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Abstract
Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting membrane potential and accelerated protein catabolism. The factors that induce these changes remain unknown. Conversely, functional recovery following denervation depends on successful reinnervation. Here, we show that activation of nicotinic acetylcholine receptors (nAChRs) by quantal release of acetylcholine (ACh) from motoneurons is sufficient to prevent changes induced by denervation. Using in vitro assays, ACh and non-hydrolysable ACh analogs repressed the expression of connexin43 and connexin45 hemichannels, which promote muscle atrophy. In co-culture studies, connexin43/45 hemichannel knockout or knockdown increased innervation of muscle fibers by dorsal root ganglion neurons. Our results show that ACh released by motoneurons exerts a hitherto unknown function independent of myofiber contraction. nAChRs and connexin hemichannels are potential molecular targets for therapeutic intervention in a variety of pathological conditions with reduced synaptic neuromuscular transmission.
Highlights
Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting membrane potential and accelerated protein catabolism
Denervation induces severe muscle atrophy and weakness[4,5,6], which are preceded by a set of poorly understood cellular alterations, such as fall of resting membrane potential (RMP)[7,8], ionic imbalance[9,10,11], and accelerated protein catabolism[12,13,14]
Since the evaluation of the involvement of different neuronal derived factors in vivo could cause undesired effects beyond the neuromuscular junction (NMJ), we used primary cultures of dispersed myofibers to evaluate whether neuronderived factors prevent the phenotypic changes that characterize denervated skeletal myofibers
Summary
Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting membrane potential and accelerated protein catabolism. In order to evaluate the effect of the different factors released by the nerve, we use cultured skeletal myofibers as an in vitro denervated model, which we demonstrate recapitulated the genetic and biochemical alterations found in denervated muscles in vivo. These alterations include increased expression of atrophy genes called “atrogenes” atrogin-1 (Fbxo32) and MuRF1 (Trim63)[31,32], and increased expression of the autophagy gene Bnip[333], without alterations of pro-apoptotic genes and proteins[34,35]
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