PMC:4719559 / 20326-25152 JSONTXT

{"project":"TEST0","denotations":[{"id":"26793301-70-76-73104","span":{"begin":649,"end":651},"obj":"[\"11959690\"]"},{"id":"26793301-74-80-73105","span":{"begin":653,"end":655},"obj":"[\"867049\"]"},{"id":"26793301-78-84-73106","span":{"begin":657,"end":659},"obj":"[\"16581971\"]"},{"id":"26793301-94-100-73107","span":{"begin":673,"end":675},"obj":"[\"8390511\"]"},{"id":"26793301-98-104-73108","span":{"begin":677,"end":679},"obj":"[\"9561280\"]"},{"id":"26793301-230-236-73109","span":{"begin":1059,"end":1061},"obj":"[\"2228848\"]"},{"id":"26793301-157-163-73110","span":{"begin":1574,"end":1576},"obj":"[\"2228848\"]"},{"id":"26793301-180-186-73111","span":{"begin":1934,"end":1936},"obj":"[\"4263680\"]"},{"id":"26793301-233-239-73112","span":{"begin":2172,"end":2174},"obj":"[\"16239250\"]"},{"id":"26793301-193-199-73113","span":{"begin":2370,"end":2372},"obj":"[\"11985533\", \"15856066\", \"15528398\"]"},{"id":"26793301-167-173-73114","span":{"begin":2835,"end":2837},"obj":"[\"5039977\"]"},{"id":"26793301-221-227-73115","span":{"begin":2889,"end":2891},"obj":"[\"11986394\"]"},{"id":"26793301-229-235-73116","span":{"begin":2938,"end":2940},"obj":"[\"8227351\"]"},{"id":"26793301-233-239-73117","span":{"begin":2942,"end":2944},"obj":"[\"7896599\"]"},{"id":"26793301-91-97-73118","span":{"begin":3336,"end":3338},"obj":"[\"8227351\"]"},{"id":"26793301-95-101-73119","span":{"begin":3340,"end":3342},"obj":"[\"15364880\"]"},{"id":"26793301-104-110-73120","span":{"begin":3449,"end":3451},"obj":"[\"9561280\"]"},{"id":"26793301-118-124-73121","span":{"begin":3463,"end":3465},"obj":"[\"11299226\"]"},{"id":"26793301-122-128-73122","span":{"begin":3467,"end":3469},"obj":"[\"14577487\"]"},{"id":"26793301-147-153-73123","span":{"begin":3492,"end":3494},"obj":"[\"23950166\"]"},{"id":"26793301-71-77-73124","span":{"begin":3874,"end":3876},"obj":"[\"8390511\"]"},{"id":"26793301-145-151-73125","span":{"begin":3948,"end":3950},"obj":"[\"16099888\"]"},{"id":"26793301-129-135-73126","span":{"begin":4261,"end":4263},"obj":"[\"2228848\"]"}],"text":"Why does caloric restriction severely attenuate responses during static handgrip?\nTo the best of our knowledge, this is the first experiment to examine the effects of reduced caloric intake on autonomic control during isometric handgrip exercise and the cold pressor test. Our findings, though mediated by different mechanisms, are synchronous with a previous report [17] that caloric restriction reduces reflex control of the circulation during orthostatic stress. Overall, the reduced HR and BP responses are consistent with physiological adaptation to reduced caloric intake. For example, reduced caloric or fat intake lowered HR and BP in rats [15, 16, 26] and humans [24, 27]. From this investigation, it is not apparently clear why the response is drastically reduced following caloric restriction. During static exercise, activation of central command and the mechanoreflex predominantly control the increase in HR, whereas BP is regulated by mechano- and metaboreflexes together with central command, and MSNA is mainly regulated by the metaboreflex [11]. Alterations can occur at a number of points along the muscle mechano- and metaboreflex arcs (e.g., afferent response, central integration, efferent signal) and central command in addition to changes in stimuli and end-organ responses. From our results, it seems most likely that central command and/or the mechanoreflex are attenuated.\n\nCentral command\nImmediately at the onset of exercise, central command modulates the level of sympathetic and parasympathetic efferent activity to the vasculature and heart [11]. The magnitude of control is largely influenced by the individual’s perceived effort during actual or attempted exercise, independent of absolute workload or force production. For example, increasing or decreasing central command at a given muscle tension during static exercise results in a corresponding increase or decrease in cardiovascular responses [28]. Although the exact location of integration of these signals is unknown, it appears to include regions of the insular and anterior cingulate cortexes that interact with thalamic and brainstem structures of cardiovascular integration [29]. Nutrient signaling within the hypothalamus and dorsal vagal complex that controls appetite and sympathetic outflow may modulate the influence of central command through shared neural pathways [30–32]. The blunted neural and cardiovascular responses during handgrip in this study are consistent with, but do not prove, a reduction in central command output. More mechanistic studies are needed to determine whether and how caloric restriction modulates central command.\n\nMuscle mechanoreflex\nThe mechanoreflex, which mainly consists of group III and some group IV mechanosensitive afferents that respond to stimuli such as stretch, contraction, and pressure [33], increases HR primarily through vagal inhibition [34] and may also augment sympathetic activation [35, 36]. That the HR and MSNA responses during static handgrip exercise were reduced whereas MSNA continued to increase comparable to the normocaloric intervention during muscle ischemia collectively suggest that the mechanoreflex may be impaired.\nSeveral possibilities may account for the impaired reflex. First, the sensitivity of muscle afferents is directly proportional to interstitial fluid [35, 37]. Therefore, a reduction in plasma volume and interstitial fluid that may occur with caloric restriction [27], bedrest [38, 39], or water immersion [40], may desensitize the mechanoreceptors. However, this seems unlikely since the cardiovascular responses to handgrip following the normocaloric bedrest intervention were similar to control. Second, caloric restriction may modulate central integration of the mechanoreflex, similar to that of central command. Third, reduced caloric/fat intake may decrease adrenergic sensitivity [24] while increasing endothelium-dependent and –independent vasodilation [41]. This may be consistent with the attenuated BP response; however, it would not explain the diminished sympathetic outflow compared to normocaloric conditions.\n\nMuscle metaboreflex\nStimulation of the metaboreceptors situated in the interstitial space of muscle elicits increases in MSNA and arterial pressure [11]. The metaboreflex (as well as mechanoreflex and central command) is activated during static handgrip due to buildup of metabolites from mechanical occlusion of blood vessels by the contracting muscle; however, the reflex can be isolated during post-exercise circulatory arrest when mechanical stimulation and central command influences are absent. Since the neural and hemodynamic responses during muscle occlusion were similar following all four interventions, caloric modulation of the metaboreflex is unlikely to contribute to the reduced exercise responses."}

{"project":"MyTest","denotations":[{"id":"26793301-11959690-30256723","span":{"begin":649,"end":651},"obj":"11959690"},{"id":"26793301-867049-30256724","span":{"begin":653,"end":655},"obj":"867049"},{"id":"26793301-16581971-30256725","span":{"begin":657,"end":659},"obj":"16581971"},{"id":"26793301-8390511-30256726","span":{"begin":673,"end":675},"obj":"8390511"},{"id":"26793301-9561280-30256727","span":{"begin":677,"end":679},"obj":"9561280"},{"id":"26793301-2228848-30256728","span":{"begin":1059,"end":1061},"obj":"2228848"},{"id":"26793301-2228848-30256729","span":{"begin":1574,"end":1576},"obj":"2228848"},{"id":"26793301-4263680-30256730","span":{"begin":1934,"end":1936},"obj":"4263680"},{"id":"26793301-16239250-30256731","span":{"begin":2172,"end":2174},"obj":"16239250"},{"id":"26793301-11985533-30256732","span":{"begin":2370,"end":2372},"obj":"11985533"},{"id":"26793301-15856066-30256732","span":{"begin":2370,"end":2372},"obj":"15856066"},{"id":"26793301-15528398-30256732","span":{"begin":2370,"end":2372},"obj":"15528398"},{"id":"26793301-5039977-30256733","span":{"begin":2835,"end":2837},"obj":"5039977"},{"id":"26793301-11986394-30256734","span":{"begin":2889,"end":2891},"obj":"11986394"},{"id":"26793301-8227351-30256735","span":{"begin":2938,"end":2940},"obj":"8227351"},{"id":"26793301-7896599-30256736","span":{"begin":2942,"end":2944},"obj":"7896599"},{"id":"26793301-8227351-30256737","span":{"begin":3336,"end":3338},"obj":"8227351"},{"id":"26793301-15364880-30256738","span":{"begin":3340,"end":3342},"obj":"15364880"},{"id":"26793301-9561280-30256739","span":{"begin":3449,"end":3451},"obj":"9561280"},{"id":"26793301-11299226-30256740","span":{"begin":3463,"end":3465},"obj":"11299226"},{"id":"26793301-14577487-30256741","span":{"begin":3467,"end":3469},"obj":"14577487"},{"id":"26793301-23950166-30256742","span":{"begin":3492,"end":3494},"obj":"23950166"},{"id":"26793301-8390511-30256743","span":{"begin":3874,"end":3876},"obj":"8390511"},{"id":"26793301-16099888-30256744","span":{"begin":3948,"end":3950},"obj":"16099888"},{"id":"26793301-2228848-30256745","span":{"begin":4261,"end":4263},"obj":"2228848"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Why does caloric restriction severely attenuate responses during static handgrip?\nTo the best of our knowledge, this is the first experiment to examine the effects of reduced caloric intake on autonomic control during isometric handgrip exercise and the cold pressor test. Our findings, though mediated by different mechanisms, are synchronous with a previous report [17] that caloric restriction reduces reflex control of the circulation during orthostatic stress. Overall, the reduced HR and BP responses are consistent with physiological adaptation to reduced caloric intake. For example, reduced caloric or fat intake lowered HR and BP in rats [15, 16, 26] and humans [24, 27]. From this investigation, it is not apparently clear why the response is drastically reduced following caloric restriction. During static exercise, activation of central command and the mechanoreflex predominantly control the increase in HR, whereas BP is regulated by mechano- and metaboreflexes together with central command, and MSNA is mainly regulated by the metaboreflex [11]. Alterations can occur at a number of points along the muscle mechano- and metaboreflex arcs (e.g., afferent response, central integration, efferent signal) and central command in addition to changes in stimuli and end-organ responses. From our results, it seems most likely that central command and/or the mechanoreflex are attenuated.\n\nCentral command\nImmediately at the onset of exercise, central command modulates the level of sympathetic and parasympathetic efferent activity to the vasculature and heart [11]. The magnitude of control is largely influenced by the individual’s perceived effort during actual or attempted exercise, independent of absolute workload or force production. For example, increasing or decreasing central command at a given muscle tension during static exercise results in a corresponding increase or decrease in cardiovascular responses [28]. Although the exact location of integration of these signals is unknown, it appears to include regions of the insular and anterior cingulate cortexes that interact with thalamic and brainstem structures of cardiovascular integration [29]. Nutrient signaling within the hypothalamus and dorsal vagal complex that controls appetite and sympathetic outflow may modulate the influence of central command through shared neural pathways [30–32]. The blunted neural and cardiovascular responses during handgrip in this study are consistent with, but do not prove, a reduction in central command output. More mechanistic studies are needed to determine whether and how caloric restriction modulates central command.\n\nMuscle mechanoreflex\nThe mechanoreflex, which mainly consists of group III and some group IV mechanosensitive afferents that respond to stimuli such as stretch, contraction, and pressure [33], increases HR primarily through vagal inhibition [34] and may also augment sympathetic activation [35, 36]. That the HR and MSNA responses during static handgrip exercise were reduced whereas MSNA continued to increase comparable to the normocaloric intervention during muscle ischemia collectively suggest that the mechanoreflex may be impaired.\nSeveral possibilities may account for the impaired reflex. First, the sensitivity of muscle afferents is directly proportional to interstitial fluid [35, 37]. Therefore, a reduction in plasma volume and interstitial fluid that may occur with caloric restriction [27], bedrest [38, 39], or water immersion [40], may desensitize the mechanoreceptors. However, this seems unlikely since the cardiovascular responses to handgrip following the normocaloric bedrest intervention were similar to control. Second, caloric restriction may modulate central integration of the mechanoreflex, similar to that of central command. Third, reduced caloric/fat intake may decrease adrenergic sensitivity [24] while increasing endothelium-dependent and –independent vasodilation [41]. This may be consistent with the attenuated BP response; however, it would not explain the diminished sympathetic outflow compared to normocaloric conditions.\n\nMuscle metaboreflex\nStimulation of the metaboreceptors situated in the interstitial space of muscle elicits increases in MSNA and arterial pressure [11]. The metaboreflex (as well as mechanoreflex and central command) is activated during static handgrip due to buildup of metabolites from mechanical occlusion of blood vessels by the contracting muscle; however, the reflex can be isolated during post-exercise circulatory arrest when mechanical stimulation and central command influences are absent. Since the neural and hemodynamic responses during muscle occlusion were similar following all four interventions, caloric modulation of the metaboreflex is unlikely to contribute to the reduced exercise responses."}

{"project":"0_colil","denotations":[{"id":"26793301-11959690-73104","span":{"begin":649,"end":651},"obj":"11959690"},{"id":"26793301-867049-73105","span":{"begin":653,"end":655},"obj":"867049"},{"id":"26793301-16581971-73106","span":{"begin":657,"end":659},"obj":"16581971"},{"id":"26793301-8390511-73107","span":{"begin":673,"end":675},"obj":"8390511"},{"id":"26793301-9561280-73108","span":{"begin":677,"end":679},"obj":"9561280"},{"id":"26793301-2228848-73109","span":{"begin":1059,"end":1061},"obj":"2228848"},{"id":"26793301-2228848-73110","span":{"begin":1574,"end":1576},"obj":"2228848"},{"id":"26793301-4263680-73111","span":{"begin":1934,"end":1936},"obj":"4263680"},{"id":"26793301-16239250-73112","span":{"begin":2172,"end":2174},"obj":"16239250"},{"id":"26793301-5039977-73114","span":{"begin":2835,"end":2837},"obj":"5039977"},{"id":"26793301-11986394-73115","span":{"begin":2889,"end":2891},"obj":"11986394"},{"id":"26793301-8227351-73116","span":{"begin":2938,"end":2940},"obj":"8227351"},{"id":"26793301-7896599-73117","span":{"begin":2942,"end":2944},"obj":"7896599"},{"id":"26793301-8227351-73118","span":{"begin":3336,"end":3338},"obj":"8227351"},{"id":"26793301-15364880-73119","span":{"begin":3340,"end":3342},"obj":"15364880"},{"id":"26793301-9561280-73120","span":{"begin":3449,"end":3451},"obj":"9561280"},{"id":"26793301-11299226-73121","span":{"begin":3463,"end":3465},"obj":"11299226"},{"id":"26793301-14577487-73122","span":{"begin":3467,"end":3469},"obj":"14577487"},{"id":"26793301-23950166-73123","span":{"begin":3492,"end":3494},"obj":"23950166"},{"id":"26793301-8390511-73124","span":{"begin":3874,"end":3876},"obj":"8390511"},{"id":"26793301-16099888-73125","span":{"begin":3948,"end":3950},"obj":"16099888"},{"id":"26793301-2228848-73126","span":{"begin":4261,"end":4263},"obj":"2228848"},{"id":"26793301-11985533-73113","span":{"begin":2370,"end":2372},"obj":"11985533"},{"id":"26793301-15528398-73113","span":{"begin":2370,"end":2372},"obj":"15528398"},{"id":"26793301-15856066-73113","span":{"begin":2370,"end":2372},"obj":"15856066"}],"text":"Why does caloric restriction severely attenuate responses during static handgrip?\nTo the best of our knowledge, this is the first experiment to examine the effects of reduced caloric intake on autonomic control during isometric handgrip exercise and the cold pressor test. Our findings, though mediated by different mechanisms, are synchronous with a previous report [17] that caloric restriction reduces reflex control of the circulation during orthostatic stress. Overall, the reduced HR and BP responses are consistent with physiological adaptation to reduced caloric intake. For example, reduced caloric or fat intake lowered HR and BP in rats [15, 16, 26] and humans [24, 27]. From this investigation, it is not apparently clear why the response is drastically reduced following caloric restriction. During static exercise, activation of central command and the mechanoreflex predominantly control the increase in HR, whereas BP is regulated by mechano- and metaboreflexes together with central command, and MSNA is mainly regulated by the metaboreflex [11]. Alterations can occur at a number of points along the muscle mechano- and metaboreflex arcs (e.g., afferent response, central integration, efferent signal) and central command in addition to changes in stimuli and end-organ responses. From our results, it seems most likely that central command and/or the mechanoreflex are attenuated.\n\nCentral command\nImmediately at the onset of exercise, central command modulates the level of sympathetic and parasympathetic efferent activity to the vasculature and heart [11]. The magnitude of control is largely influenced by the individual’s perceived effort during actual or attempted exercise, independent of absolute workload or force production. For example, increasing or decreasing central command at a given muscle tension during static exercise results in a corresponding increase or decrease in cardiovascular responses [28]. Although the exact location of integration of these signals is unknown, it appears to include regions of the insular and anterior cingulate cortexes that interact with thalamic and brainstem structures of cardiovascular integration [29]. Nutrient signaling within the hypothalamus and dorsal vagal complex that controls appetite and sympathetic outflow may modulate the influence of central command through shared neural pathways [30–32]. The blunted neural and cardiovascular responses during handgrip in this study are consistent with, but do not prove, a reduction in central command output. More mechanistic studies are needed to determine whether and how caloric restriction modulates central command.\n\nMuscle mechanoreflex\nThe mechanoreflex, which mainly consists of group III and some group IV mechanosensitive afferents that respond to stimuli such as stretch, contraction, and pressure [33], increases HR primarily through vagal inhibition [34] and may also augment sympathetic activation [35, 36]. That the HR and MSNA responses during static handgrip exercise were reduced whereas MSNA continued to increase comparable to the normocaloric intervention during muscle ischemia collectively suggest that the mechanoreflex may be impaired.\nSeveral possibilities may account for the impaired reflex. First, the sensitivity of muscle afferents is directly proportional to interstitial fluid [35, 37]. Therefore, a reduction in plasma volume and interstitial fluid that may occur with caloric restriction [27], bedrest [38, 39], or water immersion [40], may desensitize the mechanoreceptors. However, this seems unlikely since the cardiovascular responses to handgrip following the normocaloric bedrest intervention were similar to control. Second, caloric restriction may modulate central integration of the mechanoreflex, similar to that of central command. Third, reduced caloric/fat intake may decrease adrenergic sensitivity [24] while increasing endothelium-dependent and –independent vasodilation [41]. This may be consistent with the attenuated BP response; however, it would not explain the diminished sympathetic outflow compared to normocaloric conditions.\n\nMuscle metaboreflex\nStimulation of the metaboreceptors situated in the interstitial space of muscle elicits increases in MSNA and arterial pressure [11]. The metaboreflex (as well as mechanoreflex and central command) is activated during static handgrip due to buildup of metabolites from mechanical occlusion of blood vessels by the contracting muscle; however, the reflex can be isolated during post-exercise circulatory arrest when mechanical stimulation and central command influences are absent. Since the neural and hemodynamic responses during muscle occlusion were similar following all four interventions, caloric modulation of the metaboreflex is unlikely to contribute to the reduced exercise responses."}

{"project":"2_test","denotations":[{"id":"26793301-11959690-30256723","span":{"begin":649,"end":651},"obj":"11959690"},{"id":"26793301-867049-30256724","span":{"begin":653,"end":655},"obj":"867049"},{"id":"26793301-16581971-30256725","span":{"begin":657,"end":659},"obj":"16581971"},{"id":"26793301-8390511-30256726","span":{"begin":673,"end":675},"obj":"8390511"},{"id":"26793301-9561280-30256727","span":{"begin":677,"end":679},"obj":"9561280"},{"id":"26793301-2228848-30256728","span":{"begin":1059,"end":1061},"obj":"2228848"},{"id":"26793301-2228848-30256729","span":{"begin":1574,"end":1576},"obj":"2228848"},{"id":"26793301-4263680-30256730","span":{"begin":1934,"end":1936},"obj":"4263680"},{"id":"26793301-16239250-30256731","span":{"begin":2172,"end":2174},"obj":"16239250"},{"id":"26793301-11985533-30256732","span":{"begin":2370,"end":2372},"obj":"11985533"},{"id":"26793301-15856066-30256732","span":{"begin":2370,"end":2372},"obj":"15856066"},{"id":"26793301-15528398-30256732","span":{"begin":2370,"end":2372},"obj":"15528398"},{"id":"26793301-5039977-30256733","span":{"begin":2835,"end":2837},"obj":"5039977"},{"id":"26793301-11986394-30256734","span":{"begin":2889,"end":2891},"obj":"11986394"},{"id":"26793301-8227351-30256735","span":{"begin":2938,"end":2940},"obj":"8227351"},{"id":"26793301-7896599-30256736","span":{"begin":2942,"end":2944},"obj":"7896599"},{"id":"26793301-8227351-30256737","span":{"begin":3336,"end":3338},"obj":"8227351"},{"id":"26793301-15364880-30256738","span":{"begin":3340,"end":3342},"obj":"15364880"},{"id":"26793301-9561280-30256739","span":{"begin":3449,"end":3451},"obj":"9561280"},{"id":"26793301-11299226-30256740","span":{"begin":3463,"end":3465},"obj":"11299226"},{"id":"26793301-14577487-30256741","span":{"begin":3467,"end":3469},"obj":"14577487"},{"id":"26793301-23950166-30256742","span":{"begin":3492,"end":3494},"obj":"23950166"},{"id":"26793301-8390511-30256743","span":{"begin":3874,"end":3876},"obj":"8390511"},{"id":"26793301-16099888-30256744","span":{"begin":3948,"end":3950},"obj":"16099888"},{"id":"26793301-2228848-30256745","span":{"begin":4261,"end":4263},"obj":"2228848"}],"text":"Why does caloric restriction severely attenuate responses during static handgrip?\nTo the best of our knowledge, this is the first experiment to examine the effects of reduced caloric intake on autonomic control during isometric handgrip exercise and the cold pressor test. Our findings, though mediated by different mechanisms, are synchronous with a previous report [17] that caloric restriction reduces reflex control of the circulation during orthostatic stress. Overall, the reduced HR and BP responses are consistent with physiological adaptation to reduced caloric intake. For example, reduced caloric or fat intake lowered HR and BP in rats [15, 16, 26] and humans [24, 27]. From this investigation, it is not apparently clear why the response is drastically reduced following caloric restriction. During static exercise, activation of central command and the mechanoreflex predominantly control the increase in HR, whereas BP is regulated by mechano- and metaboreflexes together with central command, and MSNA is mainly regulated by the metaboreflex [11]. Alterations can occur at a number of points along the muscle mechano- and metaboreflex arcs (e.g., afferent response, central integration, efferent signal) and central command in addition to changes in stimuli and end-organ responses. From our results, it seems most likely that central command and/or the mechanoreflex are attenuated.\n\nCentral command\nImmediately at the onset of exercise, central command modulates the level of sympathetic and parasympathetic efferent activity to the vasculature and heart [11]. The magnitude of control is largely influenced by the individual’s perceived effort during actual or attempted exercise, independent of absolute workload or force production. For example, increasing or decreasing central command at a given muscle tension during static exercise results in a corresponding increase or decrease in cardiovascular responses [28]. Although the exact location of integration of these signals is unknown, it appears to include regions of the insular and anterior cingulate cortexes that interact with thalamic and brainstem structures of cardiovascular integration [29]. Nutrient signaling within the hypothalamus and dorsal vagal complex that controls appetite and sympathetic outflow may modulate the influence of central command through shared neural pathways [30–32]. The blunted neural and cardiovascular responses during handgrip in this study are consistent with, but do not prove, a reduction in central command output. More mechanistic studies are needed to determine whether and how caloric restriction modulates central command.\n\nMuscle mechanoreflex\nThe mechanoreflex, which mainly consists of group III and some group IV mechanosensitive afferents that respond to stimuli such as stretch, contraction, and pressure [33], increases HR primarily through vagal inhibition [34] and may also augment sympathetic activation [35, 36]. That the HR and MSNA responses during static handgrip exercise were reduced whereas MSNA continued to increase comparable to the normocaloric intervention during muscle ischemia collectively suggest that the mechanoreflex may be impaired.\nSeveral possibilities may account for the impaired reflex. First, the sensitivity of muscle afferents is directly proportional to interstitial fluid [35, 37]. Therefore, a reduction in plasma volume and interstitial fluid that may occur with caloric restriction [27], bedrest [38, 39], or water immersion [40], may desensitize the mechanoreceptors. However, this seems unlikely since the cardiovascular responses to handgrip following the normocaloric bedrest intervention were similar to control. Second, caloric restriction may modulate central integration of the mechanoreflex, similar to that of central command. Third, reduced caloric/fat intake may decrease adrenergic sensitivity [24] while increasing endothelium-dependent and –independent vasodilation [41]. This may be consistent with the attenuated BP response; however, it would not explain the diminished sympathetic outflow compared to normocaloric conditions.\n\nMuscle metaboreflex\nStimulation of the metaboreceptors situated in the interstitial space of muscle elicits increases in MSNA and arterial pressure [11]. The metaboreflex (as well as mechanoreflex and central command) is activated during static handgrip due to buildup of metabolites from mechanical occlusion of blood vessels by the contracting muscle; however, the reflex can be isolated during post-exercise circulatory arrest when mechanical stimulation and central command influences are absent. Since the neural and hemodynamic responses during muscle occlusion were similar following all four interventions, caloric modulation of the metaboreflex is unlikely to contribute to the reduced exercise responses."}