PMID- 24833777 OWN - NLM STAT- MEDLINE DCOM- 20150303 LR - 20161125 IS - 1522-1601 (Electronic) IS - 0161-7567 (Linking) VI - 117 IP - 1 DP - 2014 Jul 1 TI - Activating cAMP/PKA signaling in skeletal muscle suppresses the ubiquitin-proteasome-dependent proteolysis: implications for sympathetic regulation. PG - 11-9 LID - 10.1152/japplphysiol.01055.2013 [doi] AB - 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 ( approximately 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 muM). 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 muM), 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 Ub-ligases can be mediated by the activation of cAMP/PKA signaling, with the inhibition of forkhead box class O1 transcription factor. CI - Copyright (c) 2014 the American Physiological Society. FAU - Silveira, W A AU - Silveira WA AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; FAU - Goncalves, D A AU - Goncalves DA AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; FAU - Graca, F A AU - Graca FA AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; FAU - Andrade-Lopes, A L AU - Andrade-Lopes AL AD - Division of Cellular Pharmacology, Department of Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil. FAU - Bergantin, L B AU - Bergantin LB AD - Division of Cellular Pharmacology, Department of Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil. FAU - Zanon, N M AU - Zanon NM AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; FAU - Godinho, R O AU - Godinho RO AD - Division of Cellular Pharmacology, Department of Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil. FAU - Kettelhut, I C AU - Kettelhut IC AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; Department of Biochemistry/Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; and. FAU - Navegantes, L C C AU - Navegantes LC AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; navegantes@fmrp.usp.br. LA - eng PT - Journal Article DEP - 20140515 PL - United States TA - J Appl Physiol (1985) JT - Journal of applied physiology (Bethesda, Md. : 1985) JID - 8502536 RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Forkhead Transcription Factors) RN - 0 (Muscle Proteins) RN - 0 (RNA, Messenger) RN - 0 (Ubiquitin) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) RN - X4W3ENH1CV (Norepinephrine) SB - IM MH - Animals MH - Cyclic AMP/*metabolism MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Forkhead Transcription Factors/metabolism MH - Male MH - Muscle Proteins/metabolism MH - Muscle, Skeletal/*metabolism MH - Norepinephrine/metabolism MH - Phosphorylation/physiology MH - Proteasome Endopeptidase Complex/*metabolism MH - Protein Kinases/*metabolism MH - Proteolysis MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA, Messenger/metabolism MH - Rats MH - Rats, Wistar MH - Signal Transduction/*physiology MH - Sympathetic Nervous System/*metabolism MH - Ubiquitin/*metabolism MH - Ubiquitin-Protein Ligases/metabolism OTO - NOTNLM OT - MuRF1 OT - atrogin-1 OT - catecholamines OT - proteolysis OT - sympathectomy EDAT- 2014/05/17 06:00 MHDA- 2015/03/04 06:00 CRDT- 2014/05/17 06:00 PHST- 2014/05/17 06:00 [entrez] PHST- 2014/05/17 06:00 [pubmed] PHST- 2015/03/04 06:00 [medline] AID - japplphysiol.01055.2013 [pii] AID - 10.1152/japplphysiol.01055.2013 [doi] PST - ppublish SO - J Appl Physiol (1985). 2014 Jul 1;117(1):11-9. doi: 10.1152/japplphysiol.01055.2013. Epub 2014 May 15.