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Sporadic inclusion body myositis (sIBM) is characterised by skeletal muscle inflammation, progressive muscle loss and weakness, which is largely refractory to immunosuppressive treatment. Low-load blood-flow restricted (BFR) training has been shown to evoke gains in myofibre cross sectional area (mCSA) in healthy adults. This could partially be due to the activation and integration of muscle satellite cells (SC) resulting in myonuclei addition. Consequently, this study investigated the effect of 12-weeks lower limb low-load BFR resistance training in sIBM patients on SC and myonuclei content, myofibre size and capillarization. Muscle biopsies from sIBM patients randomised to 12-weeks of low-load BFR resistance training (n = 11) or non-exercising controls (CON) (n = 9) were analysed for SC and myonuclei content, myofibre size and capillarization using three-colour immunofluorescence microscopy and computerised quantification procedures. No between-group differences (time-by-group interactions) or within-groups changes were observed for resident SCs (Pax7(+)/Six1(+)), proliferating SCs (Pax7(+)/ Ki67(+)), myonuclei (Six1(+)), type 1 mCSA or capillary number (CD31(+)). However, a time-by-group interaction for type 2 mCSA was observed (p = 0.04). Satellite cell content, myonuclei number, mCSA and capillary density remained unaffected following 12-weeks low-load BFR resistance training, indicating limited myogenic capacity and satellite cell plasticity in long-term sIBM patients. (C) 2022 The Authors. Published by Elsevier B.V.

Recent years have seen growing scholarly interest in female physiology in general. Moreover, particular attention has been devoted to how concentrations of female sex hormones vary during the menstrual cycle and menopausal transition and how hormonal contraception and hormonal therapy influence skeletal muscle tissue. While much effort has been paid to macro outcomes, such as muscle function or mass, rather less attention has been paid to mechanistic work that may help explain the underlying mechanism through which sex hormones regulate skeletal muscle tissue. Evidence from animal studies shows a strong relationship between the female sex hormone estrogen and satellite cells (SCs), a population of muscle stem cells involved in skeletal muscle regulation. A few human studies investigating this relationship have been published only recently. Thus, the purpose of this study was to bring an updated review on female sex hormones and their role in SC regulation. First, we describe how SCs regulate skeletal muscle maintenance and repair and introduce sex hormone signaling within the muscle. Second, we present evidence from animal studies elucidating how estrogen deficiency and supplementation influence SCs. Third, we present results from investigations from human trials including women whose concentrations of female hormones differ due to menopause, hormone therapy, hormonal contraceptives, and the menstrual cycle. Finally, we discuss research and methodological recommendations for future studies aiming at elucidating the link between female sex hormones and SCs with respect to aging and training.

Background & aims: Sarcopenia is a muscle disorder associated with loss of muscle mass, strength and function. Early screening, diagnosis and treatment may improve outcome in different disease conditions. A wide variety of tools for estimation of muscle mass is available and each tool has specific technical requirements. However, different investigational settings and lack of homogeneity of populations influence the definition of gold standards, proving it difficult to systematically adopt these tools. Recently, the European Working Group on Sarcopenia in Older People (EWGSOP) published a revised recommendation (EWGSOP-2) and algorithm for using tools for screening and diagnosing sarcopenia. However, agreement of the EWGSOP2 criteria with other classifications is poor and although an overview of available tools is valuable, for the purpose of clinical decision-making the reverse is useful; a given scenario asks for the most suitable tools.Results: Tools were identified for screening, diagnostics and longitudinal monitoring of muscle mass. For each of these clinical scenarios the most appropriate tools were listed and for each technique their usability is specified based on sensitivity and specificity. Based on this information a specific recommendation is made for each clinical scenario.Conclusion: This narrative review provides an overview of currently available tools and future developments for different clinical scenarios such as screening, diagnosis and longitudinal monitoring of alterations in muscle status. It supports clinical decision-making in choosing the right tools for muscle mass quantification depending on the need within a given clinical scenario as well as the local availability and expertise. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.

Aging is typified by a progressive decline in mitochondrial activity and stress resilience. Here, we review how mitochondrial stress pathways have pleiotropic effects on cellular and systemic homeostasis, which can comprise protective or detrimental responses during aging. We describe recent evidence arguing that defects in these conserved adaptive pathways contribute to aging and age-related diseases. Signaling pathways regulating the mitochondrial unfolded protein response, mitochondrial membrane dynamics, and mitophagy are discussed, emphasizing how their failure contributes to heteroplasmy and de-regulation of key metabolites. Our current understanding of how these processes are controlled and interconnected explains how mitochondria can widely impact fundamental aspects of aging.

BackgroundMitochondrial dysfunction has been implicated in sarcopenia. P-31 magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function. MethodsTwenty Chinese men with sarcopenia (SARC, age = 73.1 +/- 4.1 years) and 19 healthy aged and sex-matched controls (CON, age = 70.3 +/- 4.2 years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest-exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations. ResultsDespite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06 +/- 0.59 vs. 0.57 +/- 0.22, moderate: 0.93 +/- 0.43 vs. 0.58 +/- 0.68, high: 0.70 +/- 0.57 vs. 0.43 +/- 0.51 mmol L-1 min(-1) bar(-1) cm(-2), P = 0.003

Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD(+)) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD(+) levels that were more similar to those found in younger individuals. NAD(+) abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD(+) and health status in human aging.

Satellite cells are essential for skeletal muscle regeneration, repair, and adaptation. The activity of satellite cells is influenced by their interactions with muscle-resident endothelial cells. We postulate that the microvascular network between muscle fibers plays a critical role in satellite cell function. Exercise-induced angiogenesis can mitigate the decline in satellite cell function with age.

Branched-chain amino acid (BCAA) catabolism has been considered to have an emerging role in the pathogenesis of metabolic disturbances in obesity and type 2 diabetes (T2D). Several studies showed elevated plasma BCAA levels in humans with insulin resistance and patients with T2D, although the underlying reason is unknown. Dysfunctional BCAA catabolism could theoretically be an underlying factor. In vitro and animal work collectively show that modulation of the BCAA catabolic pathway alters key metabolic processes affecting glucose homeostasis, although an integrated understanding of tissue-specific BCAA catabolism remains largely unknown, especially in humans. Proof-of-concept studies in rodents -and to a lesser extent in humans - strongly suggest that enhancing BCAA catabolism improves glucose homeostasis in metabolic disorders, such as obesity and T2D. In this review, we discuss several hypothesized mechanistic links between BCAA catabolism and insulin resistance and overview current available tools to modulate BCAA catabolism in vivo. Furthermore, this review considers whether enhancing BCAA catabolism forms a potential future treatment strategy to promote metabolic health in insulin resistance and T2D.

This Review provides insight into sexual dimorphism in adipose tissue distribution and substrate metabolism in adipose tissue, skeletal muscle and liver, as well as the underlying mechanisms. The effects of these sex differences on cardiometabolic health are outlined and the potential for developing sex-specific prevention and treatment strategies is discussed.Obesity is associated with many adverse health effects, such as an increased cardiometabolic risk. Despite higher adiposity for a given BMI, premenopausal women are at lower risk of cardiometabolic disease than men of the same age. This cardiometabolic advantage in women seems to disappear after the menopause or when type 2 diabetes mellitus develops. Sexual dimorphism in substrate supply and utilization, deposition of excess lipids and mobilization of stored lipids in various key metabolic organs (such as adipose tissue, skeletal muscle and the liver) are associated with differences in tissue-specific insulin sensitivity and cardiometabolic risk profiles between men and women. Moreover, lifestyle-related factors and epigenetic and genetic mechanisms seem to affect metabolic complications and disease risk in a sex-specific manner. This Review provides insight into sexual dimorphism in adipose tissue distribution, adipose tissue, skeletal muscle and liver substrate metabolism and tissue-specific insulin sensitivity in humans, as well as the underlying mechanisms, and addresses the effect of these sex differences on cardiometabolic health. Additionally, this Review highlights the implications of sexual dimorphism in the pathophysiology of obesity-related cardiometabolic risk for the development of sex-specific prevention and treatment strategies.

Fatty acids are an important energy source during exercise. Training status and substrate availability are determinants of the relative and absolute contribution of fatty acids and glucose to total energy expenditure. Endurance-trained athletes have a high oxidative capacity, while, in insulin-resistant individuals, fat oxidation is compromised. Fatty acids that are oxidised during exercise originate from the circulation (white adipose tissue lipolysis), as well as from lipolysis of intramyocellular lipid droplets. Moreover, hepatic fat may contribute to fat oxidation during exercise. Nowadays, it is clear that myocellular lipid droplets are dynamic organelles and that number, size, subcellular distribution, lipid droplet coat proteins and mitochondrial tethering of lipid droplets are determinants of fat oxidation during exercise. This review summarises recent insights into exercise-mediated changes in lipid metabolism and insulin sensitivity in relation to lipid droplet characteristics in human liver and muscle.

BACKGROUND: Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it.RESEARCH QUESTION: Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients?STUDY DESIGN AND METHODS: In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones.RESULTS: Muscle loss was similar between arms (-1.1% [95% CI, -6.1% to -4.0%]; P =.676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; PINTERPRETATION: Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe.

Fatty acids are an important energy source during exercise. Training status and substrate availability are determinants of the relative and absolute contribution of fatty acids and glucose to total energy expenditure. Endurance-trained athletes have a high oxidative capacity, while, in insulin-resistant individuals, fat oxidation is compromised. Fatty acids that are oxidised during exercise originate from the circulation (white adipose tissue lipolysis), as well as from lipolysis of intramyocellular lipid droplets. Moreover, hepatic fat may contribute to fat oxidation during exercise. Nowadays, it is clear that myocellular lipid droplets are dynamic organelles and that number, size, subcellular distribution, lipid droplet coat proteins and mitochondrial tethering of lipid droplets are determinants of fat oxidation during exercise. This review summarises recent insights into exercise-mediated changes in lipid metabolism and insulin sensitivity in relation to lipid droplet characteristics in human liver and muscle. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00125-020-05170-z) contains a slideset of the figures for download, which is available to authorised users.

Extensive research performed over the past 10 years has resulted in dietary nitrate being considered a nutritional supplement that can improve exercise performance. However, there is still limited insight in the metabolic fate of dietary nitrate following the appearance of nitrate and nitrite in the circulation. Recent observations in humans suggest the storage of nitrate in skeletal muscle tissue. This short review discusses the possibility of nitrate being stored and utilized in human skeletal muscle tissue, and why confirming this may increase our understanding of how the nitrate -nitrite -NO pathway improves exercise performance. Further insight in skeletal muscle nitrate storage and metabolism may provide answers to current gaps in knowledge, such as the ergogenic benefit of acute vs multiday dietary nitrate supplementation, as well as the suggested muscle fiber -type specific effects on exercise performance. In this mini -review, specific questions that need further exploration are also discussed.

Branched-chain amino acid (BCAA) catabolism has been considered to have an emerging role in the pathogenesis of metabolic disturbances in obesity and type 2 diabetes (T2D). Several studies showed elevated plasma BCAA levels in humans with insulin resistance and patients with T2D, although the underlying reason is unknown. Dysfunctional BCAA catabolism could theoretically be an underlying factor. In vitro and animal work collectively show that modulation of the BCAA catabolic pathway alters key metabolic processes affecting glucose homeostasis, although an integrated understanding of tissue-specific BCAA catabolism remains largely unknown, especially in humans. Proof-of-concept studies in rodents -and to a lesser extent in humans – strongly suggest that enhancing BCAA catabolism improves glucose homeostasis in metabolic disorders, such as obesity and T2D. In this review, we discuss several hypothesized mechanistic links between BCAA catabolism and insulin resistance and overview current available tools to modulate BCAA catabolism in vivo. Furthermore, this review considers whether enhancing BCAA catabolism forms a potential future treatment strategy to promote metabolic health in insulin resistance and T2D.

Sustained ryanodine receptor (RyR) Ca2+ leak is associated with pathological conditions such as heart failure or skeletal muscle weakness. We report that a single session of sprint interval training (SIT), but not of moderate intensity continuous training (MICT), triggers RyR1 protein oxidation and nitrosylation leading to calstabin1 dissociation in healthy human muscle and in in vitro SIT models (simulated SIT or S-SIT). This is accompanied by decreased sarcoplasmic reticulum Ca2+ content, increased levels of mitochondrial oxidative phosphorylation proteins, supercomplex formation and enhanced NADH-linked mitochondrial respiratory capacity. Mechanistically, (S-)SIT increases mitochondrial Ca2+ uptake in mouse myotubes and muscle fibres, and decreases pyruvate dehydrogenase phosphorylation in human muscle and mouse myotubes. Countering Ca2+ leak or preventing mitochondrial Ca2+ uptake blunts S-SIT-induced adaptations, a result supported by proteomic analyses. Here we show that triggering acute transient Ca2+ leak through RyR1 in healthy muscle may contribute to the multiple health promoting benefits of exercise., Ryanodine receptor type 1 (RyR1) are involved in skeletal muscle contraction. Here, the authors show that a transient calcium leak in response to exercise-induced post translational modifications of RyR1 causes mitochondrial remodeling to improve respiration.

Satellite cells are essential for skeletal muscle regeneration, repair, and adaptation. The activity of satellite cells is influenced by their interactions with muscle-resident endothelial cells. We postulate that the microvascular network between muscle fibers plays a critical role in satellite cell function. Exercise-induced angiogenesis can mitigate the decline in satellite cell function with age.

Muscle glycogen is the main substrate during high-intensity exercise and large reductions can occur after relatively short durations. Moreover, muscle glycogen is stored heterogeneously and similarly displays a heterogeneous and fiber-type specific depletion pattern with utilization in both fast- and slow-twitch fibers during high-intensity exercise, with a higher degradation rate in the former. Thus, depletion of individual fast- and slow-twitch fibers has been demonstrated despite muscle glycogen at the whole-muscle level only being moderately lowered. In addition, muscle glycogen is stored in specific subcellular compartments, which have been demonstrated to be important for muscle function and should be considered as well as global muscle glycogen availability. In the present review, we discuss the importance of glycogen metabolism for single and intermittent bouts of high-intensity exercise and outline possible underlying mechanisms for a relationship between muscle glycogen and fatigue during these types of exercise. Traditionally this relationship has been attributed to a decreased ATP resynthesis rate due to inadequate substrate availability at the whole-muscle level, but emerging evidence points to a direct coupling between muscle glycogen and steps in the excitation-contraction coupling including altered muscle excitability and calcium kinetics.

Introduction: Pulmonary rehabilitation (PR) is one of the core components in the management of patients with chronic obstructive pulmonary disease (COPD). In order to achieve the maximal level of independence, autonomy, and functioning of the patient, targeted therapies and interventions based on the identification of physical, emotional and social traits need to be provided by a dedicated, interdisciplinary PR team. Areas covered: The review discusses cardiopulmonary exercise testing in the selection of different modes of training modalities. Neuromuscular electrical stimulation as well as gait assessment and training are discussed as well as add-on therapies as oxygen, noninvasive ventilator support or endoscopic lung volume reduction in selected patients. The potentials of pulsed inhaled nitric oxide in patients with underlying pulmonary hypertension is explored as well as nutritional support. The impact of sleep quality on outcomes of PR is reviewed. Expert opinion: Individualized, comprehensive intervention based on thorough assessment of physical, emotional, and social traits in COPD patients forms a continuous challenge for health-care professionals and PR organizations in order to dynamically implement and adapt these strategies based on dynamic, more optimal understanding of underlying pathophysiological mechanisms.

In 1919, August Krogh published his seminal work on skeletal muscle oxygenation. Krogh’s observations indicated that muscle capillary diameter is actively regulated, rather than a passive result of arterial blood flow regulation. Indeed, combining a mathematical model with the number of ink-filled capillaries he observed in muscle cross sections taken at different workloads, Krogh was able to account for muscle tissue’s remarkably efficient oxygen extraction during exercise in terms of passive diffusion from nearby capillaries. Krogh was awarded the 1920 Nobel Prize for his account of muscle oxygenation. Today, his observations are engrained in the notion of capillary recruitment: the opening of previously closed capillaries. While the binary distinction between “closed” and “open” was key to Krogh’s model argument, he did in fact report a continuum of capillary diameters, degrees of erythrocyte deformation, and perfusion states. Indeed, modern observations question the presence of closed muscle capillaries. We therefore examined whether changes in capillary flow patterns and hematocrit among open capillaries can account for oxygen extraction in muscle across orders-of-magnitude changes in blood flow. Our four-compartment model of oxygen extraction in muscle confirms this notion and provides a framework for quantifying the impact of changes in microvascular function on muscle oxygenation in health and disease. Our results underscore the importance of capillary function for oxygen extraction in muscle tissue as first proposed by Krogh. While Krogh’s model calculations still hold, our model predictions support that capillary recruitment can be viewed in the context of continuous, rather than binary, erythrocyte distributions among capillaries.NEW & NOTEWORTHY Oxygen extraction in working muscle is extremely efficient in view of single capillaries properties. The underlying mechanisms have been widely debated. Here, we develop a four-compartment model to quantify the influence of each of the hypothesized mechanisms on muscle oxygenation. Our results show that changes in capillary flow pattern and hematocrit can account for the high oxygen extraction observed in working muscle, while capillary recruitment is not required to account for these extraction properties.

Summary Insulin resistance and muscle mass loss often coincide in individuals with type 2 diabetes. Most patients with type 2 diabetes are overweight, and it is well established that obesity and derangements in lipid metabolism play an important role in the development of insulin resistance in these individuals. Specifically, increased adipose tissue mass and dysfunctional adipose tissue lead to systemic lipid overflow and to low‐grade inflammation via altered secretion of adipokines and cytokines. Furthermore, an increased flux of fatty acids from the adipose tissue may contribute to increased fat storage in the liver and in skeletal muscle, resulting in an altered secretion of hepatokines, mitochondrial dysfunction, and impaired insulin signalling in skeletal muscle. Recent studies suggest that obesity and lipid derangements in adipose tissue can also lead to the development of muscle atrophy, which would make insulin resistance and muscle atrophy two sides of the same coin. Unfortunately, the exact relationship between lipid accumulation, type 2 diabetes, and muscle atrophy remains largely unexplored. The aim of this review is to discuss the relationship between type 2 diabetes and muscle loss and to discuss some of the joint pathways through which lipid accumulation in organs may affect peripheral insulin sensitivity and muscle mass.

High-circulating lipid availability attenuates protein feeding-induced muscle protein synthesis (MPS). Whether the combined effects of exercise and protein ingestion can rescue this inhibition is unknown. In a parallel-groups design, middle-aged sedentary males (n = 28) matched for fat-free mass and body mass index received a 5-h intravenous infusion of either saline/control (n = 9), 20% intralipid infusion (n = 9), or intralipid with concomitant exercise (n = 10). Two hours into each of these infusions, participants received a primed constant infusion of L-(ring-[C-13](6))-phenylalanine. Muscle biopsies were taken immediately after control and lipid infusions, at which time, a 30-g protein beverage was ingested. Further biopsies were taken 2 and 4 h after protein ingestion. Intralipid increased plasma free fatty acid concentrations from similar to 0.4-2 mM, resulting in an attenuated MPS response to protein ingestion, which was prevented by exercise. Intralipid resulted in a lower peak aminoacidemia following protein ingestion that was exacerbated by prior exercise, suggesting efficiency of the working skeletal muscle to utilize amino acid substrate to drive the postprandial anabolic response. We conclude that in the face of high-fat availability, exercise preserves the sensitivity of skeletal muscle to the anabolic properties of amino acids.-Smiles, W. J., Churchward-Venne, T. A., van Loon, L. J. C., Hawley, J. A., Camera, D. M. A single bout of strenuous exercise overcomes lipid-induced anabolic resistance to protein ingestion in overweight, middle-aged men.

Objective Trapezius myalgia or, more specifically, myofascial dysfunction of the upper trapezius mainly affects women performing jobs requiring prolonged low level activation of the muscle. This continuous low muscle load can be accompanied by a shift to a more anaerobic energy metabolism, causing pain. The aim of the study was to investigate whether morphological signs of an impaired aerobic metabolism are present in female office workers with trapezius myalgia. Design Muscle biopsy analysis, using electron and light microscopy, was performed to compare mitochondrial and fat droplet morphology, and irregular muscle fibers, between female office workers with (n = 17) and without (n = 15) work-related trapezius myalgia. Results The patient group showed a significantly higher mean area (P = 0.023) and proportion (P = 0.029) for the subsarcolemmal and intermyofibrillar mitochondria respectively, compared with the control group. A significantly lower mean area of subsarcolemmal lipid droplets was found in the patient group (P = 0.015), which also displayed a significantly higher proportion of lipid droplets touching the mitochondria (P = 0.035). A significantly higher amount of muscle fibers with cytochrome c oxidase-deficient areas were found in the patient group (P = 0.030). Conclusions The results of the present study may be indicative for an impaired oxidative metabolism in work-related trapezius myalgia. However, additional research is necessary to confirm this hypothesis.

Background & aims: Sarcopenia is a muscle disorder associated with loss of muscle mass, strength and function. Early screening, diagnosis and treatment may improve outcome in different disease conditions. A wide variety of tools for estimation of muscle mass is available and each tool has specific technical requirements. However, different investigational settings and lack of homogeneity of populations influence the definition of gold standards, proving it difficult to systematically adopt these tools. Recently, the European Working Group on Sarcopenia in Older People (EWGSOP) published a revised recommendation (EWGSOP-2) and algorithm for using tools for screening and diagnosing sarcopenia. However, agreement of the EWGSOP2 criteria with other classifications is poor and although an overview of available tools is valuable, for the purpose of clinical decision-making the reverse is useful; a given scenario asks for the most suitable tools. Results: Tools were identified for screening, diagnostics and longitudinal monitoring of muscle mass. For each of these clinical scenarios the most appropriate tools were listed and for each technique their usability is specified based on sensitivity and specificity. Based on this information a specific recommendation is made for each clinical scenario. Conclusion: This narrative review provides an overview of currently available tools and future developments for different clinical scenarios such as screening, diagnosis and longitudinal monitoring of alterations in muscle status. It supports clinical decision-making in choosing the right tools for muscle mass quantification depending on the need within a given clinical scenario as well as the local availability and expertise. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.

BACKGROUND: Short-term ( 0.05). Immobilization led to 2.3 ± 0.4%, 2.7 ± 0.2%, and 2.0 ± 0.4% decreases in quadriceps muscle volume (P < 0.05) of the immobilized leg in the HIGH, LOW, and NO groups (P < 0.05), respectively, with no significant differences between groups (P > 0.05). D2O ingestion resulted in comparable plasma free [2H]-alanine enrichments during immobilization (∼2.5 mole percentage excess) across groups (P > 0.05). Daily MyoPS rates during immobilization were 30 ± 2% (HIGH), 26 ± 3% (LOW), and 27 ± 2% (NO) lower in the immobilized compared with the control leg, with no significant differences between groups (P > 0.05). CONCLUSIONS: Three days of muscle disuse induces considerable declines in muscle mass and daily MyoPS rates. However, daily protein intake does not modulate any ofthese muscle deconditioning responses.Clinical trial registry number: NCT03797781.

Due to the invasiveness of a muscle biopsy, there is fragmentary information on the existence and possible origin of a sexual dimorphism in the skeletal muscle concentrations of the energy delivery-related metabolites carnosine, creatine, and carnitine. As these metabolites can be noninvasively monitored by proton magnetic resonance spectroscopy, this technique offers the possibility to investigate if sexual dimorphisms are present in an adult reference population and if these dimorphisms originated during puberty using a longitudinal design. Concentrations of carnosine, creatine, and carnitine were examined using proton magnetic resonance spectroscopy in the soleus and gastrocnemius muscles of an adult reference population of female (n = 50) and male adults (n = 50). For the longitudinal follow-up over puberty, 29 boys and 28 girls were scanned prepuberty. Six years later, 24 boys and 24 girls were rescanned postpuberty. A sexual dimorphism was present in carnosine and creatine, but not carnitine, in the adult reference population. Carnosine was 28.5% higher in the gastrocnemius (P < 0.001) and carnosine and creatine were respectively 19.9% (P < 0.001) and 18.2% (P < 0.001) higher in the soleus of male when compared with female adults. Through puberty, carnosine increased more in male subjects compared with female subjects, both in the gastrocnemius (+10.43% and -10.83%, respectively; interaction effect: P = 0.002) and in the soleus ( +24.30% and +5.49%, respectively; interaction effect: P = 0.012). No significant effect of puberty was found in either creatine (interaction effect: P = 0.307) or carnitine (interaction effect: P = 0.066). A sexual dimorphism in the adult human muscle is present in carnosine and creatine, but not in carnitine. NEW & NOTEWORTHY This is the first study to investigate sexual dimorphisms in skeletal muscle carnosine, creatine, and carnitine concentrations in a substantial adult reference population (n = 100). A sexual dimorphism is present in both carnosine and creatine at adult age. The origin of the sexual dimorphisms is investigated using a longitudinal design over puberty in 24 males and 24 females. The sexual dimorphism in carnosine originated partly during puberty for carnosine, but not for creatine.

This Review provides insight into sexual dimorphism in adipose tissue distribution and substrate metabolism in adipose tissue, skeletal muscle and liver, as well as the underlying mechanisms. The effects of these sex differences on cardiometabolic health are outlined and the potential for developing sex-specific prevention and treatment strategies is discussed.Obesity is associated with many adverse health effects, such as an increased cardiometabolic risk. Despite higher adiposity for a given BMI, premenopausal women are at lower risk of cardiometabolic disease than men of the same age. This cardiometabolic advantage in women seems to disappear after the menopause or when type 2 diabetes mellitus develops. Sexual dimorphism in substrate supply and utilization, deposition of excess lipids and mobilization of stored lipids in various key metabolic organs (such as adipose tissue, skeletal muscle and the liver) are associated with differences in tissue-specific insulin sensitivity and cardiometabolic risk profiles between men and women. Moreover, lifestyle-related factors and epigenetic and genetic mechanisms seem to affect metabolic complications and disease risk in a sex-specific manner. This Review provides insight into sexual dimorphism in adipose tissue distribution, adipose tissue, skeletal muscle and liver substrate metabolism and tissue-specific insulin sensitivity in humans, as well as the underlying mechanisms, and addresses the effect of these sex differences on cardiometabolic health. Additionally, this Review highlights the implications of sexual dimorphism in the pathophysiology of obesity-related cardiometabolic risk for the development of sex-specific prevention and treatment strategies.

BackgroundLow carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility.MethodsIn a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis.ResultsL-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this.ConclusionAcute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.

BACKGROUND: Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it. RESEARCH QUESTION: Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients? STUDY DESIGN AND METHODS: In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones. RESULTS: Muscle loss was similar between arms (-1.1% [95% CI, -6.1% to -4.0%]; P =.676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P INTERPRETATION: Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe.

When muscle biopsies first began to be used routinely in research on exercise physiology five decades ago, it soon become clear that the muscle content of glycogen is an important determinant of exercise performance. Glycogen particles are stored in distinct pools within the muscles, but the role of each pool during exercise and how this is affected by diet is unknown. Here, the effects of diet and exercise on these pools, as well as their relationship to endurance during prolonged cycling were examined. We demonstrate here that an improved endurance capacity with high carbohydrate loading is associated with a temporal shift in the utilization of the distinct stores of glycogen pools and is closely linked to the content of the glycogen pool closest to actin and myosin (intramyofibrillar glycogen). These findings highlight the functional importance of distinguishing between different subcellular microcompartments of glycogen in individual muscle fibres ABSTRACT: In muscle cells, glycogen is stored in three distinct subcellular pools: between or within myofibrils (inter- and intramyofibrillar glycogen, respectively) or beneath the sarcolemma (subsarcolemmal glycogen) and these pools may well have different functions. Here, we investigated the effect of diet and exercise on the content of these distinct pools and their relation to endurance capacity in type 1 and 2 muscle fibres. Following consumption of three different diets (MIX, high in carbohydrate = HIGH, or low in carbohydrate = LOW) for 72 h, 11 men cycled at 75% of VCO2 max until exhaustion. The volumetric content of the glycogen pools in muscle biopsies obtained before, during, and after exercise were quantified by transmission electron micrograph. Mean (SD) time to exhaustion was 150 (30), 112 (22), and 69 (18) minutes in the HIGH, MIX, and LOW trials, respectively (P < 0.001). As shown by multiple regression analyses, the intramyofibrillar glycogen content in type 1 fibres, particularly after 60 min of exercise, correlated the strongest with time to exhaustion. In the HIGH trial, intramyofibrillar glycogen was spared during the initial 60 min of exercise, which was associated with above levels and utilisation of subsarcolemmal glycogen above normal. In all trials, utilisation of subsarcolemmal and intramyofibrillar glycogen was more pronounced than that of intermyofibrillar glycogen in relative terms. In conclusion, the muscle pool of intramyofibrillar glycogen appears to be the most important for endurance capacity in humans. In addition, a local abundance of subsarcolemmal glycogen reduces the utilization of intramyofibrillar glycogen during exercise. This article is protected by copyright. All rights reserved.

Background: Whey and micellar casein are high-quality dairy proteins that can stimulate postprandial muscle protein synthesis rates. How whey and casein compare with milk protein in their capacity to stimulate postprandial myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis rates during postexercise recovery is currently unknown.Objective: The objective of this study was to compare postprandial MyoPS and MitoPS rates after protein-carbohydrate co-ingestion with milk protein, whey, or micellar casein during recovery from a single bout of concurrent resistance-and endurance-type exercise in young healthy men.Methods: In a randomized, double-blind, parallel-group design, 48 healthy, young, recreationally active men (mean +/- SEM age: 23 +/- 0.3 y) received a primed continuous infusion of L-[ring-C-13(6)]-phenylalanine and L-[ring-3,5-H-2(2)]-tyrosine and ingested 45 g carbohydrate with 0 g protein (CHO), 20 g milk protein (MILK), 20 g whey protein (WHEY), or 20 g micellar casein protein (CASEIN) after a sequential bout of resistance-and endurance-type exercise (i.e., concurrent exercise). Blood and muscle biopsies were collected over 360 min during recovery from exercise to assess MyoPS and MitoPS rates and signaling through mammalian target of rapamycin complex 1 (mTORC1).Results: Despite temporal differences in postprandial plasma leucine concentrations between treatments (P Conclusion: MyoPS and MitoPS rates do not differ after co-ingestion of either milk protein, whey protein, or micellar casein protein with carbohydrate during recovery from a single bout of concurrent resistance-and endurance-type exercise in recreationally active young men. Co-ingestion of protein with carbohydrate results in greater MyoPS, but not MitoPS rates, when compared with the ingestion of carbohydrate only during recovery from concurrent exercise.

Purpose Moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) are associated with different adjustments in motor output. Changes in motor unit (MU) peripheral properties may contribute to these adjustments, but this is yet to be elucidated. This study evaluated early changes in MU conduction velocity (MUCV) and MU action potential amplitude after 2 wk of either HIIT or MICT. Methods Sixteen men were assigned to either an MICT group or HIIT group (n = 8 each), and participated in six training sessions over 14 d. HIIT: 8 to 12 x 60-s intervals at 100% peak power output. Moderate-intensity continuous training: 90 to 120 min continuous cycling at similar to 65% VO2peak. Preintervention and postintervention, participants performed maximal voluntary contractions (MVC) and submaximal (10%, 30%, 50%, and 70% of MVC) isometric knee extensions while high-density EMG was recorded from the vastus medialis (VM) and vastus lateralis (VL) muscles. The high-density EMG was decomposed into individual MU by convolutive blind-source separation and tracked preintervention and postintervention. Results Both training interventions induced changes in MUCV, but these changes depended on the type of training (P < 0.001). The HIIT group showed higher values of MUCV after training at all torque levels (P < 0.05), MICT only displayed changes in MUCV at low torque levels (10%-30% MVC, P < 0.002). There were no changes in MU action potential amplitude for either group (P = 0.2). Conclusions Two weeks of HIIT or MICT elicit differential changes in MUCV, likely due to the contrasting load and volume used in such training regimes. This new knowledge on the neuromuscular adaptations to training has implications for exercise prescription.

Nebulin is a very large protein required for assembly of the contractile machinery in muscle. Mutations in the nebulin gene NEB are a common cause of nemaline myopathy. Nebulin mRNA is alternatively-spliced so that each mRNA contains either exon 143 or exon 144. We have produced monoclonal antibodies specific for the regions of nebulin encoded by these two exons, enabling analysis of expression of isoforms at the protein level for the first time. All antibodies recognized a protein of the expected size (600–900 kD) and stained cross-striations of sarcomeres in muscle sections. Expression of exon 143 is developmentally-regulated since newly-formed myotubes in cell culture expressed nebulin with exon 144 only; this was confirmed at the mRNA level by qPCR. In fetal muscle, nebulin with exon 143 was expressed in some myotubes by 12-weeks of gestation and strongly-expressed in most myotubes by 17-weeks. In mature human muscle, the exon 144 antibody stained all fibres, but the exon 143 antibody staining varied from very strong in some fibres to almost-undetectable in other fibres. The results show that nebulin containing exon 144 is the default isoform early in myogenesis, while regulated expression of nebulin containing exon 143 occurs at later stages of muscle development.

Numerous situations, such as the recovery from illness or rehabilitation after injury, necessitate a period of muscle disuse in otherwise healthy individuals. Even a few days of immobilization or bed rest can lead to substantial loss of skeletal muscle tissue and compromise metabolic health. The decline in muscle mass is attributed largely to a decline in postabsorptive and postprandial muscle protein synthesis rates. Reintroduction of some level of muscle contraction by the application of neuromuscular electrical stimulation (NMES) can augment both postabsorptive and postprandial muscle protein synthesis rates and, as such, prevent or attenuate muscle loss during short-term disuse in various clinical populations. Whereas maintenance of habitual dietary protein consumption is a prerequisite for muscle mass maintenance, supplementing dietary protein above habitual intake levels does not prevent muscle loss during disuse in otherwise healthy humans. Combining the anabolic properties of physical activity (or surrogates) with appropriate nutritional support likely further increases the capacity to preserve skeletal muscle mass during a period of disuse. Therefore, effective interventional strategies to prevent or alleviate muscle disuse atrophy should include both exercise (mimetics) and appropriate nutritional support.

AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser237 in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake. Here, we show AMPK heterotrimers containing the α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosine-binding (PTB) domains of TBC1D1 and is increased by two different pharmacological activators of AMPK (AICAR and A769962). The interaction enhances the efficiency by which AMPK phosphorylates TBC1D1 on its key regulatory site, Ser237. Furthermore, the interaction is reduced by a naturally occurring R125W mutation in the PTB1 domain of TBC1D1, previously found to be associated with severe familial obesity in females, with a concomitant reduction in Ser237 phosphorylation. Our observations provide evidence for a functional difference between AMPK α-subunits and extend the repertoire of protein kinases that interact with substrates via stabilisation mechanisms that modify the efficacy of substrate phosphorylation.

Supplementation with dietary inorganic nitrate ([Formula: see text]) is increasingly recognized to confer cardioprotective effects in both healthy and clinical populations. While the mechanism(s) remains ambiguous, in skeletal muscle oral consumption of NaNO3 has been shown to improve mitochondrial efficiency. Whether NaNO3 has similar effects on mitochondria within the heart is unknown. Therefore, we comprehensively investigated the effect of NaNO3 supplementation on in vivo left ventricular (LV) function and mitochondrial bioenergetics. Healthy male Sprague-Dawley rats were supplemented with NaNO3 (1 g/l) in their drinking water for 7 days. Echocardiography and invasive hemodynamics were used to assess LV morphology and function. Blood pressure (BP) was measured by tail-cuff and invasive hemodynamics. Mitochondrial bioenergetics were measured in LV isolated mitochondria and permeabilized muscle fibers by high-resolution respirometry and fluorometry. Nitrate decreased ( P < 0.05) BP, LV end-diastolic pressure, and maximal LV pressure. Rates of LV relaxation (when normalized to mean arterial pressure) tended ( P = 0.13) to be higher with nitrate supplementation. However, nitrate did not alter LV mitochondrial respiration, coupling efficiency, or oxygen affinity in isolated mitochondria or permeabilized muscle fibers. In contrast, nitrate increased ( P < 0.05) the propensity for mitochondrial H2O2 emission in the absence of changes in cellular redox state and decreased the sensitivity of mitochondria to ADP (apparent Km). These results add to the therapeutic potential of nitrate supplementation in cardiovascular diseases and suggest that nitrate may confer these beneficial effects via mitochondrial redox signaling.

There is a growing body of evidence that links nutrition to muscle mass, strength and function in older adults, suggesting that it has an important role to play both in the prevention and management of sarcopenia. This review summarises the discussions of a working group [ESCEO working group meeting 8th September 2016] that met to review current evidence and to consider its implications for preventive and treatment strategies. The review points to the importance of 'healthier' dietary patterns that are adequate in quality in older age, to ensure sufficient intakes of protein, vitamin D, antioxidant nutrients and long-chain polyunsaturated fatty acids. In particular, there is substantial evidence to support the roles of dietary protein and physical activity as key anabolic stimuli for muscle protein synthesis. However, much of the evidence is observational and from high-income countries. Further high-quality trials, particularly from more diverse populations, are needed to enable an understanding of dose and duration effects of individual nutrients on function, to elucidate mechanistic links, and to define optimal profiles and patterns of nutrient intake for older adults. (C) 2017 The Authors. Published by Elsevier Ltd.

Satellite cells are indispensable for skeletal muscle repair and regeneration and are associated with muscle growth in humans. Aerobic exercise training results in improved skeletal muscle health also translating to an increase in satellite cell pool activation. We postulate that aerobic exercise improves satellite cell function in skeletal muscle.

It is widely believed that an active cool-down is more effective for promoting post-exercise recovery than a passive cool-down involving no activity. However, research on this topic has never been synthesized and it therefore remains largely unknown whether this belief is correct. This review compares the effects of various types of active cool-downs with passive cool-downs on sports performance, injuries, long-term adaptive responses, and psychophysiological markers of post-exercise recovery. An active cool-down is largely ineffective with respect to enhancing same-day and next-day(s) sports performance, but some beneficial effects on next-day(s) performance have been reported. Active cool-downs do not appear to prevent injuries, and preliminary evidence suggests that performing an active cool-down on a regular basis does not attenuate the long-term adaptive response. Active cool-downs accelerate recovery of lactate in blood, but not necessarily in muscle tissue. Performing active cool-downs may partially prevent immune system depression and promote faster recovery of the cardiovascular and respiratory systems. However, it is unknown whether this reduces the likelihood of post-exercise illnesses, syncope, and cardiovascular complications. Most evidence indicates that active cool-downs do not significantly reduce muscle soreness, or improve the recovery of indirect markers of muscle damage, neuromuscular contractile properties, musculotendinous stiffness, range of motion, systemic hormonal concentrations, or measures of psychological recovery. It can also interfere with muscle glycogen resynthesis. In summary, based on the empirical evidence currently available, active cool-downs are largely ineffective for improving most psychophysiological markers of post-exercise recovery, but may nevertheless offer some benefits compared with a passive cool-down.

Satellite cells are indispensable for skeletal muscle repair and regeneration and are associated with muscle growth in humans. Aerobic exercise training results in improved skeletal muscle health also translating to an increase in satellite cell pool activation. We postulate that aerobic exercise improves satellite cell function in skeletal muscle.

Summary: Glucagon, the principal hyperglycemic hormone, is secreted from pancreatic islet α cells as part of the counter-regulatory response to hypoglycemia. Hence, secretory output from α cells is under high demand in conditions of low glucose supply. Many tissues oxidize fat as an alternate energy substrate. Here, we show that glucagon secretion in low glucose conditions is maintained by fatty acid metabolism in both mouse and human islets, and that inhibiting this metabolic pathway profoundly decreases glucagon output by depolarizing α cell membrane potential and decreasing action potential amplitude. We demonstrate, by using experimental and computational approaches, that this is not mediated by the KATP channel, but instead due to reduced operation of the Na+-K+ pump. These data suggest that counter-regulatory secretion of glucagon is driven by fatty acid metabolism, and that the Na+-K+ pump is an important ATP-dependent regulator of α cell function. : Glucagon is secreted from pancreatic α cells in hypoglycemic conditions. Briant et al. demonstrate that this response is fueled by fatty acid oxidation. The energy generated by oxidation is used to maintain membrane potential dynamics, action potential morphology, and Na+-K+ pump activity. Keywords: islet, metabolism, glucose, Ca2+, KATP, liver, fasting

Intramyocellular lipid (IMCL) hampers insulin sensitivity, albeit not in endurance-trained athletes (Trained). Compared to type 2 diabetes mellitus (T2DM) patients, Trained subjects have high levels of perilipin 5 (PLIN5). In the present study, we tested whether the fraction of PLIN5-coated lipid droplets (LDs) is a determinant of skeletal muscle insulin sensitivity and contributes to the athlete's paradox. Muscle biopsies were taken from eight Trained, Lean sedentary, Obese and T2DM subjects. Trained, Obese and T2DM subjects were matched for total IMCL content. Confocal images were analysed for lipid area fraction, LD size and number and PLIN5+ and PLIN5- LDs were measured. A stepwise linear regression was performed to identify factors explaining observed variance in glucose infusion rate (GIR). Trained and T2DM subjects stored IMCL differently; Trained subjects had a higher number of LDs compared to T2DM subjects (0.0370.004m(-2)vs. 0.0230.003m(-2), P=0.024) that were non-significantly smaller (0.270.01m(2)vs. 0.320.02m(2), P=0.197, Trained vs. T2DM). Even though total PLIN5 protein content was almost double in Trained vs. T2DM subjects (1.650.21AU vs. 0.89 +/- 0.09AU, P=0.004), PLIN5 coating did not affect LD number or size significantly. Of the observed variance in GIR, the largest fraction by far (70.2%) was explained by maximal oxygen uptake. Adding PLIN5 protein content or PLIN5+ LDs increased the explained variance in GIR (74.7% and 80.7% for PLIN5 protein content and PLIN5+ LDs, respectively). Thus, the putative relationship between PLIN5 and insulin sensitivity is at best indirect and is apparent only in conjunction with maximal oxygen uptake. Hence, PLIN5 abundance cannot be causally linked to the athlete's paradox.