4.9. Improving Muscular Blood Supply
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]. 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]. Microvascular alterations and impaired nitric oxide (NO) production are key causes of decreased blood flow to the skeletal muscle. Poor muscular blood supply induces muscle wasting via a mechanism that entails impaired glucose metabolism and suboptimal protein anabolism [156,157]. In addition, ischemic injury in skeletal muscle is associated with high ROS release from polymorphonuclear leukocytes, which infiltrate muscle tissues. 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]. Therefore, improving vascularization and blood supply to skeletal muscle is a possible mechanism for the prevention of muscle wasting.
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). They detected improvements in all the 3 parameters only in young groups, and those effects were associated with proper insulin activity. Thus, the authors suggested that refeeding effects on muscular blood supply may be hindered by dysfunctions in postprandial circulation and glucose dysregulation [157]. 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]. 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. 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]. 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). 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]. Likewise, bee pollen (both neat and processed) increased blood vessels in the gastrocnemius muscle of rats undergoing muscle injury because of vigorous exercise [90]. Treating C2C12 myoblasts with propolis ethanolic extract increased VEGF production [108]. VEGF is a pro-angiogenic factor that contributes to angiogenesis by recruiting endothelial cells and promoting their differentiation to form new vascular networks. VEGF protects skeletal muscle undergoing unloading against the progression of capillary regression [110]. Its expression in skeletal muscle and associated angiogenic response increase following exercise due to change in the activity of HIF-1α and AMPK. It promotes the generation of ATP following mitochondrial biogenesis in order to meet oxygen demand [158]. Altogether, these reports signify that bee products and endurance exercise share common mechanisms to produce their vitality effects in skeletal muscle.