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Control of muscle mass by cAMP signaling pathway

Grant number: 12/24524-6
Support type:Research Projects - Thematic Grants
Duration: June 01, 2013 - May 31, 2018
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Isis Do Carmo Kettelhut
Grantee:Isis Do Carmo Kettelhut
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Co-Principal Investigators:Luiz Carlos Carvalho Navegantes
Associated scholarship(s):14/17926-6 - The role of CREB in the control of Redd1 in skeletal muscle under stress conditions, BE.PQ
13/08553-9 - The role of the beta-arrestin signaling pathway in the control of cardiac muscle mass and cardiomyocytes culture of rodents, BP.PD
12/18861-0 - FOXO hyperacetylation as a mechanism of suppression of atrophy gene program induced by beta2-adrenergic signaling in rodent skeletal muscle, BP.PD

Abstract

In our previous thematic project, we have shown that the sympathetic nervous system through the beta 2-adrenoceptors activation inhibits the activity of ubiquitin-proteasome system (UPS), the major proteolytic system involved in muscle wasting. This effect is due to the suppression of "atrophy program" (atrophy-related genes or atrogenes) and involves the cAMP signaling pathway. However, the mechanisms that underlie such function of cAMP and its downstream effectors in the control of muscle mass remain unknown. Therefore, the main goals of the present project are: 1-To investigate the involvement of histone deacetylases and the CREB co-activators (p300/CBP) in the acetylation of Foxo as a mechanism of inhibition of atrogenes induced by beta 2-agonists; 2-To verify the role of PKA/CREB as an adaptive mechanism response to attenuate muscle loss in chronically denervated muscles; 3-To explore the possible interaction between cAMP and myostatin signaling pathway in the control of muscle mass; 4-To investigate the antiproteolitic mechanisms and signaling pathways involved in the anabolic action of additional cAMP-inducing agents (CGRP and Urocortins) and 5-To establish whether the adrenergic mechanisms regulating protein turnover in the brown adipose tissue are similar to those in the skeletal muscle. To that end, we shall use molecular and biochemical approaches to measure proteolytic activities and the expression of genes and proteins in tissues and cells. Furthermore, in vivo techniques of molecular biology, such as gene transfer by electroporation and the analysis of transcriptional factor activity by imaging system will be implanted in our lab. Therefore, Foxo acetylation status will be able to be correlated with the in vivo transcriptional activity of Foxo and the expression level of atrogenes in muscles from rodents submitted to different atrophic models and treated with beta 2-agonists and other compounds. To further investigate the signaling pathways involved in the anticatabolic action of cAMP, skeletal muscles will be transfected with dominant negative forms of PKA, CREB, ERK2 or Akt. These results may contribute to the development of therapeutic strategies to combat muscle atrophy. (AU)

Scientific publications (12)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MACHADO, JULIANO; SILVEIRA, WILIAN A.; GONCALVES, DAWIT A.; SCHAVINSKI, ALINE ZANATTA; KHAN, MUZAMIL M.; ZANON, NEUSA M.; DIAZ, MAURICIO BERRIEL; RUDOLF, RUEDIGER; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. alpha-Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles. MOLECULAR METABOLISM, v. 28, p. 91-106, OCT 2019. Web of Science Citations: 0.
GONCALVES, DAWIT A.; SILVEIRA, WILIAN A.; MANFREDI, LEANDRO H.; GRACA, FLAVIA A.; ARMANI, ANDREA; BERTAGGIA, ENRICO; O'NEILL, BRIAN T.; LAUTHERBACH, NATALIA; MACHADO, JULIANO; NOGARA, LEONARDO; PEREIRA, MARCELO G.; ARCIDIACONO, DILETTA; REALDON, STEFANO; KAHN, C. RONALD; SANDRI, MARCO; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ CARLOS C. Insulin/IGF1 signalling mediates the effects of beta(2)-adrenergic agonist on muscle proteostasis and growth. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 10, n. 2, p. 455-475, APR 2019. Web of Science Citations: 1.
PRZYGODDA, FRANCIELE; MANFREDI, LEANDRO HENRIQUE; MACHADO, JULIANO; GONCALVES, DAWIT A. P.; ZANON, NEUSA M.; BONAGAMBA, LENI G. H.; MACHADO, BENEDITO H.; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. C. Acute intermittent hypoxia in rats activates muscle proteolytic pathways through a gluccorticoid-dependent mechanism. Journal of Applied Physiology, v. 122, n. 5, p. 1114-1124, MAY 2017. Web of Science Citations: 2.
MANFREDI, L. H.; LUSTRINO, D.; MACHADO, J.; SILVEIRA, W. A.; ZANON, N. M.; NAVEGANTES, L. C.; KETTELHUT, I. C. Adrenodemedullation activates the Ca2+-dependent proteolysis in soleus muscles from rats exposed to cold. Journal of Applied Physiology, v. 122, n. 2, p. 317-326, FEB 2017. Web of Science Citations: 1.
MANFREDI, L. H.; PAULA-GOMES, S.; ZANON, N. M.; KETTELHUT, I. C. Myostatin promotes distinct responses on protein metabolism of skeletal and cardiac muscle fibers of rodents. Brazilian Journal of Medical and Biological Research, v. 50, n. 12 2017. Web of Science Citations: 4.
FORESTO, CAMILA SILVA; PAULA-GOMES, SILVIA; SILVEIRA, WILIAN ASSIS; GRACA, FLAVIA APARECIDA; KETTELHUT, ISIS DO CARMO; PINHEIRO GONCALVES, DAWIT ALBIEIRO; MATTIELLO-SVERZUT, ANA CLAUDIA. Morphological and molecular aspects of immobilization-induced muscle atrophy in rats at different stages of postnatal development: the role of autophagy. Journal of Applied Physiology, v. 121, n. 3, p. 646-660, SEP 1 2016. Web of Science Citations: 3.
MACHADO, JULIANO; MANFREDI, LEANDRO H.; SILVEIRA, WILIAN A.; GONCALVES, DAWIT A. P.; LUSTRINO, DANILO; ZANON, NEUSA M.; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. Calcitonin gene-related peptide inhibits autophagic-lysosomal proteolysis through cAMP/PKA signaling in rat skeletal muscles. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, v. 72, p. 40-50, MAR 2016. Web of Science Citations: 10.
KHAN, MUZAMIL MAJID; LUSTRINO, DANILO; SILVEIRA, WILLIAN A.; WILD, FRANZISKA; STRAKA, TATJANA; ISSOP, YASMIN; O'CONNOR, EMILY; COX, DAN; REISCHL, MARKUS; MARQUARDT, TILL; LABEIT, DITTMAR; LABEIT, SIEGFRIED; BENOIT, EVELYNE; MOLGO, JORDI; LOCHMUELLER, HANNS; WITZEMANN, VEIT; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. C.; POZZAN, TULLIO; RUDOLF, RUEDIGER. Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease. Proceedings of the National Academy of Sciences of the United States of America, v. 113, n. 3, p. 746-750, JAN 19 2016. Web of Science Citations: 35.
PEREIRA, MARCELO G.; SILVA, MEIRICRIS T.; CARLASSARA, EDUARDO O. C.; GONCALVES, DAWIT A.; ABRAHAMSOHN, PAULO A.; KETTELHUT, ISIS C.; MORISCOT, ANSELMO S.; AOKI, MARCELO S.; MIYABARA, ELEN H. Leucine Supplementation Accelerates Connective Tissue Repair of Injured Tibialis Anterior Muscle. NUTRIENTS, v. 6, n. 10, p. 3981-4001, OCT 2014. Web of Science Citations: 16.
SILVEIRA, W. A.; GONCALVES, D. A.; GRACA, F. A.; ANDRADE-LOPES, A. L.; BERGANTIN, L. B.; ZANON, N. M.; GODINHO, R. O.; KETTELHUT, I. C.; NAVEGANTES, L. C. C. Activating cAMP/PKA signaling in skeletal muscle suppresses the ubiquitin-proteasome-dependent proteolysis: implications for sympathetic regulation. Journal of Applied Physiology, v. 117, n. 1, p. 11-19, JUL 2014. Web of Science Citations: 16.
GRACA, FLAVIA A.; GONCALVES, DAWIT A. P.; SILVEIRA, WILIAN A.; LIRA, EDUARDO C.; CHAVES, VALERIA ERNESTANIA; ZANON, NEUSA M.; GAROFALO, MARIA ANTONIETA R.; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. C. Epinephrine depletion exacerbates the fasting-induced protein breakdown in fast-twitch skeletal muscles. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 305, n. 12, p. E1483-E1494, DEC 2013. Web of Science Citations: 9.
RUDOLF, RUEDIGER; KHAN, MUZAMIL M.; LUSTRINO, DANILO; LABEIT, SIEGFRIED; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. C. Alterations of cAMP-dependent signaling in dystrophic skeletal muscle. FRONTIERS IN PHYSIOLOGY, v. 4, 2013. Web of Science Citations: 13.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.