiogenic factors.

T633

102984-103039

Sentence

denotes

Propolis had no effect on soleus muscle weight or FCSA.

T634

103040-103196

Sentence

denotes

However, the relative soleus muscle-to-body weight and the capillary to muscle fiber ratio of the soleus muscle were significantly higher in EG than in CG3.

T635

103197-103472

Sentence

denotes

Propolis decreased the number of apoptotic endothelial cells, improved levels of SOD-1, ROS, and VEGF leading to increased capillary number, luminal diameter, and capillary volume in the EG to the levels of CG1 and CG2, which were all significantly different from CG3. [110]

T636

103473-103792

Sentence

denotes

Gavage propolis (200-mg/kg body weight/d/28 d) Adult female Wistar rats undergoing crush injuries of the sciatic nerve EG: propolisCG1: curcuminCG2: methylprednisoloneCG3: sham ratsCG4: untreated rats with sciatic nerve injury Gastrocnemius muscle mass, motor function, nerve fiber myelination, and nerve conduction.

T637

103794-103983

Sentence

denotes

Propolis and curcumin significantly restored gastrocnemius muscle mass, improved walking, nerve fiber myelination, and motor conduction to the gastrocnemius muscle compared with CG4. [113]

T638

103984-104386

Sentence

denotes

Dietary fresh monofloral bee pollen 5% or 10% (3 weeks) Malnourished old male Wistar rats (22-month-old) EG1 and EG2: refeeding diet + bee pollen 5% and 10%, respectivelyCG1: refeeding dietCG2: no treatmentCG3: untreated normal weight rats Body weight and composition, muscle mass, muscle protein synthesis rate, plasma cytokines, mitochondrial enzyme activity, and mTOR/p70S6kinase/4eBP1 signaling.

T639

104388-104504

Sentence

denotes

Bee pollen restored visceral and subcutaneous adipose tissues and increased plantaris and gastrocnemius muscle mass.

T640

104505-104742

Sentence

denotes

10% pollen restored the levels of cytokines to normal, boosted muscle protein synthesis, and increased complex IV activity while both 5% and 10% increased the activity CS and the phosphorylation of mTOR/p70S6kinase/4eBP1 signaling. [36]

T641

104743-105288

Sentence

denotes

Oral crude and processed monofloral Indian mustard bee pollen (100, 200, and 300 mg/kg body weight/4 weeks) Adult male Wistar rats and Swiss albino mice EG1: neat bee pollen + acute eccentric swimmingEG2: processed bee pollen + acute eccentric swimmingCG1: no treatmentCG2: bee pollen onlyCG3: acute eccentric swimming + vehicle gum acacia Body weight, relative weight of the gastrocnemius muscle, SOD, GSH, MDA, NO, total protein content, lipid peroxidation, myostatin mRNA, β-actin, mitochondrial complex I, II, III, and IV enzyme activity.

T642

105290-105576

Sentence

denotes

Crude (300 mg/kg) and processed (200 and 300 mg/kg) bee pollen prevented myofiber fragmentation and restored body weight and the relative weight of the gastrocnemius muscle as well as mitochondrial complex-I, -II, -III, and -IV enzyme activity to normal (CG1 and CG2) compared with CG3.

T643

105577-105731

Sentence

denotes

Both bee pollen treatments decreased MDA, NO, total protein content, lipid peroxidation, and myostatin and increased SOD and GSH in skeletal muscle. [90]

T644

105732-105736

Sentence

denotes

N.B.

T645

105737-105850

Sentence

denotes

All studies were conducted in vivo unless otherwise indicated. pRJ: protease-treated royal jelly, No: number, SC:

T646

105851-105947

Sentence

denotes

Satellite cells, EG: experimental group, CG: control group, min: minute, d: day, h: hour, IGF-1:

T647

105948-105977

Sentence

denotes

Insulin growth factor 1, AKT:

T648

105978-106051

Sentence

denotes

Serine/threonine protein kinase, AS160: AKT substrate of 160 kDa, BALB/c:

T649

106052-106072

Sentence

denotes

Bagg albino, 10-HDA:

T650

106073-106622

Sentence

denotes

10-Hydroxy-decanoic acid, ROS: reactive oxygen species, HET: genetically heterogeneous mice, AST: aspartate aminotransferase, ALT: alanine aminotransferase, T-CHO: total cholesterol, TLR4: toll-like receptors 4, TG: triglyceride, HFD: high fat diet, LPS: lipopolysaccharide, HDL: high density lipoprotein, LDL: low density lipoprotein, HOMA-IR: homeostatic model assessment of insulin resistance, PUFA: polyunsaturated fatty acids, TNFR1: tumor necrosis factor receptor 1, HU: hind limb unloading, IKK: IκB kinase, DMSO: dimethyle sulfoxoide, AICAR:

T651

106623-107372

Sentence

denotes

5-aminoimidazole-4-carboxamide ribonucleoside, CAPE: caffeic acid phenethyl ester, AGEs: advanced glycation end products, MMP-12: metalloproteinase-12, MyoD: myogenic differentiation 1; VEGF: vascular endothelial growth factor, NF-κB: nuclear factor kappa B, MDA: malondialdehyde, SOD: superoxide dismutase, CAT: catalase, and GPX: glutathione peroxidase, LIF: leukemia inhibitory factor, CXCL-10: chemokine (C-X-C motif) ligand 10, CCL: C-C chemokine ligand, MCP-1: monocyte chemotactic protein-1, COX-2: cyclooxygenase-2, iNOS: inducible nitric oxide synthase, PARP: poly (ADP-ribose) polymerase, AMPK: adenosine monophosphate activated protein kinase, PI3K: phosphatidylinositol 3-kinase, IR: insulin receptor, GLUT4: glucose transporter 4, OGTT:

T652

107373-107858

Sentence

denotes

Oral Glucose Tolerance Test, FCSA: fiber cross-sectional area, mTOR: mammalian target of rapamycin, p70S6kinase: P70 ribosomal proteins S6 kinase, 4eBP1: eukaryotic translation initiation 4E-binding protein 1, SOD: superoxide dismutase, GSH: glutathione, MDA: malonaldehyde, NO: nitric oxide, MGO: methylglyoxal, EDL: extensor digitorum longus, IL-6: interleukin-6, IL-1β: interleukin-1β, TLR4: toll-like receptor 4, CS: citrate synthase, β-HAD: β-hydroxyacyl coenzyme A dehydrogenase.

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