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

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

Author Silveira, W. A. Google Scholar
Goncalves, D. A. Google Scholar
Graca, F. A. Google Scholar
Andrade-Lopes, A. L. Autor UNIFESP Google Scholar
Bergantin, L. B. Autor UNIFESP Google Scholar
Zanon, N. M. Google Scholar
Godinho, R. O. Autor UNIFESP Google Scholar
Kettelhut, I. C. Google Scholar
Navegantes, L. C. C. Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
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.
Keywords catecholamines
sympathectomy
proteolysis
atrogin-1
MuRF1
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Pesquisa
Grant number FAPESP: 08/06694-6
FAPESP: 10/11083-6
FAPESP: 12/18861-0
FAPESP: 12/24524-6
FAPESP: 10/11015-0
Conselho Nacional de Pesquisa: 140094/07-5
Conselho Nacional de Pesquisa: 306101/09-2
Conselho Nacional de Pesquisa: 303786/08-6
Date 2014-07-01
Published in Journal of Applied Physiology. Bethesda: Amer Physiological Soc, v. 117, n. 1, p. 11-19, 2014.
ISSN 8750-7587 (Sherpa/Romeo, impact factor)
Publisher Amer Physiological Soc
Extent 11-19
Origin http://dx.doi.org/10.1152/japplphysiol.01055.2013
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000339169300002
URI http://repositorio.unifesp.br/handle/11600/37902

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