Muscle fatigue is the decline in performance of muscles observed during periods of intense activity. ATP consumption exceeds production during intense activity and there are multiple changes in intracellular metabolites which may contribute to the changes in crossbridge activity. It is also well-established that a reduction in activation, either through action potential changes or reduction in Ca2+ release from the sarcoplasmic reticulum (SR), makes an additional contribution to fatigue. In this review we focus on the role of intracellular inorganic phosphate (Pi) whose concentration can increase rapidly from around 5–30 mM during intense fatigue. Studies from skinned muscle fibers show that these changes substantially impair myofibrillar performance although the effects are strongly temperature dependent. Increased Pi can also cause reduced Ca2+ release from the SR and may therefore contribute to the reduced activation. In a recent study, we have measured both Pi and Ca2+ release in a blood-perfused mammalian preparation and the results from this preparation allows us to test the extent to which the combined effects of Pi and Ca2+ changes may contribute to fatigue.

We investigated the influence of postsynaptic tyrosine kinase signaling in a mouse model of muscle‐specific kinase (MuSK) myasthenia gravis (MG). Mice administered repeated daily injections of IgG from MuSK MG patients developed impaired neuromuscular transmission due to progressive loss of acetylcholine receptor (AChR) from the postsynaptic membrane of the neuromuscular junction. In this model, anti‐MuSK‐positive IgG caused a reduction in motor endplate immunolabeling for phosphorylated Src‐Y418 and AChR β‐subunit‐Y390 before any detectable loss of MuSK or AChR from the endplate. Adeno‐associated viral vector (rAAV) encoding MuSK fused to enhanced green fluorescent protein (MuSK‐EGFP) was injected into the tibialis anterior muscle to increase MuSK synthesis. When mice were subsequently challenged with 11 daily injections of IgG from MuSK MG patients, endplates expressing MuSK‐EGFP retained more MuSK and AChR than endplates of contralateral muscles administered empty vector. Recordings of compound muscle action potentials from myasthenic mice revealed less impairment of neuromuscular transmission in muscles that had been injected with rAAV‐MuSK‐EGFP than contralateral muscles (empty rAAV controls). In contrast to the effects of MuSK‐EGFP, forced expression of rapsyn‐EGFP provided no such protection to endplate AChR when mice were subsequently challenged with MuSK MG IgG. In summary, the immediate in vivo effect of MuSK autoantibodies was to suppress MuSK‐dependent tyrosine phosphorylation of proteins in the postsynaptic membrane, while increased MuSK synthesis protected endplates against AChR loss. These results support the hypothesis that reduced MuSK kinase signaling initiates the progressive disassembly of the postsynaptic membrane scaffold in this mouse model of MuSK MG.

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Key points Adeno‐associated viral vector was used to elevate the expression of muscle specific kinase (MuSK) and rapsyn (a cytoplasmic MuSK effector protein) in the tibialis anterior muscle of wild‐type and dystrophic (mdx) mice. In mdx mice, enhanced expression of either MuSK or rapsyn ameliorated the acute loss of muscle force associated with strain injury. Increases in sarcolemmal immunolabelling for utrophin and β‐dystroglycan suggest a mechanism for the protective effect of MuSK in mdx muscles. MuSK also caused subtle changes to the structure and function of the neuromuscular junction, suggesting novel roles for MuSK in muscle physiology and pathophysiology. Abstract Muscle specific kinase (MuSK) has a well‐defined role in stabilizing the developing mammalian neuromuscular junction, but MuSK might also be protective in some neuromuscular diseases. In the dystrophin‐deficient mdx mouse model of Duchenne muscular dystrophy, limb muscles are especially fragile. We injected the tibialis anterior muscle of 8‐week‐old mdx and wild‐type (C57BL10) mice with adeno‐associated viral vectors encoding either MuSK or rapsyn (a cytoplasmic MuSK effector protein) fused to green fluorescent protein (MuSK‐GFP and rapsyn‐GFP, respectively). Contralateral muscles injected with empty vector served as controls. One month later mice were anaesthetized with isoflurane and isometric force‐producing capacity was recorded from the distal tendon. MuSK‐GFP caused an unexpected decay in nerve‐evoked tetanic force, both in wild‐type and mdx muscles, without affecting contraction elicited by direct electrical stimulation of the muscle. Muscle fragility was probed by challenging muscles with a strain injury protocol consisting of a series of four strain‐producing eccentric contractions in vivo. When applied to muscles of mdx mice, eccentric contraction produced an acute 27% reduction in directly evoked muscle force output, affirming the susceptibility of mdx muscles to strain injury. mdx muscles overexpressing MuSK‐GFP or rapsyn‐GFP exhibited significantly milder force deficits after the eccentric contraction challenge (15% and 14%, respectively). The protective effect of MuSK‐GFP in muscles of mdx mice was associated with increased immunolabelling for utrophin and β‐dystroglycan in the sarcolemma. Elevating the expression of MuSK or rapsyn revealed several distinct synaptic and extrasynaptic effects, suggesting novel roles for MuSK signalling in muscle physiology and pathophysiology.