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Silveira, W.A.* ; Machado, J. ; Lautherbach, N.* ; Lustrino, D.* ; Paula-Gomes, S.* ; Pereira, M.G.* ; Miyabara, E.H.* ; Sandri, M.* ; Kettelhut, I.C.* ; Navegantes, L.C.*

cAMP-dependent protein kinase inhibits FoxO activity and regulates skeletal muscle plasticity in mice.

FASEB J. 34, 12946-12962 (2020)

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Open Access Green as soon as Postprint is submitted to ZB.

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Although we have shown that catecholamines suppress the activity of the Ubiquitin-Proteasome System (UPS) and atrophy-related genes expression through a cAMP-dependent manner in skeletal muscle from rodents, the underlying mechanisms remain unclear. Here, we report that a single injection of norepinephrine (NE; 1 mg kg(-1); s.c) attenuated the fasting-induced up-regulation of FoxO-target genes in tibialis anterior (TA) muscles by the stimulation of PKA/CREB and Akt/FoxO1 signaling pathways. In addition, muscle-specific activation of PKA by the overexpression of PKA catalytic subunit (PKAcat) suppressed FoxO reporter activity induced by (1) a wild-type; (2) a non-phosphorylatable; (3) a non-phosphorylatable and non-acetylatable forms of FoxO1 and FoxO3; (4) downregulation of FoxO protein content, and probably by (5) PGC-1 alpha up-regulation. Consistently, the overexpression of the PKAcat inhibitor (PKI) up-regulated FoxO activity and the content of Atrogin-1 and MuRF1, as well as induced muscle fiber atrophy, the latter effect being prevented by the overexpression of a dominant negative (d. n.) form of FoxO (d.n.FoxO). The sustained overexpression of PKAcat induced fiber-type transition toward a smaller, slower, and more oxidative phenotype and improved muscle resistance to fatigue. Taken together, our data provide the first evidence that endogenous PKA activity is required to restrain the basal activity of FoxO and physiologically important to maintain skeletal muscle mass.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Adrenergic Signaling ; Protein Metabolism ; Skeletal Muscle Atrophy ; Skeletal Muscle Plasticity ; Ubiquitin-proteasome System; Acetyltransferase Activity; Hepatic Gluconeogenesis; Erk1/2 Activation; Ubiquitin Ligases; Atrophy; Proteolysis; Pgc-1-alpha; Receptor; Suppresses; Creb

ISSN (print) / ISBN 0892-6638

e-ISSN 1530-6860

Journal FASEB Journal

Quellenangaben Volume: 34, Issue: 9, Pages: 12946-12962

Publisher Wiley

Publishing Place Bethesda, Md.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)

Grants Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
CAPES
Association Francaise contre les Myopathies
LeDucq Foundation
Associazione Italiana per la Ricerca sul Cancro (AIRC)
RISE