Calcitonin gene-related peptide inhibits autophagic-lysosomal proteolysis through cAMP/PKA signaling in rat skeletal muscles

Autor(es)

Machado, Juliano ^[1] ; Manfredi, Leandro H. ^[1] ; Silveira, Wilian A. ^[1] ; Goncalves, Dawit A. P. ^[1] ; Lustrino, Danilo ^[1] ; Zanon, Neusa M. ^[1] ; Kettelhut, Isis C. ^{[1, 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, BR-14049900 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY; v. 72, p. 40-50, MAR 2016.
• Citações Web of Science: 10

Resumo

Calcitonin gene-related peptide (CGRP) is a neuropeptide released by motor neuron in skeletal muscle and modulates the neuromuscular transmission by induction of synthesis and insertion of acetylcholine receptor on postsynaptic muscle membrane; however, its role in skeletal muscle protein metabolism remains unclear. We examined the in vitro and in vivo effects of CGRP on protein breakdown and signaling pathways in control skeletal muscles and muscles following denervation (DEN) in rats. In isolated muscles, CGRP (10(-10) to 10(-6) M) reduced basal and DEN-induced activation of overall proteolysis in a concentration-dependent manner. The in vitro anti-proteolytic effect of CGRP was completely abolished by CGRP8-37, a CGRP receptor antagonist. CGRP down-regulated the lysosomal proteolysis, the mRNA levels of LC3b, Gabarapl1 and cathepsin L and the protein content of LC3-II in control and denervated muscles. In parallel, CGRP elevated CAMP levels, stimulated PKA/CREB signaling and increased Foxo1 phosphorylation in both conditions. In denervated muscles and starved C2C12 cells, Rp-8-Br-cAMPs or PKI, two PKA inhibitors, completely abolished the inhibitory effect of CGRP on Foxo1, 3 and 4 and LC3 lipidation. A single injection of CGRP (100 mu g kg(-1)) in denervated rats increased the phosphorylation levels of CREB and Akt, inhibited Foxo transcriptional activity, the LC3 lipidation as well as the mRNA levels of LC3b and cathepsin L, two bona fide targets of Foxo. This study shows for the first time that CGRP exerts a direct inhibitory action on autophagic-lysosomal proteolysis in control and denervated skeletal muscle by recruiting cAMP/PICA signaling, effects that are related to inhibition of Foxo activity and LC3 lipidation. (C) 2016 Published by Elsevier Ltd. (AU)

• Processo FAPESP: 12/05697-7 - Interação funcional entre o sistema colinérgico e adrenérgico na manutenção da massa muscular e da placa motora
• Beneficiário: Danilo Lustrino Borges
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• 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
• Linha de fomento: Auxílio à Pesquisa - Regular
• 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
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/51456-1 - Role and mechanism of action of anabolic stimuli on neuromuscular trophicity
• Beneficiário: Isis Do Carmo Kettelhut
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/24524-6 - Controle da massa muscular pela via de sinalização do AMPc
• Beneficiário: Isis Do Carmo Kettelhut
• Linha de fomento: Auxílio à Pesquisa - Temático