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Perturbations in K+ have long been considered a key factor in skeletal muscle fatigue. However, the exercise-induced changes in K+ intra-to-extracellular gradient is by itself insufficiently large to be a major cause for the force decrease during fatigue unless combined to other ion gradient changes such as for Na+. Whilst several studies described K+-induced force depression at high extracellular [K+] ([K+]e), others reported that small increases in [K+]e induced potentiation during submaximal activation frequencies, a finding that has mostly been ignored. There is evidence for decreased Cl− ClC-1 channel activity at muscle activity onset, which may limit K+-induced force depression, and large increases in ClC-1 channel activity during metabolic stress that may enhance K+ induced force depression. The ATP-sensitive K+ channel (KATP channel) is also activated during metabolic stress to lower sarcolemmal excitability. Taking into account all these findings, we propose a revised concept in which K+ has two physiological roles: (1) K+-induced potentiation and (2) K+-induced force depression. During low-moderate intensity muscle contractions, the K+-induced force depression associated with increased [K+]e is prevented by concomitant decreased ClC-1 channel activity, allowing K+-induced potentiation of sub-maximal tetanic contractions to dominate, thereby optimizing muscle performance. When ATP demand exceeds supply, creating metabolic stress, both KATP and ClC-1 channels are activated. KATP channels contribute to force reductions by lowering sarcolemmal generation of action potentials, whilst ClC-1 channel enhances the force-depressing effects of K+, thereby triggering fatigue. The ultimate function of these changes is to preserve the remaining ATP to prevent damaging ATP depletion.

This historical review traces key discoveries regarding K+ and Na+ ions in skeletal muscle at rest and with exercise, including contents and concentrations, Na+,K+-ATPase (NKA) and exercise effects on plasma [K+] in humans. Following initial measures in 1896 of muscle contents in various species, including humans, electrical stimulation of animal muscle showed K+ loss and gains in Na+, Cl− and H20, then subsequently bidirectional muscle K+ and Na+ fluxes. After NKA discovery in 1957, methods were developed to quantify muscle NKA activity via rates of ATP hydrolysis, Na+/K+ radioisotope fluxes, [3H]-ouabain binding and phosphatase activity. Since then, it became clear that NKA plays a central role in Na+/K+ homeostasis and that NKA content and activity are regulated by muscle contractions and numerous hormones. During intense exercise in humans, muscle intracellular [K+] falls by 21 mM (range − 13 to − 39 mM), interstitial [K+] increases to 12–13 mM, and plasma [K+] rises to 6–8 mM, whilst post-exercise plasma [K+] falls rapidly, reflecting increased muscle NKA activity. Contractions were shown to increase NKA activity in proportion to activation frequency in animal intact muscle preparations. In human muscle, [3H]-ouabain-binding content fully quantifies NKA content, whilst the method mainly detects α2 isoforms in rats. Acute or chronic exercise affects human muscle K+, NKA content, activity, isoforms and phospholemman (FXYD1). Numerous hormones, pharmacological and dietary interventions, altered acid–base or redox states, exercise training and physical inactivity modulate plasma [K+] during exercise. Finally, historical research approaches largely excluded female participants and typically used very small sample sizes.

Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder of childhood marked by progressive debilitating muscle weakness and wasting, and ultimately death in the second or third decade of life. Wnt7a signaling through its receptor Fzd7 accelerates and augments regeneration by stimulating satellite stem cell expansion through the planar cell polarity pathway, as well as myofiber hypertrophy through the AKT/mammalian target of rapamycin (mTOR) anabolic pathway. We investigated the therapeutic potential of the secreted factor Wnt7a for focal treatment of dystrophic DMD muscles using the mdx mouse model, and found that Wnt7a treatment efficiently induced satellite cell expansion and myofiber hypertrophy in treated mucles in mdx mice. Importantly, Wnt7a treatment resulted in a significant increase in muscle strength, as determined by generation of specific force. Furthermore, Wnt7a reduced the level of contractile damage, likely by inducing a shift in fiber type toward slow-twitch. Finally, we found that Wnt7a similarly induced myotube hypertrophy and a shift in fiber type toward slow-twitch in human primary myotubes. Taken together, our findings suggest that Wnt7a is a promising candidate for development as an ameliorative treatment for DMD.

Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5’UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway. One potential approach for the treatment of Duchenne muscular dysrophy is to increase expression of the dystrophin homolog utrophin. Here, the authors show that eEF1A2 regulates utrophin expression, and show that 2 FDA-approved drugs upregulate eEIF1A2 and utrophin level in mice, leading to improvement of the dystrophic phenotype.

The overall objective was to determine how no extracellular glucose and/or low glycogen content affect fatigue kinetics in mouse flexor digitorum brevis (FDB) single muscle fibers. High glycogen content (Hi GLY), near normal in situ level, was obtained by incubating fibers in culture medium containing glucose and insulin while low glycogen content (Lo GLY), at about 19% of normal in situ level, was achieved by incubating fibers without glucose. Neither Lo GLY nor the absence of extracellular glucose (0GLU) affected tetanic [Ca2+]i prior to fatigue. The number of contracting unfatigued fibers versus stimulus strength relationship of Lo GLY‐0GLU fibers was shifted to higher voltages compared to Hi GLY fibers exposed to 5.5 mM glucose (5GLU). The relationship for Lo GLY‐0GLU fibers was shifted back toward that of Hi GLY‐5GLU fibers when glucose was reintroduced, whereas the removal of glucose from Hi GLY‐5GLU fibers had no effect. Fatigue was elicited with one 200 ms long tetanic contraction every s for 3 min. Both Lo GLY and 0GLU increased the rate at which intracellular tetanic concentration ([Ca2+]i) declined and unstimulated [Ca2+]i increased during fatigue in the order of the least fatigue resistant > mid fatigue resistant > the most fatigue resistant fibers.

Background Duchenne muscular dystrophy (DMD) is associated with impaired muscle regeneration, progressive muscle weakness, damage, and wasting. While the cause of DMD is an X-linked loss of function mutation in the gene encoding dystrophin, the exact mechanisms that perpetuate the disease progression are unknown. Our laboratory has demonstrated that pannexin 1 (Panx1 in rodents; PANX1 in humans) is critical for the development, strength, and regeneration of male skeletal muscle. In normal skeletal muscle, Panx1 is part of a multiprotein complex with dystrophin. We and others have previously shown that Panx1 levels and channel activity are dysregulated in various mouse models of DMD. Methods We utilized myoblast cell lines derived from DMD patients to assess PANX1 expression and function. To investigate how Panx1 dysregulation contributes to DMD, we generated a dystrophic ( mdx ) mouse model that lacks Panx1 ( Panx1 −/− /mdx ). In depth characterization of this model included histological analysis, as well as locomotor, and physiological tests such as muscle force and grip strength assessments. Results Here, we demonstrate that PANX1 levels and channel function are reduced in patient-derived DMD myoblast cell lines. Panx1 −/− /mdx mice have a significantly reduced lifespan, and decreased body weight due to lean mass loss. Their tibialis anterior were more affected than their soleus muscles and displayed reduced mass, myofiber loss, increased centrally nucleated myofibers, and a lower number of muscle stem cells compared to that of Panx1 + / + /mdx mice. These detrimental effects were associated with muscle and locomotor functional impairments. In vitro, PANX1 overexpression in patient-derived DMD myoblasts improved their differentiation and fusion. Conclusions Collectively, our findings suggest that PANX1/Panx1 dysregulation in DMD exacerbates several aspects of the disease. Moreover, our results suggest a potential therapeutic benefit to increasing PANX1 levels in dystrophic muscles.

The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Overall, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration.

The overall objective was to determine how no extracellular glucose and/or low glycogen content affect fatigue kinetics in mouse flexor digitorum brevis (FDB) single muscle fibers. High glycogen content (Hi GLY), near normal in situ level, was obtained by incubating fibers in culture medium containing glucose and insulin while low glycogen content (Lo GLY), at about 19% of normal in situ level, was achieved by incubating fibers without glucose. Neither Lo GLY nor the absence of extracellular glucose (0GLU) affected tetanic [Ca 2+ ] i prior to fatigue. The number of contracting unfatigued fibers versus stimulus strength relationship of Lo GLY‐0GLU fibers was shifted to higher voltages compared to Hi GLY fibers exposed to 5.5 mM glucose (5GLU). The relationship for Lo GLY‐0GLU fibers was shifted back toward that of Hi GLY‐5GLU fibers when glucose was reintroduced, whereas the removal of glucose from Hi GLY‐5GLU fibers had no effect. Fatigue was elicited with one 200 ms long tetanic contraction every s for 3 min. Both Lo GLY and 0GLU increased the rate at which intracellular tetanic concentration ([Ca 2+ ] i ) declined and unstimulated [Ca 2+ ] i increased during fatigue in the order of the least fatigue resistant > mid fatigue resistant > the most fatigue resistant fibers.

The mechanisms responsible for the onset and progressive worsening of episodic muscle stiffness and weakness in hyperkalemic periodic paralysis (HyperKPP) are not fully understood. Using a knock‐in HyperKPP mouse model harboring the M1592V NaV1.4 channel mutant, we interrogated changes in physiological defects during the first year, including tetrodotoxin‐sensitive Na+ influx, hindlimb electromyographic (EMG) activity and immobility, muscle weakness induced by elevated [K+]e, myofiber‐type composition, and myofiber damage. In situ EMG activity was greater in HyperKPP than wild‐type gastrocnemius, whereas spontaneous muscle contractions were observed in vitro. We suggest that both the greater EMG activity and spontaneous contractions are related to periods of hyperexcitability during which fibers generate action potentials by themselves in the absence of any stimulation and that these periods are the cause of the muscle stiffness reported by patients. HyperKPP muscles had a greater sensitivity to the K+‐induced force depression than wild‐type muscles. So, an increased interstitial K+ concentration locally near subsets of myofibers as a result of the hyperexcitability likely produced partial loss of force rather than complete paralysis. NaV1.4 channel protein content reached adult level by 3 weeks postnatal in both wild type and HyperKPP and apparent symptoms did not worsen after the first month of age suggesting (i) that the phenotypic behavior of M1592V HyperKPP muscles results from defective function of mutant NaV1.4 channels rather than other changes in protein expression after the first month and (ii) that the lag in onset during the first decade and the progression of human HyperKPP symptoms during adolescence are a function of NaV1.4 channel content. This study further characterized the mechanisms that cause muscle stiffness and weakness in Hyperkalemic Periodic Paralysis (HyperKPP). Muscle stiffness is caused by an increased membrane hyperexcitability as action potentials are generated in the absence of motorneuron stimulation in random as opposed to myotonic discharges as clinically defined. Muscle weakness is caused by localized increases in extracellular potassium concentration that cause membrane hypoexcitability in a few fibers at a time.

One objective of this study was to document how individual FDB muscle fibers depend on the myoprotection of KATP channels during fatigue. Verapamil, a CaV1.1 channel blocker, prevents large increases in unstimulated force during fatigue in KATP‐channel‐deficient muscles. A second objective was to determine if verapamil reduces unstimulated [Ca2+]i in KATP‐channel‐deficient fibers. We measured changes in myoplasmic [Ca2+] ([Ca2+]i) using two KATP‐channel‐deficient models: (1) a pharmacological approach exposing fibers to glibenclamide, a channel blocker, and (2) a genetic approach using fibers from null mice for the Kir6.2 gene. Fatigue was elicited with one tetanic contraction every sec for 3 min. For all conditions, large differences in fatigue kinetics were observed from fibers which had greater tetanic [Ca2+]i at the end than at the beginning of fatigue to fibers which eventually completely failed to release Ca2+ upon stimulation. Compared to control conditions, KATP‐channel‐deficient fibers had a greater proportion of fiber with large decreases in tetanic [Ca2+]i, fade and complete failure to release Ca2+ upon stimulation. There was, however, a group of KATP‐channel‐deficient fibers that had similar fatigue kinetics to those of the most fatigue‐resistant control fibers. For the first time, differences in fatigue kinetics were observed between Kir6.2‐/‐ and glibenclamide‐exposed muscle fibers. Verapamil significantly reduced unstimulated and tetanic [Ca2+]i. It is concluded that not all fibers are dependent on the myoprotection of KATP channels and that the decrease in unstimulated force by verapamil reported in a previous studies in glibenclamide‐exposed fibers is due to a reduction in Ca2+ load by reducing Ca2+ influx through CaV1.1 channels between and during contractions. This study is the first to demonstrate the large variability in fatigue kinetics between mouse fibers at the physiological temperature of 37°C. It also documents that not all fibers are dependent on the myoprotective effect of KATP channel during fatigue. Finally, it demonstrates that the large increase in unstimulated force during fatigue in KATP channel is related to a calcium load due to an influx of calcium between and during contractions.