Activating cAMP/PKA signaling in skeletal muscle suppresses the ubiquitin-proteasome-dependent proteolysis: implications for sympathetic regulation

Author(s)

Silveira, W. A. ^[1] ; Goncalves, D. A. ^[1] ; Graca, F. A. ^[1] ; Andrade-Lopes, A. L. ^[2] ; Bergantin, L. B. ^[2] ; Zanon, N. M. ^[1] ; Godinho, R. O. ^[2] ; Kettelhut, I. C. ^{[1, 3]} ; Navegantes, L. C. C. ^[1]

Affiliation

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

^[2] Univ Fed Sao Paulo UNIFESP, Dept Pharmacol, Div Cellular Pharmacol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem Immunol, BR-14049900 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Journal of Applied Physiology; v. 117, n. 1, p. 11-19, JUL 2014.
• Web of Science Citations: 15

Abstract

Although we have recently demonstrated that plasma catecholamines induce antiproteolytic effects on skeletal muscle (Graca FA, Goncalves DAP, Silveira WA, Lira EC, Chaves VE, Zanon NM, Garofalo MAR, Kettelhut IC, Navegantes LCC. Am J Physiol Endocrinol Metab. 305: E1483-E1494, 2013), the role of the muscle sympathetic innervation and, more specifically, norepinephrine (NE) in regulating the ubiquitin (Ub)-proteasome system (UPS) remains unknown. Based on previous findings that chemical sympathectomy acutely reduces UPS activity, we hypothesized that muscle NE depletion induces adrenergic supersensitivity in rat skeletal muscles. We report that surgical sympathetic denervation (SDEN), a condition in which only muscle NE from both hindlimbs is depleted, transiently reduced the overall proteolysis and the UPS activity (similar to 25%) in both soleus and extensor digitorum longus muscles. This antiproteolytic response was accompanied by increased activity of adenylyl cyclase (112%), levels of cyclic adenosine monophosphate (cAMP; 191%), and the serine phosphorylation of cAMP response element-binding protein (32%). In extensor digitorum longus from normal rats, NE (10(-4) M) in vitro increased the levels of cAMP (115%) and the serine phosphorylation of both cAMP response element-binding protein (2.7-fold) and forkhead box class O1 transcription factor. Similar effects were observed in C2C12 cells incubated with forskolin (10 mu M). In parallel, NE significantly reduced the basal UPS (21%) activity and the mRNA levels of atrophy-related Ub-ligases. Similar responses were observed in isolated muscles exposed to 6-BNZ-cAMP (500 mu M), a specific PKA activator. The phosphorylation levels of Akt were not altered by SDEN, NE, forskolin or 6-BNZ-cAMP. Our results demonstrate that SDEN induces muscle adrenergic supersensitivity for cAMP leading to the suppression of UPS, and that the suppressive effects of NE on UPS activity and expression of Ubligases can be mediated by the activation of cAMP/PKA signaling, with the inhibition of forkhead box class O1 transcription factor. (AU)

• FAPESP's process: 08/06694-6 - Neural control of protein metabolism
• Grantee: Isis Do Carmo Kettelhut
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/24524-6 - Control of muscle mass by cAMP signaling pathway
• Grantee: Isis Do Carmo Kettelhut
• Support Opportunities: Research Projects - Thematic Grants
• 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 Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 10/11015-0 - Intracellular mechanisms involved in anticatabolic effect of the epinephrine in skeletal muscle of fasted rats
• Grantee: Flávia Aparecida Graça
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/11083-6 - ROLE OF EPAC IN CONTROL OF PROTEIN METABOLISM IN SKELETAL MUSCLE
• Grantee: Wilian de Assis Silveira
• Support Opportunities: Scholarships in Brazil - Doctorate