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The active participation of skeletal muscles is a unique characteristic of exertional heat stroke. Nevertheless, the only well-documented link between skeletal muscle activities and exertional heat stroke pathophysiology is the extensive muscle damage (e. g., rhabdomyolysis) and subsequent leakage of intramuscular content into the circulation of exertional heat stroke victims. Here, we will present and discuss rarely explored roles of skeletal muscles in the context of exertional heat stroke pathophysiology and recovery. This includes an overview of heat production that contributes to severe hyperthermia and the synthesis and secretion of bioactive molecules, such as cytokines, chemokines and acute phase proteins. These molecules can alter the overall inflammatory status from pro- to anti-inflammatory, affecting other organ systems and influencing recovery. The activation of innate immunity can determine whether a victim is ready to return to physical activity or experiences a prolonged convalescence. We also provide a brief discussion on whether heat acclimation can shift skeletal muscle secretory phenotype to prevent or aid recovery from exertional heat stroke. We conclude that skeletal muscles should be considered as a key organ system in exertional heat stroke pathophysiology. [ABSTRACT FROM AUTHOR]

We evaluated effects of calorie restriction (CR: consuming 60–65% of ad libitum [AL] intake) initiated late-in-life with or without acute exercise on insulin-stimulated glucose uptake (ISGU) of skeletal muscle by studying four groups of 26-month-old rats: sedentary-AL, sedentary-CR (8-week duration), 3 hours post-exercise (3hPEX)-AL and 3hPEX-CR. ISGU was determined in isolated epitrochlearis muscles incubated ± insulin. Muscles were assessed for signaling proteins (immunoblotting) and lipids (mass spectrometry). ISGU from sedentary-CR and 3hPEX-AL exceeded sedentary-AL; 3hPEX-CR exceeded all other groups. Akt (Ser473, Thr308) and Akt substrate of 160 kDa (AS160; Ser588, Thr642, Ser704) phosphorylation levels tracked with ISGU. Among the 477 lipids detected, 114 were altered by CR (including reductions in 15 of 25 acylcarnitines), and 27 were altered by exercise (including reductions in 18 of 22 lysophosphatidylcholines) with only six lipids overlapping between CR and exercise. ISGU significantly correlated with 23 lipids, including: acylcarnitine 20:1 (r =.683), lysophosphatidylethanolamine19:0 (r = −.662), acylcarnitine 24:0 (r =.611), and plasmenyl-phosphatidylethanolamine 37:5 (r = −.603). Muscle levels of ceramides (a lipid class previously linked to insulin resistance) were not altered by CR and/or exercise nor significantly correlated with ISGU, implicating other mechanisms (which potentially involve other lipids identified in this study) for greater ISGU and Akt and AS160 phosphorylation with these interventions. [ABSTRACT FROM AUTHOR]

Key points: The pathogenic mechanism and the neuromuscular reflex‐related phenotype (e.g. tremors accompanied by clonus) of Amish nemaline myopathy, as well as of other recessively inherited TNNT1 myopathies, remain to be clarified.The truncated slow skeletal muscle isoform of troponin T (ssTnT) encoded by the mutant TNNT1 gene is unable to incorporate into myofilaments and is degraded in muscle cells.By contrast to extrafusal muscle fibres, spindle intrafusal fibres of normal mice contain a significant level of cardiac TnT and a low molecular weight splice form of ssTnT. Intrafusal fibres of ssTnT‐knockout mice have significantly increased cardiac TnT.Rotarod and balance beam tests have revealed abnormal neuromuscular co‐ordination in ssTnT‐knockout mice and a blunted response to a spindle sensitizer, succinylcholine.The loss of ssTnT and a compensatory increase of cardiac TnT in intrafusal nuclear bag fibres may increase myofilament Ca2+‐sensitivity and tension, impairing spindle function, thus identifying a novel mechanism for the development of targeted treatment. A nonsense mutation at codon Glu180 of TNNT1 gene causes Amish nemaline myopathy (ANM), a recessively inherited disease with infantile lethality. TNNT1 encodes the slow skeletal muscle isoform of troponin T (ssTnT). The truncated ssTnT is unable to incorporate into myofilament and is degraded in muscle cells. The symptoms of ANM include muscle weakness, atrophy, contracture and tremors accompanied by clonus. An ssTnT‐knockout (KO) mouse model recapitulates key features of ANM such as atrophy of extrafusal slow muscle fibres and increased fatigability. However, the neuromuscular reflex‐related symptoms of ANM have not been explained. By isolating muscle spindles from ssTnT‐KO and control mice aiming to examine the composition of myofilament proteins, we found that, in contrast to extrafusal fibres, intrafusal fibres contain a significant level of cardiac TnT and the low molecular weight splice form of ssTnT. Intrafusal fibres from ssTnT‐KO mice have significantly increased cardiac TnT. Rotarod and balance beam tests revealed impaired neuromuscular co‐ordination in ssTnT‐KO mice, indicating abnormality in spindle functions. Unlike the wild‐type control, the beam running ability of ssTnT‐KO mice had a blunted response to a spindle sensitizer, succinylcholine. Immunohistochemistry detected ssTnT and cardiac TnT in nuclear bag fibres, whereas fast skeletal muscle TnT was detected in nuclear chain fibres, and cardiac α‐myosin was present in one of the two nuclear bag fibres. The loss of ssTnT and a compensatory increase of cardiac TnT in nuclear bag fibres would increase myofilament Ca2+‐sensitivity and tension, thus affecting spindle activities. This mechanism provides an explanation for the pathophysiology of ANM, as well as a novel target for treatment. Key points: The pathogenic mechanism and the neuromuscular reflex‐related phenotype (e.g. tremors accompanied by clonus) of Amish nemaline myopathy, as well as of other recessively inherited TNNT1 myopathies, remain to be clarified.The truncated slow skeletal muscle isoform of troponin T (ssTnT) encoded by the mutant TNNT1 gene is unable to incorporate into myofilaments and is degraded in muscle cells.By contrast to extrafusal muscle fibres, spindle intrafusal fibres of normal mice contain a significant level of cardiac TnT and a low molecular weight splice form of ssTnT. Intrafusal fibres of ssTnT‐knockout mice have significantly increased cardiac TnT.Rotarod and balance beam tests have revealed abnormal neuromuscular co‐ordination in ssTnT‐knockout mice and a blunted response to a spindle sensitizer, succinylcholine.The loss of ssTnT and a compensatory increase of cardiac TnT in intrafusal nuclear bag fibres may increase myofilament Ca2+‐sensitivity and tension, impairing spindle function, thus identifying a novel mechanism for the development of targeted treatment. [ABSTRACT FROM AUTHOR]

5′ AMP-activated protein kinase (AMPK) activation may be part of the exercise-induced process that enhances insulin sensitivity. Independent of exercise, acute prior treatment of skeletal muscles isolated from young rats with a pharmacological AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), causes subsequently improved insulin-stimulated glucose uptake (GU). However, efficacy of a single prior AICAR exposure on insulin-stimulated GU in muscles from old animals has not been studied. The purpose of this study was to determine whether brief, prior exposure to AICAR (3.5 h before GU assessment) leads to subsequently increased GU in insulin-stimulated skeletal muscles from old rats. Epitrochlearis muscles from 24-month-old male rats were isolated and initially incubated ±AICAR (60 min), followed by incubation without AICAR (3 h), then incubation ±insulin (50 min). Muscles were assessed for GU (via 3-O-methyl-[3H]-glucose accumulation) and site-specific phosphorylation of key proteins involved in enhanced GU, including AMPK, Akt, and Akt substrate of 160 kDa (AS160), via Western blotting. Prior ex vivo AICAR treatment resulted in greater GU by insulin-stimulated muscles from 24-month-old rats. Prior AICAR treatment also resulted in greater phosphorylation of AMPK (T172) and AS160 (S588, T642, and S704). Glucose transporter type 4 (GLUT4) protein abundance was unaffected by prior AICAR and/or insulin treatment. These findings demonstrate that skeletal muscles from older rats are susceptible to enhanced insulin-stimulated GU after brief activation of AMPK by prior AICAR. Consistent with earlier research using muscles from young rodents, increased phosphorylation of AS160 is implicated in this effect, which was not attributable to altered GLUT4 glucose transporter protein abundance. [ABSTRACT FROM AUTHOR]

Background: Decreased cortical excitability has been proposed as a potential mechanism underlying task failure during sustained muscular contractions, and cortical excitability may decrease with old age. We tested the hypothesis that transcranial direct current stimulation, which has been reported to raise cortical excitability, would prolong the time to task failure during a sustained muscular contraction in older adults.Methods: Thirteen older adults (68.3±2.0 years; eight women and five men) performed isometric, elbow flexions to failure while receiving sham or anodal transcranial direct current stimulation. Order of stimulation was randomized, and the subjects and investigators were blinded to condition. Time to task failure was measured alongside selected psychological indices of perceived exertion and affect.Results: Anodal transcranial direct current stimulation prolonged mean time to task failure by approximately 15% (16.9±2.2 vs 14.7±1.8 minutes) and slowed the rate of increase in rating of perceived exertion (0.29±0.03 vs 0.31±0.03) relative to the sham condition.Conclusions: These preliminary findings suggest that anodal transcranial direct current stimulation enhances time to task failure of a sustained, submaximal contraction in older adults by potentially increasing cortical excitability and/or influencing the perception of exertion. These results raise the question of whether interventions that acutely increase cortical excitability could enhance physical function and/or exercise-induced adaptations in older adults. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Testosterone (T) induces motor dysfunction in transgenic (Tg) mice that overexpress wild-type androgen receptor (AR) in skeletal muscles. Because many genes implicated in motor neuron disease are expressed in skeletal muscle, mutant proteins may act in muscle to cause dysfunction in motor neuron disease. Methods We examined contractile properties of the extensor digitorum longus (EDL) and soleus (SOL) muscles in vitro after 5 and 3 days of T treatment in motor-impaired Tg female mice. Results Both muscles showed deficits in tetanic force after 5 days of T treatment, without losses in muscle mass, protein content, or fiber number. After 3 days of T treatment, only SOL showed a deficit in tetanic force comparable to that of 5 days of treatment. In both treatments, EDL showed slowed twitch kinetics, whereas SOL showed deficits in the twitch/tetanus ratio. Conclusions These results suggest calcium-handling mechanisms in muscle fibers are defective in motor-impaired mice. Muscle Nerve 47: 823-834, 2013 [ABSTRACT FROM AUTHOR]