2. Academic Validation
  3. Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation

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

  • Nat Commun. 2020 Feb 26;11(1):1073. doi: 10.1038/s41467-019-14063-8.
Bruno A Cisterna 1 2 3,  Aníbal A Vargas 4,  Carlos Puebla 4,  Paola Fernández 5,  Rosalba Escamilla 6 5,  Carlos F Lagos 7,  María F Matus 8 9,  Cristian Vilos 10 11,  Luis A Cea 12,  Esteban Barnafi 13,  Hugo Gaete 13,  Daniel F Escobar 14,  Christopher P Cardozo 15 16,  Juan C Sáez 17 18
Affiliations

Affiliations

  • 1 Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile. bcisterna@uc.cl.
  • 2 Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile. bcisterna@uc.cl.
  • 3 Centro de Investigaciones Médicas, Escuela de Medicina, Universidad de Talca, Talca, Chile. bcisterna@uc.cl.
  • 4 Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile.
  • 5 Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile.
  • 6 Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • 7 Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile.
  • 8 Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile.
  • 9 Department of Physics, Nanoscience Center (NSC), University of Jyväskylä, FI-40014, Jyväskylä, Finland.
  • 10 Centro de Investigaciones Médicas, Escuela de Medicina, Universidad de Talca, Talca, Chile.
  • 11 Centro para el Desarrollo de la Nanociencia y Nanotecnología (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile.
  • 12 Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile.
  • 13 Sección de Biología Molecular, Laboratorio Barnafi Krause, Santiago, Chile.
  • 14 Sección de Biotecnología, Departamento de Salud Ambiental. Instituto de Salud Pública de Chile, Santiago, Chile.
  • 15 National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
  • 16 Departments of Medicine and Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 17 Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile. jsaez@bio.puc.cl.
  • 18 Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile. jsaez@bio.puc.cl.
PMID: 32103010 DOI: 10.1038/s41467-019-14063-8
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.

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