Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile.
Nat Commun. 2020 Feb 26;11(1):1073. doi: 10.1038/s41467-019-14063-8.
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.
去神经支配骨骼肌会导致严重的肌肉萎缩，这之前会发生细胞变化，如质膜通透性增加、静息膜电位降低和蛋白质分解加速。引起这些变化的因素尚不清楚。相反，去神经支配后的功能恢复取决于成功的再神经支配。在这里，我们表明，运动神经元中乙酰胆碱（ACh）的量子释放激活烟碱型乙酰胆碱受体（nAChRs）足以防止去神经支配引起的变化。通过体外测定，ACh 和不可水解的 ACh 类似物抑制了缝隙连接蛋白 43 和 45 半通道的表达，这些半通道促进肌肉萎缩。在共培养研究中，连接蛋白 43/45 半通道敲除或敲低增加了背根神经节神经元对肌纤维的支配。我们的结果表明，运动神经元释放的 ACh 发挥了一种以前未知的、独立于肌纤维收缩的功能。nAChRs 和连接蛋白半通道是治疗各种病理状况（如突触神经肌肉传递减少）的潜在分子靶点。
