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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 8
[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
Total Affiliations: 2
Document type: Journal article
Web of Science Citations: 10

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)

FAPESP's process: 12/24524-6 - Control of muscle mass by cAMP signaling pathway
Grantee:Isis Do Carmo Kettelhut
Support type: Research Projects - Thematic Grants
FAPESP's process: 11/11003-5 - The role of calcitonin-gene related peptide (CGRP) in the control of protein metabolism in normal and denervated rat skeletal muscle
Grantee:Luiz Carlos Carvalho Navegantes
Support type: Regular Research Grants
FAPESP's process: 12/51456-1 - Role and mechanism of action of anabolic stimuli on neuromuscular trophicity
Grantee:Isis Do Carmo Kettelhut
Support type: Regular Research Grants
FAPESP's process: 12/05697-7 - Functional interaction between cholinergic and adrenergic systems in the maintenance of muscle mass and motor endplate
Grantee:Danilo Lustrino Borges
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 12/18861-0 - FOXO hyperacetylation as a mechanism of suppression of atrophy gene program induced by beta2-adrenergic signaling in rodent skeletal muscle
Grantee:Dawit Albieiro Pinheiro Gonçalves
Support type: Scholarships in Brazil - Post-Doctorate