Skeletal Muscle Fatigue Resistance Research Articles

Novel peptides from sea cucumber intestines hydrolyzed by neutral protease alleviate exercise-induced fatigue via upregulating the glutaminemediated Ca2+ /Calcineurin signaling pathway in mice.

Sea cucumber intestines are considered a valuable resource in the sea cucumber processing industry due to their balanced amino acid composition. Studies have reported that peptides rich in glutamate and branched-chain amino acids have anti-fatigue properties. However, the function of the sea cucumber intestine in reducing exercise-induced fatigue remains unclear. In this study, we enzymatically hydrolyzed low molecular weight peptides from sea cucumber intestines (SCIP) and administered SCIP orally to mice to examine its effects on exercise-induced fatigue using swimming and pole-climbing exhaustion experiments. The results revealed that supplementation with SCIP significantly prolonged the exhaustion time of swimming in mice, decreased blood lactate and urea nitrogen levels, and increased liver and muscle glycogen levels following a weight-loaded swimming test. Immunofluorescence analysis indicated a notable increase the proportion of slow-twitch muscle fiber and a significant decrease the proportion of fast-twitch muscle fiber following SCIP supplementation. Furthermore, SCIP upregulated mRNA expression levels of Ca2+ /Calcineurin upstream and downstream regulators, thereby contributing to the promotion of skeletal muscle fiber type conversion. This study presents the initial evidence establishing SCIP as a potential enhancer of skeletal muscle fatigue resistance, consequently providing a theoretical foundation for the valuable utilization of sea cucumber intestines.

An electrical stimulation intervention protocol to prevent disuse atrophy and muscle strength decline: an experimental study in rat

BackgroundSkeletal muscle is negatively impacted by conditions such as spaceflight or prolonged bed rest, resulting in a dramatic decline in muscle mass, maximum contractile force, and muscular endurance. Electrical stimulation (ES) is an essential tool in neurophysiotherapy and an effective means of preventing skeletal muscle atrophy and dysfunction. Historically, ES treatment protocols have used either low or high frequency electrical stimulation (LFES/HFES). However, our study tests the use of a combination of different frequencies in a single electrical stimulation intervention in order to determine a more effective protocol for improving both skeletal muscle strength and endurance.MethodsAn adult male SD rat model of muscle atrophy was established through 4 weeks of tail suspension (TS). To investigate the effects of different frequency combinations, the experimental animals were treated with low (20 Hz) or high (100 Hz) frequency before TS for 6 weeks, and during TS for 4weeks. The maximum contraction force and fatigue resistance of skeletal muscle were then assessed before the animals were sacrificed. The muscle mass, fiber cross-sectional area (CSA), fiber type and related protein expression were examined and analyzed to gain insights into the mechanisms by which the ES intervention protocol used in this study regulates muscle strength and endurance.ResultsAfter 4 weeks of unloading, the soleus muscle mass and fiber CSA decreased by 39% and 58% respectively, while the number of glycolytic muscle fibers increased by 21%. The gastrocnemius muscle fibers showed a 51% decrease in CSA, with a 44% decrease in single contractility and a 39% decrease in fatigue resistance. The number of glycolytic muscle fibers in the gastrocnemius also increased by 29%. However, the application of HFES either prior to or during unloading showed an improvement in muscle mass, fiber CSA, and oxidative muscle fibers. In the pre-unloading group, the soleus muscle mass increased by 62%, while the number of oxidative muscle fibers increased by 18%. In the during unloading group, the soleus muscle mass increased by 29% and the number of oxidative muscle fibers increased by 15%. In the gastrocnemius, the pre-unloading group showed a 38% increase in single contractile force and a 19% increase in fatigue resistance, while in the during unloading group, a 21% increase in single contractile force and a 29% increase in fatigue resistance was observed, along with a 37% and 26% increase in the number of oxidative muscle fibers, respectively. The combination of HFES before unloading and LFES during unloading resulted in a significant elevation of the soleus mass by 49% and CSA by 90%, with a 40% increase in the number of oxidative muscle fibers in the gastrocnemius. This combination also resulted in a 66% increase in single contractility and a 38% increase in fatigue resistance.ConclusionOur results indicated that using HFES before unloading can reduce the harmful effects of muscle unloading on the soleus and gastrocnemius muscles. Furthermore, we found that combining HFES before unloading with LFES during unloading was more effective in preventing muscle atrophy in the soleus and preserving the contractile function of the gastrocnemius muscle.

High-intensity interval training in the form of isometric contraction improves fatigue resistance in dystrophin-deficient muscle.

Duchenne muscular dystrophy is a genetic muscle-wasting disorder characterized by progressive muscle weakness and easy fatigability. Here we examined whether high-intensity interval training (HIIT) in the form of isometric contraction improves fatigue resistance in skeletal muscle from dystrophin-deficient mdx52mice. Isometric HIIT was performed on plantar flexor muscles in vivo with supramaximal electrical stimulation every other day for 4weeks (a total of 15sessions). In the non-trained contralateral gastrocnemius muscle from mdx52 mice, the decreased fatigue resistance was associated with a reduction in the amount of peroxisome proliferator-activated receptor γ coactivator 1-α, citrate synthase activity, mitochondrial respiratory complex II, LC3B-II/I ratio, and mitophagy-related gene expression (i.e. Pink1, parkin, Bnip3 and Bcl2l13) as well as an increase in the phosphorylation levels of Src Tyr416 and Akt Ser473, the amount of p62, and the percentage of Evans Blue dye-positive area. Isometric HIIT restored all these alterations and markedly improved fatigue resistance in mdx52muscles. Moreover, an acute bout of HIIT increased the phosphorylation levels of AMP-activated protein kinase (AMPK) Thr172, acetyl CoA carboxylase Ser79, unc-51-like autophagy activating kinase 1 (Ulk1) Ser555, and dynamin-related protein 1 (Drp1) Ser616 in mdx52muscles. Thus, our data show that HIIT with isometric contractions significantly mitigates histological signs of pathology and improves fatigue resistance in dystrophin-deficient muscles. These beneficial effects can be explained by the restoration of mitochondrial function via AMPK-dependent induction of the mitophagy programme and de novo mitochondrial biogenesis. KEY POINTS: Skeletal muscle fatigue is often associated with Duchenne muscular dystrophy (DMD) and leads to an inability to perform daily tasks, profoundly decreasing quality of life. We examined the effect of high-intensity interval training (HIIT) in the form of isometric contraction on fatigue resistance in skeletal muscle from the mdx52mouse model of DMD. Isometric HIIT counteracted the reduced fatigue resistance as well as dystrophic changes in skeletal muscle of mdx52mice. This beneficial effect could be explained by the restoration of mitochondrial function via AMP-activated protein kinase-dependent mitochondrial biogenesis and the induction of the mitophagy programme in the dystrophic muscles.

Skeletal muscle adaptation to indirect electrical stimulation: divergence between microvascular and metabolic adaptations.

What is the central question of this study? Can we manipulate muscle recruitment to differentially enhance skeletal muscle fatigue resistance? What is the main finding and its importance? Through manipulation of muscle activation patterns, it is possible to promote distinct microvascular growth. Enhancement of fatigue resistance is closely associated with the distribution of the capillaries within the muscle, not necessarily with quantity. Additionally, at the acute stages of remodelling in response to indirect electrical stimulation, the improvement in fatigue resistance appears to be primarily driven by vascular remodelling, with metabolic adaptation of secondary importance. Exercise involves a complex interaction of factors influencing muscle performance, where variations in recruitment pattern (e.g., endurance vs. resistance training) may differentially modulate the local tissue environment (i.e., oxygenation, blood flow, fuel utilization). These exercise stimuli are potent drivers of vascular and metabolic change. However, their relative contribution to adaptive remodelling of skeletal muscle and subsequent performance is unclear. Using implantable devices, indirect electrical stimulation (ES) of locomotor muscles of rat at different pacing frequencies (4, 10 and 40Hz) was used to differentially recruit hindlimb blood flow and modulate fuel utilization. After 7days, ES promoted significant remodelling of microvascular composition, increasing capillary density in the cortex of the tibialis anterior by 73%, 110% and 55% for the 4Hz, 10 and 40Hz groups, respectively. Additionally, there was remodelling of the whole muscle metabolome, including significantly elevated amino acid turnover, with muscle kynurenic acid levels doubled by pacing at 10Hz (P<0.05). Interestingly, the fatigue index of skeletal muscle was only significantly elevated in 10Hz (58% increase) and 40Hz (73% increase) ES groups, apparently linked to improved capillary distribution. These data demonstrate that manipulation of muscle recruitment pattern may be used to differentially expand the capillary network prior to altering the metabolome, emphasising the importance of local capillary supply in promoting exercise tolerance.

Improved skeletal muscle fatigue resistance in experimental autoimmune myositis mice following high-intensity interval training

BackgroundMuscle weakness and decreased fatigue resistance are key manifestations of systemic autoimmune myopathies (SAMs). We here examined whether high-intensity interval training (HIIT) improves fatigue resistance in the skeletal muscle of experimental autoimmune myositis (EAM) mice, a widely used animal model for SAM.MethodsFemale BALB/c mice were randomly assigned to control (CNT) or EAM groups (n = 28 in each group). EAM was induced by immunization with three injections of myosin emulsified in complete Freund’s adjuvant. The plantar flexor (PF) muscles of mice with EAM were exposed to either an acute bout or 4 weeks of HIIT (a total of 14 sessions).ResultsThe fatigue resistance of PF muscles was lower in the EAM than in the CNT group (P < 0.05). These changes were associated with decreased activities of citrate synthase and cytochrome c oxidase and increased expression levels of the endoplasmic reticulum stress proteins (glucose-regulated protein 78 and 94, and PKR-like ER kinase) (P < 0.05). HIIT restored all these alterations and increased the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the mitochondrial electron transport chain complexes (I, III, and IV) in the muscles of EAM mice (P < 0.05).ConclusionsHIIT improves fatigue resistance in a SAM mouse model, and this can be explained by the restoration of mitochondria oxidative capacity via inhibition of the ER stress pathway and PGC-1α-mediated mitochondrial biogenesis.

Isometric training improves fatigue resistance in dystrophin-deficient muscle

Eccentric contractions, in which the muscle is stretched during contraction, cause substantially greater damage than isometric (ISO) contractions, in which the length of the muscle does not change during contraction. Here, we tested the hypothesis that ISO training improves fatigue resistance in skeletal muscle from dystrophin-deficient mdx52 mice (15-22 wk old). ISO training (100 Hz stimulation frequency, 0.25-s contractions every 0.5 s, 6 sets of 60 contractions) was performed on the left plantar flexor muscles in vivo with supramaximal electrical stimulation every other day for 4 wk. Compared with the normal control muscle, resistance to fatigue was reduced in the nontrained muscle from mdx52 mice, which was accompanied by a reduction in citrate synthase activity and the LC3BII/I ratio and an increase in the phosphorylation levels of Akt Ser473 and the expression levels of p62. ISO training restored these alterations and markedly increased in vivo fatigue resistance and PGC-1α expression in mdx52 muscles. Moreover, an increased number of Evans Blue dye-positive fibers was significantly reduced by ISO training in mdx52 muscles. In contrast, ISO training did not restore a reduction in the amount of SH3 and cysteine-rich domain 3 in mdx muscles. Thus, our data suggest that mitochondrial function is impaired in dystrophin-deficient muscles, which is likely to be induced by the defective autophagy due to persistent activation of Akt. ISO training inhibits the aberrant activation of Akt presumably by up-regulating the PGC-1α expression, which results in improved mitochondrial function and thus fatigue resistance in dystrophin-deficient muscles.

Larger improvements in fatigue resistance and mitochondrial function with high- than with low-intensity contractions during interval training of mouse skeletal muscle.

Interval training (IT) results in improved fatigue resistance in skeletal muscle mainly due to an increased aerobic capacity, which involves increased muscle mitochondrial content and/or improved mitochondrial function. We hypothesized that IT with high-intensity contractions is more effective in increasing mitochondrial function, and hence fatigue resistance, than low-intensity contractions. To study this hypothesis without interference from differences in muscle fiber recruitment obliged to occur during voluntary contractions, IT was performed with in situ supramaximal electrical stimulation where all muscle fibers are recruited. We compared the effect of IT with repeated low-intensity (20 Hz stimulation, IT20) and high-intensity (100 Hz stimulation, IT100) contractions on fatigue resistance and mitochondrial content and function in mouse plantar flexor muscles. Muscles were stimulated every other day for 4 weeks. The averaged peak torque during IT bouts was 4.2-fold higher with IT100 than with IT20. Both stimulation protocols markedly improved in situ fatigue resistance, although the improvement was larger with IT100. The citrate synthase activity, a biomarker of mitochondrial content, was similarly increased with IT20 and IT100. Conversely, increased expression of mitochondrial respiratory chain (MRC) complexes I, III, and IV was only observed with IT100 and this was accompanied by increases in MRC supercomplex formation and pyruvate-malate-driven state 3 respiration in isolated mitochondria. In conclusion, the IT-induced increase in fatigue resistance is larger with high-intensity than with low-intensity contractions and this is linked to improved mitochondrial function due to increased expression of MRC complexes and assembly of MRC supercomplexes.

Impaired skeletal muscle fatigue resistance during cardiac hypertrophy is prevented by functional overload- or exercise-induced functional capillarity.

Capillary rarefaction is hypothesized to contribute to impaired exercise tolerance in cardiovascular disease, but it remains a poorly exploited therapeutic target for improving skeletal muscle performance. Using an abdominal aortic coarctation rat model of compensatory cardiac hypertrophy, we determine the efficacy of aerobic exercise for the prevention of, and mechanical overload for, restoration of hindlimb muscle fatigue resistance and microvascular impairment in the early stages of heart disease. Impaired muscle fatigue resistance was found after development of cardiac hypertrophy, but this impairment was prevented by low-intensity aerobic exercise and recovered after mechanical stretch due to muscle overload. Changes in muscle fatigue resistance were closely related to functional (i.e. perfused) microvascular density, independent of arterial blood flow, emphasizing the critical importance of optimal capillary diffusion for skeletal muscle function. Pro-angiogenic therapies are an important tool for improving skeletal muscle function in the incipient stages of heart disease. Microvascular rarefaction may contribute to declining skeletal muscle performance in cardiac and vascular diseases. It remains uncertain to what extent microvascular rarefaction occurs in the earliest stages of these conditions, if impaired blood flow is an aggravating factor and whether angiogenesis restores muscle performance. To investigate this, the effects of aerobic exercise (voluntary wheel running) and functional muscle overload on the performance, femoral blood flow (FBF) and microvascular perfusion of the extensor digitorum longus (EDL) were determined in a chronic rat model of compensatory cardiac hypertrophy (CCH, induced by surgically imposed abdominal aortic coarctation). CCH was associated with hypertension (P=0.001 vs. Control) and increased relative heart mass (P < 0.001). Immediately upon placing the aortic band (i.e. before development of CCH), post-fatigue test FBF was reduced (P < 0.003), coinciding with attenuated fatigue resistance (P=0.039) indicating an acute arterial perfusion constraint on muscle performance. While FBF was normalized during CCH in chronic groups (P > 0.05) fatigue resistance remained reduced (P=0.039) and was associated with reduced (P=0.009) functional capillarity after development of CCH without intervention, indicating a microvascular limitation to muscle performance. Normalization of functional capillarity after aerobic exercise (P=0.065) and overload (P=0.329) in CCH coincided with restoration to control levels of muscle fatigue resistance (P > 0.999), although overload-induced EDL hypertrophy (P=0.027) and wheel-running velocity and duration (both P < 0.05) were attenuated after aortic banding. These data show that reductions in skeletal muscle performance during CCH can be countered by improving functional capillarity, providing a therapeutic target to improve skeletal muscle function in chronic diseases.

Fourteen days of smoking cessation improves muscle fatigue resistance and reverses markers of systemic inflammation

Cigarette smoking has a negative effect on respiratory and skeletal muscle function and is a risk factor for various chronic diseases. To assess the effects of 14 days of smoking cessation on respiratory and skeletal muscle function, markers of inflammation and oxidative stress in humans. Spirometry, skeletal muscle function, circulating carboxyhaemoglobin levels, advanced glycation end products (AGEs), markers of oxidative stress and serum cytokines were measured in 38 non-smokers, and in 48 cigarette smokers at baseline and after 14 days of smoking cessation. Peak expiratory flow (p = 0.004) and forced expiratory volume in 1 s/forced vital capacity (p = 0.037) were lower in smokers compared to non-smokers but did not change significantly after smoking cessation. Smoking cessation increased skeletal muscle fatigue resistance (p < 0.001). Haemoglobin content, haematocrit, carboxyhaemoglobin, total AGEs, malondialdehyde, TNF-α, IL-2, IL-4, IL-6 and IL-10 (p < 0.05) levels were higher, and total antioxidant status (TAS), IL-12p70 and eosinophil numbers were lower (p < 0.05) in smokers. IL-4, IL-6, IL-10 and IL-12p70 had returned towards levels seen in non-smokers after 14 days smoking cessation (p < 0.05), and IL-2 and TNF-α showed a similar pattern but had not yet fully returned to levels seen in non-smokers. Haemoglobin, haematocrit, eosinophil count, AGEs, MDA and TAS did not significantly change with smoking cessation. Two weeks of smoking cessation was accompanied with an improved muscle fatigue resistance and a reduction in low-grade systemic inflammation in smokers.

Fast skeletal muscle troponin activator CK-2066260 increases fatigue resistance by reducing the energetic cost of muscle contraction.

Key points Skeletal muscle fatigue limits performance in various physical activities, with exercise intolerance being a key symptom in a broad spectrum of diseases.We investigated whether a small molecule fast skeletal troponin activator (FSTA), CK‐2066260, can mitigate muscle fatigue by reducing the cytosolic free [Ca2+] required to produce a given submaximal force and hence decreasing the energy requirement.Isolated intact single mouse muscle fibres and rat muscles in‐situ treated with CK‐2066260 showed improved muscle endurance., which was accompanied by decreased ATP demand and reduced glycogen usage.CK‐2066260 treatment improved in‐vivo exercise capacity in healthy rats and in a rat model of peripheral artery insufficiency.In conclusion, we show that the FSTA CK‐2066260 effectively counteracts muscle fatigue in rodent skeletal muscle in vitro, in situ, and in vivo. This may translate to humans and provide a promising pharmacological treatment to patients suffering from severe muscle weakness and exercise intolerance. Skeletal muscle fatigue limits performance during physical exercise and exacerbated muscle fatigue is a prominent symptom among a broad spectrum of diseases. The present study investigated whether skeletal muscle fatigue is affected by the fast skeletal muscle troponin activator (FSTA) CK‐2066260, which increases myofibrillar Ca2+ sensitivity and amplifies the submaximal force response. Because more force is produced for a given Ca2+, we hypothesized that CK‐2066260 could mitigate muscle fatigue by reducing the energetic cost of muscle activation. Isolated single mouse muscle fibres were fatigued by 100 repeated 350 ms contractions while measuring force and the cytosolic free [Ca2+] or [Mg2+] ([Mg2+]i). When starting fatiguing stimulation at matching forces (i.e. lower stimulation frequency with CK‐2066260): force was decreased by ∼50% with and by ∼75% without CK‐2066260; [Mg2+]i was increased by ∼10% with and ∼32% without CK‐2066260, reflecting a larger decrease in [ATP] in the latter. The glycogen content in in situ stimulated rat muscles fatigued by repeated contractions at matching forces was about two times higher with than without CK‐2066260. Voluntary exercise capacity, assessed by rats performing rotarod exercise and treadmill running, was improved in the presence of CK‐2066260. CK‐2066260 treatment also increased skeletal muscle fatigue resistance and exercise performance in a rat model of peripheral artery insufficiency. In conclusion, we demonstrate that the FSTA CK‐2066260 mitigates skeletal muscle fatigue by reducing the metabolic cost of force generation.

SR Ca2+ leak in skeletal muscle fibers acts as an intracellular signal to increase fatigue resistance.

Effective practices to improve skeletal muscle fatigue resistance are crucial for athletes as well as patients with dysfunctional muscles. To this end, it is important to identify the cellular signaling pathway that triggers mitochondrial biogenesis and thereby increases oxidative capacity and fatigue resistance in skeletal muscle fibers. Here, we test the hypothesis that the stress induced in skeletal muscle fibers by endurance exercise causes a reduction in the association of FK506-binding protein 12 (FKBP12) with ryanodine receptor 1 (RYR1). This will result in a mild Ca2+ leak from the sarcoplasmic reticulum (SR), which could trigger mitochondrial biogenesis and improved fatigue resistance. After giving mice access to an in-cage running wheel for three weeks, we observed decreased FKBP12 association to RYR1, increased baseline [Ca2+]i, and signaling associated with greater mitochondrial biogenesis in muscle, including PGC1α1. After six weeks of voluntary running, FKBP12 association is normalized, baseline [Ca2+]i returned to values below that of nonrunning controls, and signaling for increased mitochondrial biogenesis was no longer present. The adaptations toward improved endurance exercise performance that were observed with training could be mimicked by pharmacological agents that destabilize RYR1 and thereby induce a modest Ca2+ leak. We conclude that a mild RYR1 SR Ca2+ leak is a key trigger for the signaling pathway that increases muscle fatigue resistance.

The influence of angiotensin-converting enzyme gene ID polymorphism on human physical fitness performance in European and other populations

Angiotensin-converting enzyme (ACE) is a component of the circulating renin–angiotensin system, which influences circulatory homeostasis through the degradation of vasodilator kinins and the generation of vasopressor angiotensin II. Various phenotypic characteristics such as diseases and human performances could be associated with genetic polymorphisms within the ACE gene. To date, one of the most well-studied genetic polymorphisms that has been shown to be associated with athletic performance is that of the ACE gene. Previous studies investigating the influences of polymorphisms and various phenotypic characteristics have produced inconsistent findings due to inter-ethnic variations in the distribution of the different ACE alleles. For example, some studies showed that the I allele was associated with fatigue resistance in skeletal muscle and endurance performance while the D allele had been associated with power or sprint performance. Nevertheless, controversy still exists regarding the above conclusion as related studies reported that the I allele was associated with a better power or sprint performance rather than with athletic endurance abilities. This article discusses the inter-ethnic variations of the distribution of the different ACE alleles in several ethnic groups such as in European, African, American, and Asian populations. Additionally, the influences of the ACE ID polymorphism on human physical fitness performances in European and other populations are discussed.

The effect of taurine and β-alanine supplementation on taurine transporter protein and fatigue resistance in skeletal muscle from mdx mice.

This study investigated the effect of taurine and β-alanine supplementation on muscle function and muscle taurine transporter (TauT) protein expression in mdx mice. Wild-type (WT) and mdx mice (5months) were supplemented with taurine or β-alanine for 4weeks, after which in vitro contractile properties, fatigue resistance and force recovery, and the expression of the TauT protein and proteins involved in excitation-contraction (E-C) coupling were examined in fast-twitch muscle. There was no difference in basal TauT protein expression or basal taurine content between mdx than WT muscle. Supplementation with taurine and β-alanine increased and reduced taurine content, respectively, in muscle from WT and mdx mice but had no effect of TauT protein. Taurine supplementation reduced body and muscle mass, and enhanced fatigue resistance and force recovery in mdx muscle. β-Alanine supplementation enhanced fatigue resistance in WT and mdx muscle. There was no difference in the basal expression of key E-C coupling proteins [ryanodine receptor 1 (RyR1), dihydropyridine receptor (DHPR), sarco(endo)plasmic reticulum Ca2+-ATPase 1 (SERCA1) or calsequestrin 1 (CSQ1)] between WT and mdx mice, and the expression of these proteins was not altered by taurine or β-alanine supplementation. These findings suggest that TauT protein expression is relatively insensitive to changes in muscle taurine content in WT and mdx mice, and that taurine and β-alanine supplementation may be viable therapeutic strategies to improve fatigue resistance of dystrophic skeletal muscle.

Cigarette smoke impairs the in situ fatigue resistance of locomotor skeletal muscle in mice (1102.18)

Muscle dysfunction is thought to contribute to exercise intolerance in smokers with COPD. In this study, cigarette smoke (CS) was hypothesized to impair skeletal muscle fatigue resistance. To test this hypothesis, adult C57Bl6 mice were exposed via a nose‐only system to daily periods of CS (5 cigarettes/period for 2 periods, 5 days/week) for 8 weeks and compared to mice delivered CS‐extract (weekly, i.p) and control, unexposed mice. Body weights were recorded each week. Gastrocnemius complex fatigue resistance was evaluated by measuring the time to reach 50% of maximal force when electrically stimulated to contract in situ. Compared to control mice, body weights were decreased in CS‐exposed mice, but not CS‐extract mice, at 3‐weeks (7.4%, p&lt;0.05), 7‐weeks (7.9%, p&lt;0.05), and 8‐weeks (12.4%, p&lt;0.001). However, gastrocnemius, soleus, and plantaris mass / body weight ratios were not different between groups. A trend to earlier fatigue was seen in CS‐extract mice (Con. 342 ± 72 sec., CS‐exposed 310 ± 111 sec., CS‐extract 177 ± 16 sec., p=0.06). These data suggest the route or amount of CS that circulates in the blood may influence the extent of peripheral skeletal muscle dysfunction.Grant Funding Source: Supported by NIH 1 PO1 HL091830‐01A1

Impaired skeletal muscle fatigue resistance in metabolic syndrome is associated with alterations in microvascular hematocrit levels and variability (675.3)

Vascular dysfunction in metabolic syndrome is associated with poor performance of in situ skeletal muscle. Prior to impaired function in skeletal muscle itself, this reflects a failure to effectively perfuse working muscle. While altered vascular reactivity, arteriolar wall stiffness and microvessel rarefaction have been implicated, the accumulated impact on mass transport/exchange is unknown. Using tracer washout and existing models for microvascular hematocrit (HMV) and permeability‐surface area product (PS), we determined these parameters for in situ skeletal muscle of lean (LZR) and obese Zucker (OZR) rats. HMV in OZR was less than for LZR; treatment with adrenergic blockers or anti‐oxidants improved HMV slightly, but imposition of all agents restored HMV fully. PS, reduced in OZR vs. LZR, was not impacted by intervention. Using in situ cremaster muscle, HMV was determined in individual microvessels. Similar to above, HMV was reduced in OZR vs. LZR, although variability was higher; with post‐intervention changes mirroring that from washout experiments. These data suggest a low, spatially variable, HMV and global loss in surface area are contributors to poor muscle performance in OZR.Grant Funding Source: Supported by National Institutes of Health and American Heart Association

Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with systemic oxidative stress and skeletal muscle dysfunction. The purpose of this study was to examine the impact of intravenous ascorbate administration (AO) on biological markers of antioxidant capacity and oxidative stress, and subsequently skeletal muscle function during dynamic, small muscle mass exercise in patients with COPD. Ten patients with spirometric evidence of COPD performed single-leg knee extensor (KE) trials matched for intensity and time (isotime) following intravenous ascorbate (2 g) or saline infusion (PL). Quadriceps fatigue was quantified by changes in force elicited by maximal voluntary contraction (MVC) and magnetic femoral nerve stimulation (Qtw,pot). AO administration significantly increased antioxidant capacity, as measured by the ferric-reducing ability of plasma (PL: 1 ± 0.1 vs. AO: 5 ± 0.2 mM), and significantly reduced malondialdehyde levels (PL: 1.16 ± 0.1 vs. AO: 0.97 ± 0.1 mmol). Additionally, resting blood pressure was significantly reduced (PL: 104 ± 4 vs. AO: 93 ± 6 mmHg) and resting femoral vascular conductance was significantly elevated after AO (PL: 2.4 ± 0.2 vs. AO: 3.6 ± 0.4 ml·min(-1)·mmHg(-1)). During isotime exercise, the AO significantly attenuated both the ventilatory and metabolic responses, and patients accumulated significantly less peripheral quadriceps fatigue, as illustrated by less of a fall in MVC (PL: -11 ± 2% vs. AO: -5 ± 1%) and Qtw,pot (PL: -37 ± 1% vs. AO: -30 ± 2%). These data demonstrate a beneficial role of AO administration on skeletal muscle fatigue in patients with COPD and further implicate systemic oxidative stress as a causative factor in the skeletal muscle dysfunction observed in this population.

N‐acetylcysteine improves skeletal muscle fatigue resistance in a model of peripheral arterial insufficiency

Oxidative stress plays a major role in the genesis of skeletal muscle dysfunction in patients with Peripheral Arterial Disease (PAD). We tested the hypothesis that administration of the antioxidant N‐acetylcysteine (NAC) would improve isolated skeletal muscle fatigue resistance in a mice model of PAD. Male Balb/c mice (n=15) were subjected to bilateral ligation of the femoral artery and after 2 weeks of recovery, received daily intraperitoneal injections of either NAC (150 mg/kg, n=7) or saline (n=8) for 15 days. At the end of the treatment, the extensor digitorium longus (EDL) and soleus (SOL) muscles were excised for analysis of the contractile function and fatigue resistance in vitro (32°C). Maximal specific force was not different between groups for both the EDL (NAC: 37.3±1.4 N/cm2; Saline: 36.1±1.5 N/cm2) and the soleus (NAC: 35.5±1.2 N/cm2; Saline: 34.1±1.2 N/cm2). In the soleus muscle, force after 10 min of submaximal tetanic stimulation (60 Hz, 300 ms trains, 0.3 trains/s) was higher (p&lt;0.05) in NAC‐treated animals (45±3% of the initial value) when compared to controls (30.3 ±3%). No differences were found in fatigue development between groups in the EDL muscle (NAC:35.7±1.9%; Saline 37.5±1.1%). These results indicate that NAC treatment substantially improves fatigue resistance in the soleus muscle in a model of peripheral arterial insufficiency.Support‐ Fapesp 2011/18197–0 (B.R.), 2010/51344–3 (CS)

Blunted temporal activity of microvascular perfusion heterogeneity in metabolic syndrome: a new attractor for peripheral vascular disease?

A key outcome for peripheral vascular disease (PVD) is a progressive decay in skeletal muscle fatigue resistance with elevated metabolic demand. We have demonstrated that PVD in obese Zucker rats (OZR) is partially due to increased perfusion distribution heterogeneity (γ) at successive microvascular bifurcations, with its cumulative impact being an increasingly heterogeneous distribution of perfusion across terminal arterioles, leading to greater tissue ischemia. To minimize this outcome, a likely compensatory mechanism against increased γ should be an increased temporal switching at bifurcations to blunt downstream deficits. Using in situ cremaster muscle, we determined that temporal activity was lower in OZR than in LZR, and this difference was present in both proximal (1A‐2A) and distal (3A‐4A) arteriolar bifurcations. While adrenoreceptor blockade (phentolamine) improved temporal activity in 1A‐2A bifurcations in OZR, this was without impact in the distal microcirculation, where only interventions against oxidant stress (TEMPOL) and thromboxane A2 activity (SQ‐29548) were effective. Analysis of the attractor for γ indicated that it was elevated in OZR, and also exhibited a reduced range, suggesting that the ability of the microcirculation to respond to any challenge is highly restricted, and may represent the major contributor to the poor muscle performance in OZR.

Neural and bioenergetic mechanisms of human skeletal muscle fatigue resistance in old age

There is strong evidence that greater resistance to muscle fatigue in older adults, most often observed during low‐velocity or isometric contractions, has a basis in the bioenergetic response to contractions. However, the role of age‐related changes in motor unit (MU) behavior has not been evaluated in this context. To test the hypothesis that fatigue resistance in old resuls from adaptations in both MU behavior and energetics, we quantified dorsiflexor muscle fatigue (torque‐time integral, %initial); mean MU discharge rate (MUDR) by in‐dwelling electrode and cytosolic pH and inorganic phosphate (Pi) by magnetic resonance spectroscopy during parallel experiments using a protocol of 12 maximal isometric contractions (12s on, 8s off) in 10 young (35±4 yr, mean±SD) and 8 older (74±5) women. Older fatigued less than young (68±7%initial vs 59.7 ±9, p&lt;0.05), had a smaller decrease in MUDR (Δ= −20±10 %initial vs −34±18, p=0.08), and tended to have less acidosis at fatigue (6.88±0.13 vs 6.77±0.16, p=0.18), with no difference in end‐exercise Pi. These data provide the first in vivo evidence of the combined roles of MUDR and energetic responses as mechanisms of fatigue resistance in older adults. NIH AG21094

A review of the thermal sensitivity of the mechanics of vertebrate skeletal muscle

Environmental temperature varies spatially and temporally, affecting many aspects of an organism's biology. In ectotherms, variation in environmental temperature can cause parallel changes in skeletal muscle temperature, potentially leading to significant alterations in muscle performance. Endotherms can also undergo meaningful changes in skeletal muscle temperature that can affect muscle performance. Alterations in skeletal muscle temperature can affect contractile performance in both endotherms and ectotherms, changing the rates of force generation and relaxation, shortening velocity, and consequently mechanical power. Such alterations in the mechanical performance of skeletal muscle can in turn affect locomotory performance and behaviour. For instance, as temperature increases, a consequent improvement in limb muscle performance causes some lizard species to be more likely to flee from a potential predator. However, at lower temperatures, they are much more likely to stand their ground, show threatening displays and even bite. There is no consistent pattern in reported effects of temperature on skeletal muscle fatigue resistance. This review focuses on the effects of temperature variation on skeletal muscle performance in vertebrates, and investigates the thermal sensitivity of different mechanical measures of skeletal muscle performance. The plasticity of thermal sensitivity in skeletal muscle performance has been reviewed to investigate the extent to which individuals can acclimate to chronic changes in their thermal environment. The effects of thermal sensitivity of muscle performance are placed in a wider context by relating thermal sensitivity of skeletal muscle performance to aspects of vertebrate species distribution.