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Objectives: To compare blood alkalosis, gastrointestinal symptoms and indicators of strong ion difference after ingestion of 500 mg.kg-1 BM sodium citrate over four different periods., Methods: Sixteen healthy and active participants ingested 500 mg.kg-1 BM sodium citrate in gelatine capsules over a 15, 30, 45 or 60 min period using a randomized cross-over experimental design. Gastrointestinal symptoms questionnaires and venous blood samples were collected before ingestion, immediately post-ingestion, and every 30 min for 480 min post-ingestion. Blood samples were analysed for blood pH, [HCO3-], [Na+], [Cl-] and plasma [citrate]. Linear mixed models were used to estimate the effect of the ingestion protocols., Results: For all treatments, blood [HCO3-] was significantly elevated above baseline for the entire 480 min post-ingestion period, and peak occurred 180 min post-ingestion. Blood [HCO3-] and pH were significantly elevated above baseline and not significantly below the peak between 150-270 min post-ingestion. Furthermore, blood pH and [HCO3-] were significantly lower for the 60 min ingestion period when compared to the other treatments. Gastrointestinal symptoms were minor for all treatments; the mean total session symptoms ratings (all times summed together) were between 9.8 and 11.6 from a maximum possible rating of 720., Conclusion: Based on the findings of this investigation, sodium citrate should be ingested over a period of less than 60 min (15, 30 or 45 min), and completed 150-270 min before exercise., Competing Interests: The authors have declared that no competing interests exist.

This review aimed to identify factors associated with (a) physiological responses, (b) gastrointestinal (GI) symptoms, and (c) exercise performance following sodium citrate supplementation. A literature search identified 33 articles. Observations of physiological responses and GI symptoms were categorized by dose (< 500, 500, and > 500 mg/kg body mass [BM]) and by timing of postingestion measurements (in minutes). Exercise performance following sodium citrate supplementation was compared with placebo using statistical significance, percentage change, and effect size. Performance observations were categorized by exercise duration (very short < 60 s, short ≥ 60 and ≤ 420 s, and longer > 420 s) and intensity (very high > 100% VO2max and high 90-100% VO2max). Ingestion of 500 mg/kg BM sodium citrate induced blood alkalosis more frequently than < 500 mg/kg BM, and with similar frequency to >500 mg/kg BM. The GI symptoms were minimized when a 500 mg/kg BM dose was ingested in capsules rather than in solution. Significant improvements in performance following sodium citrate supplementation were reported in all observations of short-duration and very high-intensity exercise with a 500 mg/kg BM dose. However, the efficacy of supplementation for short-duration, high-intensity exercise is less clear, given that only 25% of observations reported significant improvements in performance following sodium citrate supplementation. Based on the current literature, the authors recommend ingestion of 500 mg/kg BM sodium citrate in capsules to induce alkalosis and minimize GI symptoms. Supplementation was of most benefit to performance of short-duration exercise of very high intensity; further investigation is required to determine the importance of ingestion duration and timing.

Purpose: Whole-body vibration (WBV) therapy has been reported to potentially act as an exercise mimetic by improving muscle function and exercise capacity in a variety of healthy and clinical populations. Considering the important role that microvascular blood flow plays in muscle metabolism and exercise capacity, we investigated the muscle microvascular responses of acute WBV to knee extension exercise (KEX) in healthy individuals., Methods: Eleven healthy adults (age: 33 ± 2 yr; body mass index: 23.6 ± 1.1 kg·m-2) underwent 3 min of WBV, or 3 min of KEX at 25% of one-repetition maximum, in a randomized order separated by a minimum of 72 h. Femoral arterial blood flow was measured via Doppler ultrasound, and thigh muscle microvascular blood flow was measured via contrast-enhanced ultrasound at baseline and throughout the 3-min postintervention recovery period., Results: Both WBV and KEX significantly increased peak microvascular blood flow (WBV, 5.6-fold; KEX, 21-fold; both P < 0.05) during the 3-min recovery period. Despite a similar increase in femoral arterial blood flow (~4-fold; both P < 0.05 vs baseline) and whole-body oxygen consumption measured by indirect calorimetry (WBV, 48%; KEX, 60%; both P < 0.05 vs baseline) in both conditions, microvascular blood flow was stimulated to a greater extent after KEX., Conclusion: A single 3-min session of WBV in healthy individuals is sufficient to significantly enhance muscle microvascular blood flow. Despite KEX providing a more potent stimulus, WBV may be an effective method for improving microvascular blood flow in populations reported to exhibit microvascular dysfunction such as patients with type 2 diabetes., (Copyright © 2020 by the American College of Sports Medicine.)

Antioxidant supplements are commonly consumed by endurance athletes to minimize exercise-induced oxidative stress, with the intention of enhancing recovery and improving performance. There are numerous commercially available nutritional supplements that are targeted to athletes and health enthusiasts that allegedly possess antioxidant properties. However, most of these compounds are poorly investigated with respect to their in vivo redox activity and efficacy in humans. Therefore, this review will firstly provide a background to endurance exercise-related redox signalling and the subsequent adaptations in skeletal muscle and vascular function. The review will then discuss commonly available compounds with purported antioxidant effects for use by athletes. N-acetyl cysteine may be of benefit over the days prior to an endurance event; while chronic intake of combined 1000 mg vitamin C + vitamin E is not recommended during periods of heavy training associated with adaptations in skeletal muscle. Melatonin, vitamin E and α-lipoic acid appear effective at decreasing markers of exercise-induced oxidative stress. However, evidence on their effects on endurance performance are either lacking or not supportive. Catechins, anthocyanins, coenzyme Q10 and vitamin C may improve vascular function, however, evidence is either limited to specific sub-populations and/or does not translate to improved performance. Finally, additional research should clarify the potential benefits of curcumin in improving muscle recovery post intensive exercise; and the potential hampering effects of astaxanthin, selenium and vitamin A on skeletal muscle adaptations to endurance training. Overall, we highlight the lack of supportive evidence for most antioxidant compounds to recommend to athletes., Competing Interests: Declaration of competing interest The authors have none to declare., (Copyright © 2020. Published by Elsevier B.V.)

Skeletal muscle and extracellular vesicle (EV) miRNA expression increases following acute endurance exercise. However, research to date has only been performed in males. The aim of this study was to describe the expression levels of a subset of miRNAs in EVs following acute exercise and compare it to skeletal muscle miRNA expression. Twelve males (age 22.9 ± 2.6 years, mean ± SD) and eight females (age 23.0 ± 3.4 years) cycled for 60 min at 70% VO 2 peak. Muscle biopsies and blood samples were collected at rest, immediately after and 3 hr after exercise. Acute exercise did not significantly alter the expression of miR-1, miR-16, miR-23b and miR-133a/b in EVs in males and females combined. There were no correlations between EV and skeletal muscle miRNA expression in any of the measured species at any time point. Exploratory analysis revealed differential miRNA responses to exercise between males and females. In males, a weak negative correlation was observed between skeletal muscle and EV miR-16 expression immediately following exercise; however, the physiological relevance of this correlation is unknown. Additionally, when compared with values at rest, male skeletal muscle miR-16 expression significantly increased immediately following exercise, whereas miR-133a expression significantly decreased 3 hr post exercise. Our findings suggest that miRNAs isolated from EVs are not a proxy for skeletal muscle miRNA content. Our exploratory data is the first known evidence of sex-specific differences in the miRNA response to an acute bout of endurance exercise, particularly for miRNA species implicated in mitochondrial metabolism and angiogenesis., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Noncoding RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) play roles in the development and homeostasis of nearly every tissue of the body, including the regulation of processes underlying heart growth. Cardiac hypertrophy can be classified as either physiological (beneficial heart growth) or pathological (detrimental heart growth), the latter of which results in impaired cardiac function and heart failure and is predictive of a higher incidence of death due to cardiovascular disease. Several miRNAs have a functional role in exercise-induced cardiac hypertrophy, while both miRNAs and lncRNAs are heavily involved in pathological heart growth and heart failure. The latter have the potential to act as an endogenous sponge RNA and interact with specific miRNAs to control cardiac hypertrophy, adding another level of complexity to our understanding of the regulation of cardiac muscle mass. In addition to tissue-specific effects, ncRNA-mediated tissue cross talk occurs via exosomes. In particular, miRNAs can be internalized in exosomes and secreted from various cardiac and vascular cell types to promote angiogenesis, as well as protection and repair of ischemic tissues. ncRNAs hold promising therapeutic potential to protect the heart against ischemic injury and aid in regeneration. Numerous preclinical studies have demonstrated the therapeutic potential of ncRNAs, specifically miRNAs, for the treatment of cardiovascular disease. Most of these studies employ antisense oligonucleotides to inhibit miRNAs of interest; however, off-target effects often limit their potential to be translated to the clinic. In this context, approaches using viral and nonviral delivery tools are promising means to provide targeted delivery in vivo.

The effect of endurance exercise on enhancing insulin sensitivity and glucose flux has been well established with techniques such as the hyperinsulinemic clamp. Although informative, such techniques do not emulate the physiological postprandial state, and it remains unclear how exercise improves postprandial glycaemia. Accordingly, combining mixed-meal tolerance testing and the triple-stable isotope glucose tracer approach, glucose fluxes [rates of meal glucose appearance (Ra), disposal (Rd), and endogenous glucose production (EGP)] were determined following acute endurance exercise (1 h cycling; ~70% V̇o 2max ) and 4 wk of endurance training (cycling 5 days/wk). Training was associated with a modest increase in V̇o 2max (~7%, P < 0.001). Postprandial glucose and insulin responses were reduced to the same extent following acute and chronic training. Interestingly, this was not accompanied by changes to rates of meal Ra, Rd, or degree of EGP suppression. Glucose clearance (Rd relative to prevailing glucose) was, however, enhanced with acute and chronic exercise. Furthermore, the duration of EGP suppression was shorter with acute and chronic exercise, with EGP returning toward fasting levels more rapidly than pretraining conditions. These findings suggest that endurance exercise influences the efficiency of the glucoregulatory system, where pretraining rates of glucose disposal and production were achieved at lower glucose and insulin levels. Notably, there was no influence of chronic training over and above that of a single exercise bout, providing further evidence that glucoregulatory benefits of endurance exercise are largely attributed to the residual effects of the last exercise bout.

Recent research highlights the importance of redox signalling pathway activation by contraction-induced reactive oxygen species (ROS) and nitric oxide (NO) in normal exercise-related cellular and molecular adaptations in skeletal muscle. In this review, we discuss some potentially important redox signalling pathways in skeletal muscle that are involved in acute and chronic responses to contraction and exercise. Specifically, we discuss redox signalling implicated in skeletal muscle contraction force, mitochondrial biogenesis and antioxidant enzyme induction, glucose uptake and muscle hypertrophy. Furthermore, we review evidence investigating the impact of major exogenous antioxidants on these acute and chronic responses to exercise. Redox signalling pathways involved in adaptive responses in skeletal muscle to exercise are not clearly elucidated at present, and further research is required to better define important signalling pathways involved. Evidence of beneficial or detrimental effects of specific antioxidant compounds on exercise adaptations in muscle is similarly limited, particularly in human subjects. Future research is required to not only investigate effects of specific antioxidant compounds on skeletal muscle exercise adaptations, but also to better establish mechanisms of action of specific antioxidants in vivo. Although we feel it remains somewhat premature to make clear recommendations in relation to application of specific antioxidant compounds in different exercise settings, a bulk of evidence suggests that N-acetylcysteine (NAC) is ergogenic through its effects on maintenance of muscle force production during sustained fatiguing events. Nevertheless, a current lack of evidence from studies using performance tests representative of athletic competition and a potential for adverse effects with high doses (>70mg/kg body mass) warrants caution in its use for performance enhancement. In addition, evidence implicates high dose vitamin C (1g/day) and E (≥260 IU/day) supplementation in impairments to some skeletal muscle cellular adaptations to chronic exercise training. Thus, determining the utility of antioxidant supplementation in athletes likely requires a consideration of training and competition periodization cycles of athletes in addition to type, dose and duration of antioxidant supplementation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: It is clear that reactive oxygen species (ROS) produced during skeletal muscle contraction have a regulatory role in skeletal muscle adaptation to endurance exercise. However, there is much controversy in the literature regarding whether attenuation of ROS by antioxidant supplementation can prevent these cellular adaptations. Therefore, the aim of this study was to determine whether vitamin C and E supplementation attenuates performance and cellular adaptations following acute endurance exercise and endurance training., Methods: A double-blinded, placebo-controlled randomized control trial was conducted in eleven healthy young males. Participants were matched for peak oxygen consumption (VO 2peak) and randomly allocated to placebo or antioxidant (vitamin C (2 × 500 mg/day) and E (400 IU/day)) groups. Following a four-week supplement loading period, participants completed acute exercise (10 × 4 min cycling at 90% VO 2peak, 2 min active recovery). Vastus lateralis muscle samples were collected pre-, immediately-post- and 3h-post-exercise. Participants then completed four weeks of training (3 days/week) using the aforementioned exercise protocol while continuing supplementation. Following exercise training, participants again completed an acute exercise bout with muscle biopsies., Results: Acute exercise tended to increase skeletal muscle oxidative stress as measured by oxidized glutathione (GSSG) (P=0.058) and F2-isoprostanes (P=0.056), with no significant effect of supplementation. Acute exercise significantly increased mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and PGC related coactivator (PRC), with no effect of supplementation. Following endurance training, supplementation did not prevent significantly increased VO 2peak, skeletal muscle levels of citrate synthase activity or mRNA or protein abundance of cytochrome oxidase subunit 4 (COX IV) (P<0.05). However, following training, vitamin C and E supplementation significantly attenuated increased skeletal muscle superoxide dismutase (SOD) activity and protein abundance of SOD2 and TFAM., Conclusion: Following acute exercise, supplementation with vitamin C and E did not attenuate skeletal muscle oxidative stress or increased gene expression of mitochondrial biogenesis markers. However, supplementation attenuated some (SOD, TFAM) of the increased skeletal muscle adaptations following training in healthy young men., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional/performance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise., (Copyright © 2015 the American Physiological Society.)

Metabolic stresses associated with disease, ageing, and exercise increase the levels of reactive oxygen species (ROS) in skeletal muscle. These ROS have been linked mechanistically to adaptations in skeletal muscle that can be favourable (i.e. in response to exercise) or detrimental (i.e. in response to disease). The magnitude, duration (acute versus chronic), and cellular origin of the ROS are important underlying factors in determining the metabolic perturbations associated with the ROS produced in skeletal muscle. In particular, insulin resistance has been linked to excess ROS production in skeletal muscle mitochondria. A chronic excess of mitochondrial ROS can impair normal insulin signalling pathways and glucose disposal in skeletal muscle. In contrast, ROS produced in skeletal muscle in response to exercise has been linked to beneficial metabolic adaptations including mitochondrial biogenesis and muscle hypertrophy. Moreover, unlike insulin resistance, exercise-induced ROS appears to be primarily of non-mitochondrial origin. The present review summarizes the diverse ROS-targeted metabolic outcomes associated with insulin resistance versus exercise in skeletal muscle, thus, presenting two contrasting perspectives of pathologically harmful versus physiologically beneficial ROS. Here, we discuss the key sites of ROS production during exercise and the effect of ROS in skeletal muscle of people with type 2 diabetes.

Background: Maintaining skeletal muscle mitochondrial content and function is important for sustained health throughout the lifespan. Exercise stimulates important key stress signals that control skeletal mitochondrial biogenesis and function. Perturbations in mitochondrial content and function can directly or indirectly impact skeletal muscle function and consequently whole-body health and wellbeing., Scope of Review: This review will describe the exercise-stimulated stress signals and molecular mechanisms positively regulating mitochondrial biogenesis and function. It will then discuss the major myopathies, neuromuscular diseases and conditions such as diabetes and ageing that have dysregulated mitochondrial function. Finally, the impact of exercise and potential pharmacological approaches to improve mitochondrial function in diseased populations will be discussed., Major Conclusions: Exercise activates key stress signals that positively impact major transcriptional pathways that transcribe genes involved in skeletal muscle mitochondrial biogenesis, fusion and metabolism. The positive impact of exercise is not limited to younger healthy adults but also benefits skeletal muscle from diseased populations and the elderly. Impaired mitochondrial function can directly influence skeletal muscle atrophy and contribute to the risk or severity of disease conditions. Pharmacological manipulation of exercise-induced pathways that increase skeletal muscle mitochondrial biogenesis and function in critically ill patients, where exercise may not be possible, may assist in the treatment of chronic disease., General Significance: This review highlights our understanding of how exercise positively impacts skeletal muscle mitochondrial biogenesis and function. Exercise not only improves skeletal muscle mitochondrial health but also enables us to identify molecular mechanisms that may be attractive targets for therapeutic manipulation. This article is part of a Special Issue entitled Frontiers of mitochondrial research., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The identification of microRNAs (miRNAs) has established new mechanisms that control skeletal muscle adaptation to exercise. The present study investigated the mRNA regulation of components of the miRNA biogenesis pathway (Drosha, Dicer and Exportin-5), muscle enriched miRNAs, (miR-1, -133a, -133b and -206), and several miRNAs dysregulated in muscle myopathies (miR-9, -23, -29, -31 and -181). Measurements were made in muscle biopsies from nine healthy untrained males at rest, 3 h following an acute bout of moderate-intensity endurance cycling and following 10 days of endurance training. Bioinformatics analysis was used to predict potential miRNA targets. In the 3 h period following the acute exercise bout, Drosha, Dicer and Exportin-5, as well as miR-1, -133a, -133-b and -181a were all increased. In contrast miR-9, -23a, -23b and -31 were decreased. Short-term training increased miR-1 and -29b, while miR-31 remained decreased. Negative correlations were observed between miR-9 and HDAC4 protein (r=-0.71; P=0.04), miR-31 and HDAC4 protein (r=-0.87; P=0.026) and miR-31 and NRF1 protein (r=-0.77; P=0.01) 3 h following exercise. miR-31 binding to the HDAC4 and NRF1 3 untranslated region (UTR) reduced luciferase reporter activity. Exercise rapidly and transiently regulates several miRNA species in muscle. Several of these miRNAs may be involved in the regulation of skeletal muscle regeneration, gene transcription and mitochondrial biogenesis. Identifying endurance exercise-mediated stress signals regulating skeletal muscle miRNAs, as well as validating their targets and regulatory pathways post exercise, will advance our understanding of their potential role/s in human health.

Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components. A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance. This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise.

Reduced activation of exercise responsive signalling pathways have been reported in response to acute exercise after training; however little is known about the adaptive responses of the mitochondria. Accordingly, we investigated changes in mitochondrial gene expression and protein abundance in response to the same acute exercise before and after 10-d of intensive cycle training. Nine untrained, healthy participants (mean±SD; VO(2peak) 44.1±17.6 ml/kg/min) performed a 60 min bout of cycling exercise at 164±18 W (72% of pre-training VO(2peak)). Muscle biopsies were obtained from the vastus lateralis muscle at rest, immediately and 3 h after exercise. The participants then underwent 10-d of cycle training which included four high-intensity interval training sessions (6×5 min; 90-100% VO(2peak)) and six prolonged moderate-intensity sessions (45-90 min; 75% VO(2peak)). Participants repeated the pre-training exercise trial at the same absolute work load (64% of pre-training VO(2peak)). Muscle PGC1-α mRNA expression was attenuated as it increased by 11- and 4- fold (P<0.001) after exercise pre- and post-training, respectively. PGC1-α protein expression increased 1.5 fold (P<0.05) in response to exercise pre-training with no further increases after the post-training exercise bout. RIP140 protein abundance was responsive to acute exercise only (P<0.01). COXIV mRNA (1.6 fold; P<0.01) and COXIV protein expression (1.5 fold; P<0.05) were increased by training but COXIV protein expression was decreased (20%; P<0.01) by acute exercise pre- and post-training. These findings demonstrate that short-term intensified training promotes increased mitochondrial gene expression and protein abundance. Furthermore, acute indicators of exercise-induced mitochondrial adaptation appear to be blunted in response to exercise at the same absolute intensity following short-term training.

Purpose: We have previously shown that local infusion of a nitric oxide synthase (NOS) inhibitor attenuates increases in leg glucose uptake during exercise in humans. We have also shown that infusion of the NOS substrate, l-arginine (l-Arg), increases glucose clearance, although the mechanisms involved were not determined. A potential mechanism for NO-mediated glucose disposal is via interactions with NOS and the energy sensor AMP-activated protein kinase (AMPK). The aim of this study was to determine the mechanism(s) by which l-Arg infusion increases glucose disposal during exercise in humans by examining total NOS activity and AMPK signaling., Methods: Seven males cycled for 120 min at 64% ± 1% VO(2)peak, during which the [6,6-H]glucose tracer was infused. During the final 60 min of exercise, either saline alone (Control, CON), or saline containing l-Arg HCl (l-Arg, 30 g at 0.5 g·min(-1)) was coinfused in a double-blind, randomized, counterbalanced order., Results: l-Arg increased the glucose rate of disappearance and glucose clearance rate during exercise; however, this was accompanied by a 150% increase in plasma insulin concentration from 65 to 75 min (P < 0.05) that remained significantly elevated until 90 min of exercise. Skeletal muscle AMPK signaling, nNOSμ phosphorylation by AMPK, and total NOS activity increased to a similar extent in the two trials., Conclusions: The increase in glucose disposal after l-Arg infusion during exercise is likely due to the significantly higher plasma insulin concentration.

There is evidence that reactive oxygen species (ROS) signalling is required for normal increases in glucose uptake during contraction of isolated mouse skeletal muscle, and that AMP-activated protein kinase (AMPK) is involved. The aim of this study was to determine whether ROS signalling is involved in the regulation of glucose disposal and AMPK activation during moderate-intensity exercise in humans. Nine healthy males completed 80 min of cycle ergometry at 62 +/- 1% of peak oxygen consumption ( V(O(2)peak).A 6,6-(2)H-glucose tracer was infused at rest and during exercise, and in a double-blind randomised cross-over design, N-acetylcysteine (NAC) or saline (CON) was co-infused. NAC was infused at 125 mg kg(1) h(1) for 15 min and then at 25 mg kg(1) h(1) for 20 min before and throughout exercise. NAC infusion elevated plasma NAC and cysteine, and muscle NAC and cysteine concentrations during exercise. Although neither NAC infusion nor exercise significantly affected muscle reduced or oxidised glutathione (GSH or GSSG) concentration (P > 0.05), S-glutathionylation (an indicator of oxidative stress) of a protein band of approximately 270 kDa was increased approximately 3-fold with contraction and this increase was prevented by NAC infusion. Despite this, exercised-induced increases in tracer determined glucose disposal, plasma lactate, plasma non-esterified fatty acids (NEFAs), and decreases in plasma insulin were not affected by NAC infusion. In addition, skeletal muscle AMPKalpha and acetyl-CoA carboxylase-beta (ACCbeta) phosphorylation increased during exercise by approximately 3- and approximately 6-fold (P < 0.05), respectively, and this was not affected by NAC infusion. Unlike findings in mouse muscle ex vivo, NAC does not attenuate skeletal muscle glucose disposal or AMPK activation during moderate-intensity exercise in humans.

The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance (cycling) training 1) increased insulin-stimulated Akt pSer(473) and 2) altered the abundance of the protein tyrosine phosphatases (PTPases), PTP1B and SHP2. In healthy, untrained men (n = 8; 24 +/- 1 yr), glucose infusion rate during a hyperinsulinemic euglycemic clamp, when compared with untrained values, was not improved 24 h following a single 60-min bout of endurance cycling but was significantly increased ( approximately 30%; P < 0.05) 24 h following completion of 7 days of exercise training. Insulin-stimulated Akt pSer(473) was approximately 50% higher (P < 0.05) 24 h following the acute bout of exercise, with this effect remaining after 7 days of training (P < 0.05). Insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation were not altered 24 h after acute exercise and short-term training. Insulin did not acutely regulate the localization of the PTPases, PTP1B or SHP2, although cytosolic protein abundance of SHP2 was increased (P < 0.05; main effect) 24 h following acute exercise and short-term training. In conclusion, insulin-sensitive Akt pSer(473) and cytosolic SHP2 protein abundance are higher after acute exercise and short-term training, and this effect appears largely due to the residual effects of the last bout of prior exercise. The significance of exercise-induced alterations in cytosolic SHP2 and insulin-stimulated Akt pSer(473) on the improvement in insulin sensitivity requires further elucidation.

There is evidence that increasing carbohydrate (CHO) availability during exercise by raising preexercise muscle glycogen levels attenuates the activation of AMPKalpha2 during exercise in humans. Similarly, increasing glucose levels decreases AMPKalpha2 activity in rat skeletal muscle in vitro. We examined the effect of CHO ingestion on skeletal muscle AMPK signaling during exercise in nine active male subjects who completed two 120-min bouts of cycling exercise at 65 +/- 1% V(O2 peak). In a randomized, counterbalanced order, subjects ingested either an 8% CHO solution or a placebo solution during exercise. Compared with the placebo trial, CHO ingestion significantly (P < 0.05) increased plasma glucose levels and tracer-determined glucose disappearance. Exercise-induced increases in muscle-calculated free AMP (17.7- vs. 11.8-fold), muscle lactate (3.3- vs. 1.8-fold), and plasma epinephrine were reduced by CHO ingestion. However, the exercise-induced increases in skeletal muscle AMPKalpha2 activity, AMPKalpha2 Thr(172) phosphorylation and acetyl-CoA Ser(222) phosphorylation, were essentially identical in the two trials. These findings indicate that AMPK activation in skeletal muscle during exercise in humans is not sensitive to changes in plasma glucose levels in the normal range. Furthermore, the rise in plasma epinephrine levels in response to exercise was greatly suppressed by CHO ingestion without altering AMPK signaling, raising the possibility that epinephrine does not directly control AMPK activity during muscle contraction under these conditions in vivo.

The effects of a single bout of exercise and exercise training on the expression of genes necessary for the transport and beta-oxidation of fatty acids (FA), together with the gene expression of transcription factors implicated in the regulation of FA homeostasis were investigated. Seven human subjects (3 male, 4 female, 28.9 +/- 3.1 yr of age, range 20-42 yr, body mass index 22.6 kg/m(2), range 17-26 kg/m(2)) underwent a 9-day exercise training program of 60 min cycling per day at 63% peak oxygen uptake (VO(2 peak); 104 +/- 14 W). On days 1 and 9 of the program, muscle biopsies were sampled from the vastus lateralis muscle at rest, at the completion of exercise, and again 3 h postexercise. Gene expression of key components of FA transport [FA translocase (FAT/CD36), plasma membrane-associated FA-binding protein], beta-oxidation [carntine palmitoyltransferase(CPT) I, beta-hydroxyacyl-CoA dehydrogenase] and transcriptional control [peroxisome proliferator-activated receptor (PPAR)alpha, PPAR gamma, PPAR gamma coactivator 1, sterol regulatory element-binding protein-1c] were unaltered by exercise when measured at the completion and at 3 h postexercise. Training increased total lipid oxidation by 24% (P < 0.05) for the 1-h cycling bout. This increased capacity for lipid oxidation was accompanied by an increased expression of FAT/CD36 and CPT I mRNA. Similarly, FAT/CD36 protein abundance was also upregulated by exercise training. We conclude that enhanced fat oxidation after exercise training is most closely associated with the genes involved in regulating FA uptake across the plasma membrane (FAT/CD36) and across the mitochondrial membrane (CPT I).

Key points: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism.We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise.Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise.High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control.Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion lead to increased muscle microvascular blood flow (MBF), whereas high‐glucose ingestion impairs MBF. We investigated whether prior cycling exercise could enhance postprandial muscle MBF and prevent MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. In a randomized cross‐over design, eight healthy young men ingested a high‐glucose mixed‐nutrient meal (1.1 g glucose/kg body weight; 45% carbohydrate, 20% protein and 35% fat) after an overnight fast (no‐exercise control) and 3 h and 24 h after moderate‐intensity cycling exercise (1 h at 70–75% V̇O2peak). Skeletal muscle MBF, measured directly by contrast‐enhanced ultrasound, was lower at 60 min and 120 min postprandially compared to baseline in all conditions (P < 0.05), with a greater decrease occurring from 60 min to 120 min in the control (no‐exercise) condition only (P < 0.001). Despite this meal‐induced decrease, MBF was still markedly higher compared to control in the 3 h post‐exercise condition at 0 min (pre‐meal; 74%, P = 0.004), 60 min (112%, P = 0.002) and 120 min (223%, P < 0.001), and in the 24 h post‐exercise condition at 120 min postprandially (132%, P < 0.001). We also report that in the 3 h post‐exercise condition postprandial blood glucose, non‐esterified fatty acids (NEFAs), and fat oxidation were substantially elevated, and the insulin response to the meal delayed compared to control. This probably reflects a combination of increased post‐exercise exogenous glucose appearance, substrate competition, and NEFA‐induced insulin resistance. We conclude that prior cycling exercise elicits long‐lasting effects on muscle MBF and partially mitigates MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. Key points: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism.We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise.Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise.High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control.Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. [ABSTRACT FROM AUTHOR]

Key points: AMP‐activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise.However, we previously showed that, although AMPK activity increases by 8–10‐fold during ∼120 min of exercise at ∼65% V̇O2peak in untrained individuals, there is no increase in these individuals after only 10 days of exercise training (longitudinal study).In a cross‐sectional study, we show that there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% V̇O2peak in endurance‐trained individuals.These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% V̇O2peak in endurance trained men.It is important that more energy is directed towards examining other potential regulators of exercise metabolism. AMP‐activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise. Indeed, AMPK is activated during exercise and activation of AMPK by 5‐aminoimidazole‐4‐carboxyamide‐ribonucleoside (AICAR) increases skeletal muscle glucose uptake and fat oxidation. However, we have previously shown that, although AMPK activity increases by 8–10‐fold during ∼120 min of exercise at ∼65% V̇O2peak in untrained individuals, there is no increase in these individuals after only 10 days of exercise training (longitudinal study). In a cross‐sectional study, we examined whether there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% V̇O2peak in endurance‐trained individuals. Eleven untrained (UT; V̇O2peak = 37.9 ± 5.6 ml.kg−1 min−1) and seven endurance trained (ET; V̇O2peak = 61.8 ± 2.2 ml.kg−1 min−1) males completed 120 min of cycling exercise at 66 ± 4% V̇O2peak (UT: 100 ± 21 W; ET: 190 ± 15 W). Muscle biopsies were obtained at rest and following 30 and 120 min of exercise. Muscle glycogen was significantly (P < 0.05) higher before exercise in ET and decreased similarly during exercise in the ET and UT individuals. Exercise significantly increased calculated skeletal muscle free AMP content and more so in the UT individuals. Exercise significantly (P < 0.05) increased skeletal muscle AMPK α2 activity (4‐fold), AMPK αThr172 phosphorylation (2‐fold) and ACCβ Ser222 phosphorylation (2‐fold) in the UT individuals but not in the ET individuals. These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% V̇O2peak in endurance trained men. Key points: AMP‐activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise.However, we previously showed that, although AMPK activity increases by 8–10‐fold during ∼120 min of exercise at ∼65% V̇O2peak in untrained individuals, there is no increase in these individuals after only 10 days of exercise training (longitudinal study).In a cross‐sectional study, we show that there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% V̇O2peak in endurance‐trained individuals.These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% V̇O2peak in endurance trained men.It is important that more energy is directed towards examining other potential regulators of exercise metabolism. [ABSTRACT FROM AUTHOR]

We investigated the relationship between markers of mitochondrial biogenesis, cell signaling, and antioxidant enzymes by depleting skeletal muscle glutathione with diethyl maleate (DEM) which resulted in a demonstrable increase in oxidative stress during exercise. Animals were divided into six groups: (1) sedentary control rats; (2) sedentary rats + DEM; (3) exercise control rats euthanized immediately after exercise; (4) exercise rats + DEM; (5) exercise control rats euthanized 4 h after exercise; and (6) exercise rats + DEM euthanized 4 h after exercise. Exercising animals ran on the treadmill at a 10% gradient at 20 m/min for the first 30 min. The speed was then increased every 10 min by 1.6 m/min until exhaustion. There was a reduction in total glutathione in the skeletal muscle of DEM treated animals compared to the control animals ( P < 0.05). Within the control group, total glutathione was higher in the sedentary group compared to after exercise ( P < 0.05). DEM treatment also significantly increased oxidative stress, as measured by increased plasma F2-isoprostanes ( P < 0.05). Exercising animals given DEM showed a significantly greater increase in peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1 α) mRNA compared to the control animals that were exercised ( P < 0.05). This study provides novel evidence that by lowering the endogenous antioxidant glutathione in skeletal muscle and inducing oxidative stress through exercise, PGC-1 α gene expression was augmented. These findings further highlight the important role of exercise induced oxidative stress in the regulation of mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Fetal growth restriction is associated with reduced pancreatic β-cell mass, contributing to impaired glucose tolerance and diabetes. Exercise training increases β-cell mass in animals with diabetes and has long-lasting metabolic benefits in rodents and humans. We studied the effect of exercise training on islet and β-cell morphology and plasma insulin and glucose, following an intraperitoneal glucose tolerance test (IPGTT) in juvenile and adult male Wistar-Kyoto rats born small. Bilateral uterine vessel ligation performed on day 18 of pregnancy resulted in Restricted offspring born small compared with sham-operated Controls and also sham-operated Reduced litter offspring that had their litter size reduced to five pups at birth. Restricted, Control, and Reduced litter offspring remained sedentary or underwent treadmill running from 5 to 9 or 20 to 24 wk of age. Early life exercise increased relative islet surface area and β-cell mass across all groups at 9 wk, partially restoring the 60-68% deficit (P < 0.05) in Restricted offspring. Remarkably, despite no further exercise training after 9 wk, β-cell mass was restored in Restricted at 24 wk, while sedentary littermates retained a 45% deficit (P = 0.05) in relative β-cell mass. Later exercise training also restored Restricted β-cell mass to Control levels. In conclusion, early life exercise training in rats born small restored β-cell mass in adulthood and may have beneficial consequences for later metabolic health and disease. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance (cycling) training 1) increased insulin-stimulated Akt pSer473 and 2) altered the abundance of the protein tyrosine phosphatases (PTPases), PTP1B and SHP2. In healthy, untrained men (n = 8; 24 ± 1 yr), glucose infusion rate during a hyperinsulinemic euglycemic clamp, when compared with untrained values, was not improved 24 h following a single 60-min bout of endurance cycling but was significantly increased (-30%; P < 0.05) 24 h following completion of 7 days of exercise training. Insulin-stimulated Akt pSer473 was -50% higher (P < 0.05) 24 h following the acute bout of exercise, with this effect remaining after 7 days of training (P < 0.05). Insulin-stimulated insulin receptor and insulin receptor substrate-i tyrosine phosphorylation were not altered 24 h after acute exercise and short-term training. Insulin did not acutely regulate the localization of the PTPases, PTP1B or SHP2, although cytosolic protein abundance of SHP2 was increased (P < 0.05; main effect) 24 h following acute exercise and short-term training. In conclusion, insulin-sensitive Akt pSer473 and cytosolic SHP2 protein abundance are higher after acute exercise and short-term training, and this effect appears largely due to the residual effects of the last bout of prior exercise. The significance of exercise-induced alterations in cytosolic SHP2 and insulin-stimulated Akt pSer473 on the improvement in insulin sensitivity requires further elucidation. [ABSTRACT FROM AUTHOR]

Key points Testosterone, the major androgen, influences the reproductive and non‐reproductive systems in males and females via binding to the androgen receptor (AR). Both circulating endogenous testosterone and muscle AR protein content are positively associated with muscle mass and strength in males, but there is no such evidence in females. Here, we tested whether circulating testosterone levels were associated with muscle mass, function, or the muscle anabolic response to resistance training in pre‐menopausal females. Twenty‐seven pre‐menopausal, untrained females (aged 23.5 ± 4.8 years) underwent a 12‐week resistance training programme. Muscle strength, size, power, and plasma and urine androgen hormone levels were measured. Skeletal muscle biopsies were collected before and after the training programme to quantify the effect of resistance training on AR content and nuclear localisation. Primary muscle cell lines were cultured from a subset (n = 6) of the participants’ biopsies and treated with testosterone to investigate its effect on myotube diameter, markers of muscle protein synthesis and AR cellular localisation. Physiological levels of total testosterone were not associated with muscle mass or strength at baseline or with the changes in muscle mass and strength that occurred in response to resistance training in our cohort of pre‐menopausal females. In contrast, bioavailable testosterone and the proportion of nuclear‐localised AR were positively associated with skeletal muscle mass and strength in pre‐menopausal females. In vitro, supra‐physiological doses of testosterone increased myocyte diameter, but this did not occur via the Akt/mTOR pathway as previously suggested. Instead, we show a marked increase in AR nuclear localisation with testosterone administration in vitro. Total circulating testosterone was not related to muscle mass or strength before or after resistance training in pre‐menopausal females. Bioavailable testosterone was positively related to exercise‐induced muscle hypertrophy in pre‐menopausal females. In vivo nuclear localisation of the androgen receptor was positively related to muscle mass in pre‐menopausal females at baseline, but not to resistance training‐induced hypertrophy. Testosterone treatment induced androgen receptor nuclear translocation but did not induce mTOR signalling in primary skeletal myocytes cultured from pre‐menopausal female muscle. [ABSTRACT FROM AUTHOR]