alpha-Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles

Autor(es)

Machado, Juliano ^{[1, 2, 3, 4]} ; Silveira, Wilian A. ^{[1, 5]} ; Goncalves, Dawit A. ^{[1, 2, 6]} ; Schavinski, Aline Zanatta ^[1] ; Khan, Muzamil M. ^{[7, 8, 9]} ; Zanon, Neusa M. ^[1] ; Diaz, Mauricio Berriel ^{[3, 4]} ; Rudolf, Ruediger ^{[7, 8, 9]} ; Kettelhut, Isis C. ^[2] ; Navegantes, Luiz C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Physiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem Immunol, Ribeirao Preto, SP - Brazil

^[3] Helmholtz Ctr Munich, IDC, D-85764 Neuherberg - Germany

^[4] Heidelberg Univ Hosp, Joint Heidelberg IDC Translat Diabet Program, Inner Med 1, D-69120 Heidelberg - Germany

^[5] Univ Fed Triangulo Mineiro, Inst Biol & Nat Sci, Uberaba, MG - Brazil

^[6] Fed Univ Minas Gerais UFMG, Exercise Physiol Lab, Sch Phys Educ Physiotherapy & Occupat Therapy, Belo Horizonte, MG - Brazil

^[7] Univ Appl Sci Mannheim, Inst Mol & Cell Biol, Mannheim - Germany

^[8] Heidelberg Univ, Inst Med Technol, Mannheim - Germany

^[9] Univ Appl Sci Mannheim, Mannheim - Germany

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR METABOLISM; v. 28, p. 91-106, OCT 2019.
• Citações Web of Science: 0

Resumo

Objective: Although it is well established that a-calcitonin gene-related peptide (CGRP) stabilizes muscle-type cholinergic receptors nicotinic subunits (AChR), the underlying mechanism by which this neuropeptide regulates muscle protein metabolism and neuromuscular junction (NMJ) morphology is unclear. Methods: To elucidate the mechanisms how CGRP controls NMJ stability in denervated mice skeletal muscles, we carried out physiological, pharmacological, and molecular analyses of atrophic muscles induced by sciatic nerve transection. Results: Here, we report that CGRP treatment in vivo abrogated the deleterious effects on NMJ upon denervation (DEN), an effect that was associated with suppression of skeletal muscle proteolysis, but not stimulation of protein synthesis. CGRP also blocked the DEN-induced increase in endocytic AChR vesicles and the elevation of autophagosomes per NMJ area. The treatment of denervated animals with rapamycin blocked the stimulatory effects of CGRP on mTORC1 and its inhibitory actions on autophagic flux and NMJ degeneration. Furthermore, CGRP inhibited the DEN-induced hyperactivation of Ca2+-dependent proteolysis, a degradative system that has been shown to destabilize NMJ. Consistently, calpain was found to be activated by cholinergic stimulation in myotubes leading to the dispersal of AChR clusters, an effect that was abolished by CGRP. Conclusion: Taken together, these data suggest that the inhibitory effect of CGRP on autophagy and calpain may represent an important mechanism for the preservation of synapse morphology when degradative machinery is exacerbated upon denervation conditions. (C) 2019 The Authors. Published by Elsevier GmbH. (AU)

• Processo FAPESP: 09/54014-7 - EMU: aquisição dos equipamentos IVIS Spectrum e microscópio de excitação por dois fótons para imagem in vivo
• Beneficiário: Enilza Maria Espreafico
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 11/11003-5 - Papel do peptídeo relacionado ao gene da calcitonina (CGRP) no metabolismo protéico em músculo esquelético de ratos normais e desnervados
• Beneficiário: Luiz Carlos Carvalho Navegantes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/24524-6 - Controle da massa muscular pela via de sinalização do AMPc
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/10089-2 - Controle neural, hormonal e nutricional da autofagia
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/18861-0 - A hiperacetilação de foxo como um mecanismo de supressão do programa gênico atrófico pela sinalização adrenérgica beta2 em músculos esqueléticos de roedores
• Beneficiário: Dawit Albieiro Pinheiro Gonçalves
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/21112-7 - CONTROLE DA MASSA MUSCULAR PELA VIA DE SINALIZAÇÃO DO AMPc
• Beneficiário: Juliano Machado
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado