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The skeletal muscle excitation-contraction coupling leading to tension development and increased mechanical stimuli change in concert, leaving it difficult to study their respective effect on molecular signalling and following adaptations. In conclusion, although the interest for mechanotransduction and deciphering relative effects of tension development and excitation in skeletal muscle has had a steep increase in later years, there is still work to do. Indeed, the present paper by Rindom et al1 is a valuable contribution to the field of mechanotransduction, as it establishes a better foundation to explore the complex network of skeletal muscle plasticity. [Extracted from the article]

Aim: Histidine‐containing dipeptides (HCDs) are pleiotropic homeostatic molecules with potent antioxidative and carbonyl quenching properties linked to various inflammatory, metabolic, and neurological diseases, as well as exercise performance. However, the distribution and metabolism of HCDs across tissues and species are still unclear. Methods: Using a sensitive UHPLC–MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n = 26, n = 25, and n = 19 tissues, respectively). Results: Our data show that tissue HCD levels are uniquely produced by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast‐twitch skeletal muscle fibres and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analogue N‐acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N‐acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine‐like fashion. Conclusion: Collectively, we provide a novel basis to unravel tissue‐specific, paracrine, and endocrine roles of HCDs in human health and disease. [ABSTRACT FROM AUTHOR]

Many neuromuscular disorders can have a differential impact on a specific myofibre type, forming the central premise of this review. The many different skeletal muscles in mammals contain a spectrum of slow‐ to fast‐twitch myofibres with varying levels of protein isoforms that determine their distinctive contractile, metabolic, and other properties. The variations in functional properties across the range of classic 'slow' to 'fast' myofibres are outlined, combined with exemplars of the predominantly slow‐twitch soleus and fast‐twitch extensor digitorum longus muscles, species comparisons, and techniques used to study these properties. Other intrinsic and extrinsic differences are discussed in the context of slow and fast myofibres. These include inherent susceptibility to damage, myonecrosis, and regeneration, plus extrinsic nerves, extracellular matrix, and vasculature, examined in the context of growth, ageing, metabolic syndrome, and sexual dimorphism. These many differences emphasise the importance of carefully considering the influence of myofibre‐type composition on manifestation of various neuromuscular disorders across the lifespan for both sexes. Equally, understanding the different responses of slow and fast myofibres due to intrinsic and extrinsic factors can provide deep insight into the precise molecular mechanisms that initiate and exacerbate various neuromuscular disorders. This focus on the influence of different myofibre types is of fundamental importance to enhance translation for clinical management and therapies for many skeletal muscle disorders. [ABSTRACT FROM AUTHOR]

The author comments on a study conducted by researcher M. Venturelli and others, which focused on mechanism for in vivo loss of skeletal muscle mass and function, known as sarcopenia, in elderly women. It mentions how exercise can help prevent sarcopenia and reflects on the in vivo loss of absolute muscle contraction in old women. It informs that the study concluded that myofibres' intrinsic contractile properties in vitro may be unaffected by age.

Aim: To develop a method for direct measurement of the fluorescent d‐glucose analogue 2‐NBDG transport across the plasma membrane of single skeletal muscle fibres and derive the theoretical framework for determining the kinetic parameters for d‐glucose transport under basal conditions. Methods: A novel method is described for measuring free 2‐NBDG transport across plasma membrane of single rat muscle fibres at rest. The 2‐NBDG uptake was >90% suppressed by 100 µM cytochalasin B in both fast‐twitch and slow‐twitch fibres, indicating that the 2‐NBDG transport is GLUT‐mediated. Fibres were identified as fast‐twitch or slow‐twitch based on the differential sensitivity of their contractile apparatus to Sr2+. Results: The time course of 2‐NBDG uptake in the presence of 50 µM 2‐NBDG follows a one‐phase exponential plateau curve and is faster in fast‐twitch (rate constant 0.053 ± 0.0024 s‐1) than in slow‐twitch fibres (rate constant 0.031 ± 0.0021 s‐1). The rate constants were markedly reduced in the presence of 20 mM d‐glucose to 0.0082 ± 0.0004 s‐1 and 0.0056 ± 0.0002 s‐1 in fast‐twitch and slow‐twitch fibres respectively. 2‐NBDG transport was asymmetric, consistent with GLUT1 being the major functional GLUT isoform transporting 2‐NBDG in muscle fibres at rest. The parameters describing the transport kinetics for both 2‐NBDG and d‐glucose (dissociation constants, Michaelis–Menten constants, maximal rates of uptake and outflow) were calculated from the measurements made with 2‐NBDG. Conclusion: Free 2‐NBDG and d‐glucose transport across the plasma membrane of single rat muscle fibres at rest is fast, conclusively showing that the rate‐limiting step in d‐glucose uptake in skeletal muscle is not necessarily the GLUT‐mediated transport of d‐glucose. [ABSTRACT FROM AUTHOR]

Aim: Assessments of mitochondrial respiration and mitochondrial content are common in skeletal muscle research and exercise science. However, many sources of technical and biological variation render these analyses susceptible to error. This study aimed to better quantify the reliability of different experimental designs and/or techniques so as to assist researchers to obtain more reliable data. Methods: We examined the repeatability of maximal mitochondrial oxidative phosphorylation in permeabilized muscle fibres via high‐resolution respirometry, and citrate synthase activity (a biomarker for mitochondrial content) in a microplate with spectrophotometery. Results: For mitochondrial respiration using permeabilized skeletal muscle fibres, the variability was reduced using three chambers and removing outliers compared to two chambers (CV reduced from 12.7% to 11.0%), and the minimal change that can be detected with 10 participants reduced from 17% to 13% according to modelling. For citrate synthase activity, the within‐plate CV (3.5%) increased when the assay was repeated after 4 hours (CV = 10.2%) and 4 weeks (CV = 30.5%). The readings were correlated, but significantly different after 4 hours and 4 weeks. Conclusion: This research provides evidence for important technical considerations when measuring mitochondrial respiration and content using citrate synthase activity as a biomarker. When assessing mitochondrial respiration in human skeletal muscle, the technical variability of high‐resolution respirometry can be reduced by increasing technical repeats and excluding outliers, practices which are not currently common. When analysing citrate synthase activity, our results highlight the importance of analysing all samples from the same study at the same time. [ABSTRACT FROM AUTHOR]

Aim: Decreased muscle strength has been frequently observed in individuals with Parkinson's disease (PD). However, this condition is still poorly examined in physically active patients. This study compared quadriceps (Q) maximal force and the contribution of central and peripheral components of force production during a maximal isometric task between physically active PD and healthy individuals. In addition, the correlation between force determinants and energy expenditure indices were investigated. Methods: Maximal voluntary contraction (MVC), resting twitch (RT) force, pennation angle (θp), physiological cross‐sectional area (PCSA) and Q volume were assessed in 10 physically active PD and 10 healthy control (CTRL) individuals matched for age, sex and daily energy expenditure (DEE) profile. Results: No significant differences were observed between PD and CTRL in MVC (142 ± 85; 142 ± 47 N m), Q volume (1469 ± 379; 1466 ± 522 cm3), PCSA (206 ± 54; 205 ± 71 cm2), θp (14 ± 7; 13 ± 3 rad) and voluntary muscle‐specific torque (MVC/PCSA [67 ± 35; 66 ± 19 N m cm−2]). Daily calories and MVC correlated (r = 0.56, P =.0099). However, PD displayed lower maximal voluntary activation (MVA) (85 ± 7; 95 ± 5%), rate of torque development (RTD) in the 0‐0.05 (110 ± 70; 447 ± 461 N m s−1) and the 0.05‐0.1 s (156 ± 135; 437 ± 371 N m s−1) epochs of MVCs, whereas RT normalized for PCSA was higher (35 ± 14; 20 ± 6 N m cm−2). Conclusion: Physically active PDs show a preserved strength of the lower limb. This resulted by increasing skeletal muscle contractility, which counterbalances neuromuscular deterioration, likely due to their moderate level of physical activity. [ABSTRACT FROM AUTHOR]

Aim: Loss of dystrophin causes oxidative stress and affects nitric oxide synthase‐mediated vascular function in striated muscle. Because tetrahydrobiopterin is an antioxidant and co‐factor for nitric oxide synthase, we tested the hypothesis that tetrahydrobiopterin would be low in mdx mice and humans deficient for dystrophin. Methods: Tetrahydrobiopterin and its metabolites were measured at rest and in response to exercise in Duchenne and Becker muscular dystrophy patients, age‐matched male controls as well as wild‐type, mdx and mdx mice transgenically overexpressing skeletal muscle‐specific dystrophins. Mdx mice were also supplemented with tetrahydrobiopterin and pathophysiology was assessed. Results: Duchenne muscular dystrophy patients had lower urinary dihydrobiopterin + tetrahydrobiopterin/specific gravity1.020 compared to unaffected age‐matched males and Becker muscular dystrophy patients. Mdx mice had low urinary and skeletal muscle dihydrobiopterin + tetrahydrobiopterin compared to wild‐type mice. Overexpression of dystrophins that localize neuronal nitric oxide synthase restored dihydrobiopterin + tetrahydrobiopterin in mdx mice to wild‐type levels while utrophin overexpression did not. Mdx mice and Duchenne muscular dystrophy patients did not increase tetrahydrobiopterin during exercise and in mdx mice tetrahydrobiopterin deficiency was likely because of lower levels of sepiapterin reductase in skeletal muscle. Tetrahydrobiopterin supplementation improved skeletal muscle strength, resistance to fatiguing and injurious contractions in vivo, increased utrophin and capillary density of skeletal muscle and lowered cardiac muscle fibrosis and left ventricular wall thickness in mdx mice. Conclusion: These data demonstrate that impaired tetrahydrobiopterin synthesis is associated with dystrophin loss and treatment with tetrahydrobiopterin improves striated muscle histopathology and skeletal muscle function in mdx mice. [ABSTRACT FROM AUTHOR]

Aim: This study sought to provide a statistically robust reference for measures of mitochondrial function from standardized high‐resolution respirometry with permeabilized human skeletal muscle (ex vivo), compare analogous values obtained via indirect calorimetry, arterial‐venous O2 differences and 31P magnetic resonance spectroscopy (in vivo) and attempt to resolve differences across complementary methodologies as necessary. Methods: Data derived from 831 study participants across research published throughout March 2009 to November 2019 were amassed to examine the biological relevance of ex vivo assessments under standard conditions, ie physiological temperatures of 37°C and respiratory chamber oxygen concentrations of ~250 to 500 μmol/L. Results: Standard ex vivo‐derived measures are lower (Z ≥ 3.01, P ≤.0258) en masse than corresponding in vivo‐derived values. Correcting respiratory values to account for mitochondrial temperatures 10°C higher than skeletal muscle temperatures at maximal exercise (~50°C): (i) transforms data to resemble (Z ≤ 0.8, P >.9999) analogous yet context‐specific in vivo measures, eg data collected during maximal 1‐leg knee extension exercise; and (ii) supports the position that maximal skeletal muscle respiratory rates exceed (Z ≥ 13.2, P <.0001) those achieved during maximal whole‐body exercise, e.g. maximal cycling efforts. Conclusion: This study outlines and demonstrates necessary considerations when actualizing the biological relevance of human skeletal muscle respiratory control, metabolic flexibility and bioenergetics from standard ex vivo‐derived assessments using permeabilized human muscle. These findings detail how cross‐procedural comparisons of human skeletal muscle mitochondrial function may be collectively scrutinized in their relationship to human health and lifespan. [ABSTRACT FROM AUTHOR]

Aim: Loading‐induced tension development is often assumed to constitute an independent cue to initiate muscle protein synthesis following resistance exercise. However, with traditional physiological models of resistance exercise, changes in loading‐induced tension development also reflect changes in neural activation patterns, and direct evidence for a mechanosensitive mechanism is therefore limited. Here, we sought to examine the importance of excitation and tension development per se on initiation of signalling, gene transcription and protein synthesis in rat skeletal muscle. Methods: Isolated rat extensor digitorum longus muscles were allocated to the following interventions: (a) Excitation‐induced eccentric contractions (ECC); (b) Passive stretching without excitation (PAS); (c) Excitation with inhibition of contractions (STIM + IMA) and; (d) Excitation in combination with both inhibition of contractions and PAS (STIM + IMA + PAS). Assessment of transcriptional and translational signalling, gene transcription and acute muscle protein synthesis was compared in stimulated vs contra‐lateral non‐stimulated control muscle. Results: Protein synthesis increased solely in muscles subjected to a combination of excitation and tension development (ECC and STIM + IMA + PAS). The same pattern was true for p38 mitogen‐activated protein kinase signalling for gene transcription as well as for gene transcription of immediate early genes FOS and JUN. In contrast, mechanistic target of rapamycin Complex 1 signalling for translation initiation increased in all muscles subjected to increased tension development (ECC and STIM + IMA + PAS as well as PAS). Conclusions: The current study suggests that exercise‐induced increases in protein synthesis as well as transcriptional signalling is dependent on the concomitant effect of excitation and tension development, whereas signalling for translation initiation is only dependent of tension development per se. [ABSTRACT FROM AUTHOR]

Within the current paradigm of the myonuclear domain theory, it is postulated that a linear relationship exists between muscle fibre size and myonuclear content. The myonuclear domain is kept (relatively) constant by adding additional nuclei (supplied by muscle satellite cells) during muscle fibre hypertrophy and nuclear loss (by apoptosis) during muscle fibre atrophy. However, data from recent animal studies suggest that myonuclei that are added to support muscle fibre hypertrophy are not lost within various muscle atrophy models. Such myonuclear permanence has been suggested to constitute a mechanism allowing the muscle fibre to (re)grow more efficiently during retraining, a phenomenon referred to as "muscle memory." The concept of "muscle memory by myonuclear permanence" has mainly been based on data attained from rodent experimental models. Whether the postulated mechanism also holds true in humans remains largely ambiguous. Nevertheless, there are several studies in humans that provide evidence to potentially support or contradict (parts of) the muscle memory hypothesis. The goal of the present review was to discuss the evidence for the existence of "muscle memory" in both animal and human models of muscle fibre hypertrophy as well as atrophy. Furthermore, to provide additional insight in the potential presence of muscle memory by myonuclear permanence in humans, we present new data on previously performed exercise training studies. Finally, suggestions for future research are provided to establish whether muscle memory really exists in humans. [ABSTRACT FROM AUTHOR]

Aim: Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta‐analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin‐induced muscle atrophy in both human and animal models. Methods: A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool. Results: Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross‐sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin‐induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin‐proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin‐induced muscle atrophy, the activation of the ubiquitin‐proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway. Conclusion: The results of the meta‐analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose‐response, separate the effects of doxorubicin from tumour‐induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Prolonged unloading of skeletal muscle, a common outcome of events such as spaceflight, bed rest and hindlimb unloading, can result in extensive metabolic, structural and functional changes in muscle fibres. With advancement in investigations of cellular and molecular mechanisms, understanding of disuse muscle atrophy has significantly increased. However, substantial gaps exist in our understanding of the processes dictating muscle plasticity during unloading, which prevent us from developing effective interventions to combat muscle loss. This review aims to update the status of knowledge and underlying mechanisms leading to cellular and molecular changes in skeletal muscle during unloading. We have also discussed advances in the understanding of contractile dysfunction during spaceflights and in ground‐based models of muscle unloading. Additionally, we have elaborated on potential therapeutic interventions that show promising results in boosting muscle mass and strength during mechanical unloading. Finally, we have identified key gaps in our knowledge as well as possible research direction for the future. [ABSTRACT FROM AUTHOR]

There was a significant reduction in SP 15 sp N-labeled muscle NO SB 3 sb SP - sp from pre- to post-exercise which has the important implication that the nitrate that accumulated in skeletal muscle following the dietary nitrate supplementation was utilized during the exercise bout. 15N-labeled dietary nitrate supplementation increases human skeletal muscle nitrate concentration and improves muscle torque production The biochemical background and physiological mechanism behind the fascinating effects of dietary nitrate supplementation is that nitric oxide (NO) can be formed nonenzymatically in the nitrate-nitrite-nitric oxide pathway via nitrite reduction. [Extracted from the article]

The author discusses a study by Greiwe et al. which clarifies several aspects of training related lymphangiogenesis and lymphatic vessel densities in skeletal muscles and myocardium and raises important questions for further investigations. It states that lymphatic vascular system is a relatively rare focus of the modern cardiovascular research.

Abstract: Intensive care interventions involve periods of mechanical ventilation, sedation and complete mechanical silencing of patients. Critical illness myopathy (CIM) is an ICU‐acquired myopathy that is associated with limb muscle weakness, muscle atrophy, electrical silencing of muscle and motor proteinopathy. The hallmark of CIM is a preferential muscle myosin loss due to increased catabolic and reduced anabolic activity. The ubiquitin proteasome pathway plays an important role, apart from recently identified novel mechanisms affecting non‐lysosomal protein degradation or autophagy. CIM is not reproduced by pure disuse atrophy, denervation atrophy, steroid‐induced atrophy or septic myopathy, although combinations of high‐dose steroids and denervation can mimic CIM. New animal models of critical illness and ICU treatment (i.e. mechanical ventilation and complete immobilization) provide novel insights regarding the time course of protein synthesis and degradation alterations, and the role of protective chaperone activities in the process of myosin loss. Altered mechano‐signalling seems involved in triggering a major part of myosin loss in experimental CIM models, and passive loading of muscle potently ameliorates the CIM phenotype. We provide a systematic overview of similarities and distinct differences in the signalling pathways involved in triggering muscle atrophy in CIM and isolated trigger factors. As preferential myosin loss is mostly determined from biochemistry analyses providing no spatial resolution of myosin loss processes within myofibres, we also provide first results monitoring myosin signal intensities during experimental ICU intervention using multi‐photon Second Harmonic Generation microscopy. Our results confirm that myosin loss is an evenly distributed process within myofibres rather than being confined to hot spots. [ABSTRACT FROM AUTHOR]

Aim Is modulation of skeletal muscle capillary supply by altering blood flow due to a presumptive shear stress response per se, or dependent on the vasodilator mechanism? Methods The response to four different vasodilators, and cotreatment with blockers of NO and prostaglandin synthesis, was compared. Femoral artery blood flow was correlated with capillary-to-fibre ratio (C:F) and protein levels of putative angiogenic compounds. Results All vasodilators induced a similar increase in blood flow after 14 days, with a similar effect on C:F (1.62 ± 0.05, 1.60 ± 0.01, 1.57 ± 0.06, 1.57 ± 0.07, respectively, all P < 0.05 vs. control 1.20 ± 0.01). Concomitant inhibitors revealed differential effects on blood flow and angiogenesis, demonstrating that a similar response may have different signalling origins. The time course of this response with the most commonly used vasodilator, prazosin, showed that blood flow increased from 0.40 mL min−1 to 0.61 mL min−1 by 28 days ( P < 0.05), dropped within 1 week after the cessation of treatment (0.54 mL min−1; P < 0.05) and returned to control levels by 6 weeks. In parallel with FBF, capillary rarefaction began within 1 week ( P < 0.05), giving C:F values similar to control by 2 weeks. Of the dominant signalling pathways, prazosin decreased muscle VEGF, but increased its cognate receptor Flk-1 (both P < 0.01); levels of eNOS varied with blood flow ( P < 0.05), and Ang-1 initially increased, while its receptor Tie-2 was unchanged, with only modest changes in the antiangiogenic factor TSP-1. Conclusion Hyperaemia-induced angiogenesis, likely in response to elevated shear stress, is independent of the vasodilator involved, with a rapid induction and quick regression following the stimulus withdrawal. [ABSTRACT FROM AUTHOR]

In a 1914 book entitled The Respiratory Function of the Blood, Joseph Barcroft stated that 'the cell takes what it needs and leaves the rest'. He postulated that there must be both a 'call for oxygen' and a 'mechanism by which the call elicits a response...' In the past century, intensive investigation has provided significant insights into the haemodynamic and biophysical mechanisms involved in supplying oxygen to skeletal muscle. However, the identification of the mechanism by which tissue oxygen needs are sensed and the affector responsible for altering the upstream vasculature to enable the need to be appropriately met has been a challenge. In 1995, Ellsworth et al. proposed that the oxygen-carrying erythrocyte, by virtue of its capacity to release the vasoactive mediator ATP in response to a decrease in oxygen saturation, could serve both roles. Several in vitro and in situ studies have established that exposure of erythrocytes to reduced oxygen tension induces the release of ATP which does result in a conducted arteriolar vasodilation with a sufficiently rapid time course to make the mechanism physiologically relevant. The components of the signalling pathway for the controlled release of ATP from erythrocytes in response to exposure to low oxygen tension have been determined. In addition, the implications of defective ATP release on human pathological conditions have been explored. This review provides a perspective on oxygen supply and the role that such a mechanism plays in meeting the oxygen needs of skeletal muscle. [ABSTRACT FROM AUTHOR]

The article discusses the adverse effects of ageing, particularly the contribution of mitochondria-derived free radicals to endothelial dysfunction in human skeletal muscle feed arteries. Also cited are the significant attenuation of endothelium-dependent dilation, reduction in phospho-eNOS/NOS (p-eNOS/eNOS) ratio and elevations in vascular superoxide levels in older people, and the possible role of mitochondria as a source of oxidative stress.

Aims Myeloperoxidase ( MPO) catalyses the formation of a wide variety of oxidants, including hypochlorous acid ( HOCl), and contributes to cardiovascular disease progression. We hypothesized that during its action MPO evokes substantial vasomotor responses. Methods Following exposure to MPO (1.92 mU mL−1) in the presence of increasing concentrations of hydrogen peroxide (H2O2), changes in arteriolar diameter of isolated gracilis skeletal muscle arterioles ( SMAs) and coronary arterioles ( CAs) and in the isometric force in basilar arteries ( BAs) of the rat were monitored. Results Myeloperoxidase increased vascular tone to different degrees in CAs, SMAs and BAs. The mechanism of increased vasoconstriction was studied in detail in SMAs. MPO-evoked vasoconstrictions were prevented by the MPO inhibitor 4-aminobenzhydrazide (50 μ m), by endothelium removal in the SMAs. Surprisingly, the HOCl scavenger L-methionine (100 μ m), the thromboxane A2 ( TXA2) antagonist SQ-29548 (1 μ m) or the non-specific cyclooxygenase ( COX) antagonist indomethacin (1 μ m) converted the MPO-evoked vasoconstrictions to pronounced vasodilations in SMAs, not seen in the presence of H2O2. In contrast to noradrenaline-induced vasoconstrictions, the MPO-evoked vasoconstrictions were not accompanied by significant increases in arteriolar [Ca2+] levels in SMAs. Conclusion These data showed that H2O2-derived HOCl to be a potent vasoconstrictor upon MPO application. HOCl activated the COX pathway, causing the synthesis and release of a TXA2-like substance to increase the Ca2+ sensitivity of the contractile apparatus in vascular smooth muscle cells and thereby to augment H2O2-evoked vasoconstrictions. Nevertheless, inhibition of the HOCl- COX- TXA2 pathway unmasked the effects of additional MPO-derived radicals with a marked vasodilatory potential in SMAs. [ABSTRACT FROM AUTHOR]

Aim Mitochondria undergo continuous changes in shape as result of complex fusion and fission processes. The physiological relevance of mitochondrial dynamics is still unclear. In the field of mitochondria bioenergetics, there is a need of tools to assess cell mitochondrial content. To develop a method to visualize mitochondrial networks in high resolution and assess mitochondrial volume. Methods Confocal fluorescence microscopy imaging of mitochondrial network stains in human vastus lateralis single muscle fibres and focused ion beam/ scanning electron microscopy (FIB/SEM) imaging, combined with 3D reconstruction was used as a tool to analyse mitochondrial morphology and measure mitochondrial fractional volume. Results Most type I and type II muscle fibres have tubular highly interconnected profusion mitochondria, which are thicker and more structured in type I muscle fibres (Fig. 1). In some muscle fibres, profission-isolated ellipsoid-shaped mitochondria were observed. Mitochondrial volume was significantly higher in type I muscle fibres and showed no correlation with any of the investigated molecular and biochemical mitochondrial measurements (Fig. 2). Three-dimensional reconstruction of FIB/SEM data sets shows that some subsarcolemmal mitochondria are physically interconnected with some intermyofibrillar mitochondria (Fig. 3). Conclusion Two microscopy methods to visualize skeletal muscle mitochondrial networks in 3D are described and can be used as tools to investigate mitochondrial dynamics in response to life-style interventions and/or in certain pathologies. Our results question the classification of mitochondria into subsarcolemmal and intermyofibrillar pools, as they are physically interconnected. [ABSTRACT FROM AUTHOR]

Magnetic resonance spectroscopy ( MRS) can give information about cellular metabolism in vivo which is difficult to obtain in other ways. In skeletal muscle, non-invasive 31 P MRS measurements of the post-exercise recovery kinetics of p H, [ PCr], [ Pi] and [ ADP] contain valuable information about muscle mitochondrial function and cellular p H homeostasis in vivo, but quantitative interpretation depends on understanding the underlying physiology. Here, by giving examples of the analysis of 31 P MRS recovery data, by some simple computational simulation, and by extensively comparing data from published studies using both 31 P MRS and invasive direct measurements of muscle O2 consumption in a common analytical framework, we consider what can be learnt quantitatively about mitochondrial metabolism in skeletal muscle using MRS-based methodology. We explore some technical and conceptual limitations of current methods, and point out some aspects of the physiology which are still incompletely understood. [ABSTRACT FROM AUTHOR]

Aim By a combined electromyographic ( EMG), mechanomyographic ( MMG) and force (F) analysis, the electromechanical delay during muscle relaxation (R-DelayTOT) was partitioned into electrochemical and mechanical components. The study aimed to evaluate the effects of fatigue on R-DelayTOT components and to assess their intersession and interday reliability Intraclass correlation coefficient (ICC). Methods During tetanic stimulations, EMG, MMG and F were recorded from the human gastrocnemius medialis muscle before and after fatigue. The latency between EMG and MMG ripple cessations (R-Δt EMG- MMGR, electrochemical R-DelayTOT component); between MMG ripple cessation and F decay onset (R-Δt MMGR-F, first R-DelayTOT mechanical component); and between F decay onset and maximum MMG negative peak (R-Δt F- MMGp-p, second R-DelayTOT mechanical component) was calculated. Results Before fatigue, R-Δt F- MMGp-p was the major contributor (61.9 ± 1.7 ms, 75%) to R-DelayTOT (82.7 ± 1.0 ms), while R-Δt EMG- MMGR and R-Δt MMGR-F accounted for 16% (13.3 ± 1.2 ms) and 9% (7.5 ± 1.0 ms) respectively. After fatigue, R-DelayTOT, R-Δt EMG- MMGR and R-Δt MMGR-F increased by 11, 41 and 67%, respectively ( P < 0.05), whereas R-Δt F- MMGp-p did not change. Consequently, the relative contribution of R-Δt EMG- MMGR, R-Δt MMGR-F and R-Δt F- MMGp-p, to R-DelayTOT changed to 20 ± 2, 12 ± 1 and 68 ± 2% respectively. Measurement reliability was always from high to very high (ICC 0.705-0.959). Conclusion Fatigue altered the processes between neuromuscular activation cessation and force decay onset, but not the second mechanical component (cross-bridges detachment rate and series elastic components release). This combined approach provided reliable measurement of the different R-DelayTOT components and it may represent a valid tool to get more insights on muscle electromechanical behaviour. [ABSTRACT FROM AUTHOR]

Aim We investigated architectural, functional and molecular responses of human skeletal muscle to concentric (CON) or eccentric (ECC) resistance training (RT). Methods Twelve young males performed 10 weeks of concentric (CON) or eccentric (ECC) resistance training (RT) ( n = 6 CON, 6 ECC). An additional 14 males were recruited to evaluate acute muscle fascicle behaviour and molecular signalling in biopsies collected from vastus lateralis (VL) after 30 min of single bouts of CON or ECC exercise. VL volume was measured by magnetic resonance imaging. Muscle architecture (fascicle length, Lf; pennation angle, PA) was evaluated by ultrasonography. Muscle remodelling signals to CON or ECC loading [MAPK/AKT-mammalian target of rapamycin (mTOR) signalling] and inflammatory pathway (TNFαMurf-1-MAFbx) were evaluated by immunoblotting. Results Despite the ~1.2-fold greater load of the ECC group, similar increases in muscle volume (+8% CON and +6% ECC) and in maximal voluntary isometric contraction (+9% CON and +11% ECC) were found after RT. However, increases in Lf were greater after ECC than CON (+12 vs. +5%) while increases in PA were greater in CON than ECC (+30 vs. +5%). Distinct architectural adaptations were associated with preferential growth in the distal regions of VL for ECC (+ECC +8% vs. +CON +2) and mid belly for CON (ECC +7 vs. CON +11%). While MAPK activation (p38MAPK, ERK1/2, p90RSK) was specific to ECC, neither mode affected AKT-mTOR or inflammatory signalling 30 min after exercise. Conclusion Muscle growth with CON and ECC RT occurs with different morphological adaptations reflecting distinct fibre fascicle behaviour and molecular responses. [ABSTRACT FROM AUTHOR]

Skeletal muscle contains intramyocellular lipid droplets within the cytoplasm of myocytes as well as intermuscular adipocytes. These depots exhibit physiological and pathological variation which has been revealed with the advent of diagnostic imaging approaches: magnetic resonance ( MR) imaging, MR spectroscopy and computed tomography ( CT). CT uses computer-processed X-rays and is now being applied in muscle physiology research. The purpose of this review is to present CT methodologies and summarize factors that influence muscle radiation attenuation, a parameter which is inversely related to muscle fat content. Pre-defined radiation attenuation ranges are used to demarcate intermuscular adipose tissue [from −190 to −30 Hounsfield units ( HU)] and muscle (−29 HU to +150 HU). Within the latter range, the mean muscle radiation attenuation [muscle ( radio) density] is reported. Inconsistent criteria for the upper and lower HU cut-offs used to characterize muscle attenuation limit comparisons between investigations. This area of research would benefit from standardized criteria for reporting muscle attenuation. Available evidence suggests that muscle attenuation is plastic with physiological variation induced by the process of ageing, as well as by aerobic training, which probably reflects accumulation of lipids to fuel aerobic work. Pathological variation in muscle attenuation reflects excess fat deposition in the tissue and is observed in people with obesity, diabetes type II, myositis, osteoarthritis, spinal stenosis and cancer. A poor prognosis and different types of morbidity are predicted by the presence of reduced mean muscle attenuation values in patients with these conditions; however, the biological features of muscle with these characteristics require further investigation. [ABSTRACT FROM AUTHOR]

Myostatin is a powerful negative regulator of skeletal muscle mass in mammalian species. It plays a key role in skeletal muscle homeostasis and has now been well described since its discovery. Myostatin is capable of inducing muscle atrophy via its inhibition of myoblast proliferation, increasing ubiquitin-proteasomal activity and downregulating activity of the IGF-Akt pathway. These well-recognized effects are seen in multiple atrophy causing situations, including injury, diseases such as cachexia, disuse and space flight, demonstrating the importance of the myostatin signalling mechanism. Based on this central role, significant work has been pursued to inhibit myostatin's actions in vivo. Importantly, several new studies have uncovered roles for myostatin distinct from skeletal muscle size. Myostatin has been suggested to play a role in cardiomyocyte homeostasis, glucose metabolism and adipocyte proliferation, all of which are examined in detail below. Based on these effects, myostatin inhibition has potential to be widely utilized in many Western diseases such as chronic obstructive pulmonary disease, type II diabetes and obesity. However, if myostatin inhibitors are to successfully translate from bench-top to bedside in the near future, awareness must be raised on these non-traditional effects of myostatin away from skeletal muscle. Indeed, further research into these novel areas is required. [ABSTRACT FROM AUTHOR]

Aim: Sprint exercise is characterized by repeated sessions of brief intermittent exercise at a high relative workload. However, little is known about the effect on mTOR pathway, an important link in the regulation of muscle protein synthesis. An earlier training study showed a greater increase in muscle fibre cross-sectional area in women than men. Therefore, we tested the hypothesis that the activation of mTOR signalling is more pronounced in women than in men. Healthy men ( n = 9) and women ( n = 8) performed three bouts of 30-s sprint exercise with 20-min rest in between. Methods: Multiple blood samples were collected over time, and muscle biopsy specimens were obtained at rest and 140 min after the last sprint. Results: Serum insulin increased by sprint exercise and more so in women than in men [gender (g) × time (t)]: P = 0.04. In skeletal muscle, phosphorylation of Akt increased by 50% (t, P = 0.001) and mTOR by 120% (t, P = 0.002) independent of gender. The elevation in p70S6k phosphorylation was larger in women (g × t, P = 0.03) and averaged 230% ( P = 0.006) as compared to 60% in men ( P = 0.04). Phosphorylation rpS6 increased by 660% over time independent of gender (t, P = 0.003). Increase in the phosphorylation of p70S6k was directly related to increase in serum insulin ( r = 0.68, P = 0.004). Conclusion: It is concluded that repeated 30-s all-out bouts of sprint exercise separated by 20 min of rest increases Akt/ mTOR signalling in skeletal muscle. Secondly, signalling downstream of mTOR was stronger in women than in men after sprint exercise indicated by the increased phosphorylation of p70S6k. [ABSTRACT FROM AUTHOR]

Aim: Mitochondrial function has previously been studied in ageing, but never in humans matched for maximal oxygen uptake ( [ABSTRACT FROM AUTHOR]

Aim: The study examined the effects of an oral acute administration of the β2-agonist salbutamol (Sal) (6 mg) vs. placebo on muscle strength and fatigability in 12 non-asthmatic recreational male athletes in a randomized double-blind protocol. Methods: Contractile properties of the right quadriceps muscle were measured during electrical stimulations, i.e. twitch, 1-s pulse trains at 20 (P20) and 80 Hz (P80) and during maximal voluntary isometric contraction (MVIC) before (PRE) and after (POST) a fatigue-producing protocol set by an electromyostimulation (30 contractions, frequency: 75 Hz, on-off ratio: 6.25-20 s). In addition, the level of muscle voluntary activation was measured. Results: In PRE and POST conditions, the peak torque (PT) of twitch, P80 and MVIC were not modified by the treatment. The PT in POST P20 was slightly, although not significantly, less affected by fatigue in Sal compared with placebo condition. Moreover, twitch half-relaxation time at PRE was smaller under Sal than under placebo ( P < 0.05). No significant changes in the degree of voluntary activation were observed with Sal treatment in PRE or POST condition. Conclusion: Although these findings did not exclude completely an effect of Sal on peripheral factors of human skeletal muscle, oral acute administration of the β2-agonist Sal seems to be without any relevant ergogenic effect on muscle contractility and fatigability in non-asthmatic recreational male athletes. [ABSTRACT FROM AUTHOR]

The O requirements of contracting skeletal muscle may increase 100-fold above rest. In 1919, August Krogh's brilliant insights recognized the capillary as the principal site for this increased blood-myocyte O flux. Based on the premise that most capillaries did not sustain RBC flux at rest, Krogh proposed that capillary recruitment [i.e. initiation of red blood cell (RBC) flux in previously non-flowing capillaries] increased the capillary surface area available for O flux and reduced mean capillary-to-mitochondrial diffusion distances. More modern experimental approaches reveal that most muscle capillaries may support RBC flux at rest. Thus, rather than contraction-induced capillary recruitment per se, increased RBC flux and haematocrit within already-flowing capillaries probably elevate perfusive and diffusive O conductances and hence blood-myocyte O flux. Additional surface area for O exchange is recruited but, crucially, this may occur along the length of already-flowing capillaries (i.e. longitudinal recruitment). Today, the capillary is still considered the principal site for O and substrate delivery to contracting skeletal muscle. Indeed, the presence of very low intramyocyte O partial pressures ( POs) and the absence of intramyocyte PO gradients, whilst refuting the relevance of diffusion distances, place an even greater importance on capillary hemodynamics. This emergent picture calls for a paradigm-shift in our understanding of the function of capillaries by de-emphasizing de novo'capillary recruitment'. Diseases such as heart failure impair blood-myocyte O flux, in part, by decreasing the proportion of RBC-flowing capillaries. Knowledge of capillary function in healthy muscle is requisite for identification of pathology and efficient design of therapeutic treatments. [ABSTRACT FROM AUTHOR]

At the interface of tissue and capillaries, pericytes (PC) may generate electrical signals to be conducted along the skeletal muscle vascular network, but they are functionally not well characterized. We aimed to isolate and cultivate muscle PC allowing to analyse functional properties considered important for signal generation and conduction. Pericytes were enzymatically isolated from hamster thigh muscles and further selected during a 16-30 days' cultivation period. PC markers were studied by fluorescence activated cell scanning (FACS) and immunocytochemistry. Electrical properties of the cultured PC were investigated by patch clamp technique as well as the membrane potential sensitive dye DiBAC(3). The cultured cells showed typical PC morphology and were positive for NG2, alpha smooth muscle actin, PDGFR-β and the gap junction protein Cx43. Expressions of at least one single or combinations of several markers were found in 80-90% of subpopulations. A subset of the patched cells expressed channel activities consistent with a Kv1.5 channel. In vivo presence of the channels was confirmed in sections of hamster thigh muscles. Interleukin-8, a myokine known to be released from exercising muscle, increased the expression but not the activity of this channel. Pharmacologic stimulation of the channel activity by flufenamic acid induced hyperpolarization of PC alone but not of endothelial cells [human umbilical vein endothelial cells (HUVEC)] alone. However, hyperpolarization was observed in HUVEC adjacent to PC when kept in co-culture. We established a culture method for PC from skeletal muscle. A first functional characterization revealed properties which potentially enable these cells to generate hyperpolarizing signals and to communicate them to endothelial cells. [ABSTRACT FROM AUTHOR]

Aim: Ataxia telangiectasia mutated (ATM) reportedly plays a role in insulin-stimulated activation of Akt in some cell types but not in others. The role of ATM in insulin signalling has not been firmly resolved for skeletal muscle cells, for which Akt phosphorylation is a pivotal step in stimulation of glucose transport. Accordingly, our aim was to determine the role of ATM in insulin effects for cell lines derived from skeletal muscle and for skeletal muscle. Methods: We examined insulin effects in L6 myotubes, mouse soleus, C2C12 myotubes and differentiated rhabdomyosarcoma (RD) cells in the presence and absence of a low concentration (1 μm) of the ATM inhibitor KU55933. We also compared insulin signalling in C2C12 cells expressing shRNA against ATM and control cell lines (empty vector; cells expressing non-targeting shRNA). Results: In L6 myotubes and mouse soleus muscle, KU55933 inhibited insulin-stimulated phosphorylation of the 160 kDa substrate of Akt (AS160) despite no effect on Akt. In contrast, KU55933 prevented insulin-stimulated Akt phosphorylation in C2C12 myotubes. Furthermore, C2C12 myotubes expressing shRNA against ATM displayed reduced insulin-stimulated Akt phosphorylation compared to controls. KU55933 also decreased insulin-stimulated Akt phosphorylation in differentiated RD cells. Conclusion: These model-dependent differences in the role of ATM in insulin action demonstrate a role of ATM in insulin-stimulated phosphorylation of Akt (in C2C12 and RD cells) but also allow the elucidation of a novel, Akt-independent role of ATM (in L6 myotubes and mouse soleus, at the level of AS160) in insulin signalling. [ABSTRACT FROM AUTHOR]

Aim: Activated satellite cells (SCs) have the ability to reacquire a quiescent, undifferentiated state. Pax7 plays a crucial role in allowing activated SCs to undergo self-renewal. Because the increase in the SC population is induced during overload-induced skeletal muscle hypertrophy, it is possible that Pax7-regulated SC self-renewal is involved in the modulation of the SC population during the functional overload of skeletal muscles. However, the characteristics of the expression patterns of Pax7 in SCs during the functional overload of adult skeletal muscles are poorly understood. Methods: Using immunohistochemical approaches, we examined the temporal and spatial expression patterns of Pax7 expressed in SCs during the functional overloading of rat skeletal muscles. Results: The time course of Pax7 expression in SCs was similar to that of the expression of the differentiation regulatory factor myogenin during the early stage of functional overload. However, the percentage of SCs that expressed Pax7 was markedly higher than that of the SCs that expressed myogenin. Coexpression of Pax7 and myogenin was not detected in SCs. In addition, the expression of cyclin-dependent kinase inhibitor p21, which regulates cell cycle arrest and differentiation, was not detected in Pax7-positive SCs. Conclusion: These results suggest that Pax7-regulated self-renewal of SCs may be induced during the early stage of functional overload and may contribute to modulating the SC population in hypertrophied muscles. Furthermore, it was suggested that the numbers of SCs which underwent self-renewal may be higher than that of SCs which were provided as the additional myonuclei for hypertrophying myofibres. [ABSTRACT FROM AUTHOR]

The author focuses on a study "Truncated splice variant PGC-1α4 is not associated with exercise induced human muscle hypertrophy" by researcher T.R. Lundberg and colleagues, appeared in a 2014 issue of the periodical. Topics include the occurrence of muscle hypertrophy (MH) from resistance exercise, the signaling mechanisms for regulation of MH and the role of transcriptional co-activator PGC-1α4 in regulation of human skeletal muscle.

The article presents the author's views regarding the potential of blood flow restriction (BFR) exercise in augmenting the skeletal muscle signalling responses. Topics mention including understanding the physiological stressors, capacity of the BFR interventions and key objective in training methods.

Aim: mTORC1 is regarded as an important key regulator of protein synthesis and hypertrophy following mechanical stimuli in skeletal muscle. However, as excitation and tension development is tightly coupled in most experimental models, very little and largely indirect evidence exist for such a mechanosensitive pathway. Here, we sought to examine whether activation of mTORC1 signalling is dependent on tension per se in rat skeletal muscle. Methods: To examine the mechanosensitivity of mTORC1, rat EDL muscles were exposed to either excitation‐induced eccentric contractions (ECC), passive stretching (PAS) with identical peak tension (Tpeak) and Tension‐Time‐Integral (TTI), or ECC with addition of inhibitors of the myosin ATPases (IMA). To further explore the relationship between tension and mTORC1 signalling, rat EDL muscles were subjected to PAS of different magnitudes of Tpeak while standardizing TTI and vice versa. Results: PAS and ECC with equal Tpeak and TTI produced similar responses in mTORC1 signalling despite different modes of tension development. When active tension during ECC was nearly abolished by addition of IMA, mTORC1 signalling was reduced to a level comparable to non‐stimulated controls. In addition, when muscles were exposed to PAS of varying levels of Tpeak with standardized TTI, activation of mTORC1 signalling displayed a positive relationship with peak tension. Conclusions: The current study directly links tension per se to activation of mTORC1 signalling, which is independent of an active EC‐coupling sequence. Moreover, activation of mTORC1 signalling displays a positive dose‐response relationship with peak tension. [ABSTRACT FROM AUTHOR]

Background: Mechanisms underlying physical inactivity‐induced insulin resistance are not well understood. In addition to a role in muscle repair, immune cell populations such as macrophages may regulate insulin sensitivity. Aim: The aim of this study was to examine if the dynamic changes in insulin sensitivity during and after recovery from reduced physical activity corresponded to changes in skeletal muscle macrophages. Methods: In this prospective clinical study, we collected muscle biopsies from healthy older adults (70 ± 2 years, n = 12) before and during a hyperinsulinaemic‐euglycaemic clamp and this occurred before (PRE) and after 2‐week reduced physical activity (RA), and following 2‐week of recovery (REC). Insulin sensitivity (hyperinsulinaemic‐euglycaemic clamp), skeletal muscle mRNA expression of inflammatory markers, and immunofluorescent quantification of skeletal muscle macrophages, myofibre‐specific satellite cell and capillary content were assessed. Results: Insulin sensitivity was decreased following reduced activity and rebounded following recovery above PRE levels. We observed an increase (P < 0.01) in muscle macrophages (CD68+CD206+: 190 [55, 324]; CD11b+CD206+: 117 [28, 205]% change from PRE) and CD68 (2.4 [1.4, 3.4]‐fold) and CCL2 (1.9 [1.3, 2.5]‐fold) mRNA following RA concurrent with increased (P < 0.03) satellite cells (55 [6, 104]%) in slow‐twitch myofibres. Moreover, the distance of satellite cells to the nearest capillary was increased 7.7 (1.7, 13.7) µm in fast‐twitch myofibres at RA (P = 0.007). Changes in macrophages were positively associated with increased insulin sensitivity following RA (R > 0.57, P < 0.05). Conclusion: These findings suggested that a dynamic response of skeletal muscle macrophages following acute changes in physical activity in healthy older adults is related to insulin sensitivity. [ABSTRACT FROM AUTHOR]

Aim: The use of platelets as biomaterials has gained intense research interest. However, the mechanisms regarding platelet‐mediated skeletal myogenesis remain to be established. The aim of this study was to determine the role of platelet releasate in skeletal myogenesis and muscle stem cell fate in vitro and ex vivo respectively. Methods: We analysed the effect of platelet releasate on proliferation and differentiation of C2C12 myoblasts by means of cell proliferation assays, immunohistochemistry, gene expression and cell bioenergetics. We expanded in vitro findings on single muscle fibres by determining the effect of platelet releasate on murine skeletal muscle stem cells using protein expression profiles for key myogenic regulatory factors. Results: TRAP6 and collagen used for releasate preparation had a more pronounced effect on myoblast proliferation vs thrombin and sonicated platelets (P < 0.05). In addition, platelet concentration positively correlated with myoblast proliferation. Platelet releasate increased myoblast and muscle stem cell proliferation in a dose‐dependent manner, which was mitigated by VEGFR and PDGFR inhibition. Inhibition of VEGFR and PDGFR ablated MyoD expression on proliferating muscle stem cells, compromising their commitment to differentiation in muscle fibres (P < 0.001). Platelet releasate was detrimental to myoblast fusion and affected differentiation of myoblasts in a temporal manner. Most importantly, we show that platelet releasate promotes skeletal myogenesis through the PDGF/VEGF‐Cyclin D1‐MyoD‐Scrib‐Myogenin axis and accelerates skeletal muscle regeneration after acute injury. Conclusion: This study provides novel mechanistic insights on the role of platelet releasate in skeletal myogenesis and set the physiological basis for exploiting platelets as biomaterials in regenerative medicine. [ABSTRACT FROM AUTHOR]

Despite substantial progress made towards a better understanding of the importance of skeletal muscle K+ regulation for human physical function and its association with several disease states (eg type‐II diabetes and hypertension), the molecular basis underpinning adaptations in K+ regulation to various stimuli, including exercise training, remains inadequately explored in humans. In this review, the molecular mechanisms essential for enhancing skeletal muscle K+ regulation and its key determinants, including Na+,K+‐ATPase function and expression, by exercise training are examined. Special attention is paid to the following molecular stressors and signaling proteins: oxygenation, redox balance, hypoxia, reactive oxygen species, antioxidant function, Na+,K+, and Ca2+ concentrations, anaerobic ATP turnover, AMPK, lactate, and mRNA expression. On this basis, an update on the effects of different types of exercise training on K+ regulation in humans is provided, focusing on recent discoveries about the muscle fibre‐type‐dependent regulation of Na+,K+‐ATPase‐isoform expression. Furthermore, with special emphasis on blood‐flow‐restricted exercise as an exemplary model to modulate the key molecular mechanisms identified, it is discussed how training interventions may be designed to maximize improvements in K+ regulation in humans. The novel insights gained from this review may help us to better understand how exercise training and other strategies, such as pharmacological interventions, may be best designed to enhance K+ regulation and thus the physical function in humans. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Expression changes in human skeletal muscle miRNAs following 10 days of bed rest in young healthy males."