Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation

Bruno A. Cisterna (), Aníbal A. Vargas, Carlos Puebla, Paola Fernández, Rosalba Escamilla, Carlos F. Lagos, María F. Matus, Cristian Vilos, Luis A. Cea, Esteban Barnafi, Hugo Gaete, Daniel F. Escobar, Christopher P. Cardozo and Juan C. Sáez ()
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Bruno A. Cisterna: Pontificia Universidad Católica de Chile
Aníbal A. Vargas: Universidad de O’Higgins
Carlos Puebla: Universidad de O’Higgins
Paola Fernández: Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso
Rosalba Escamilla: Pontificia Universidad Católica de Chile
Carlos F. Lagos: Universidad San Sebastián
María F. Matus: Universidad de Talca
Cristian Vilos: Universidad de Talca
Luis A. Cea: Universidad Autónoma de Chile
Esteban Barnafi: Sección de Biología Molecular, Laboratorio Barnafi Krause
Hugo Gaete: Sección de Biología Molecular, Laboratorio Barnafi Krause
Daniel F. Escobar: Sección de Biotecnología, Departamento de Salud Ambiental. Instituto de Salud Pública de Chile
Christopher P. Cardozo: National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center
Juan C. Sáez: Pontificia Universidad Católica de Chile

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14063-8

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