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FOXO hyperacetylation as a mechanism of suppression of atrophy gene program induced by beta2-adrenergic signaling in rodent skeletal muscle

Grant number: 12/18861-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2013
Effective date (End): February 28, 2018
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Isis Do Carmo Kettelhut
Grantee:Dawit Albieiro Pinheiro Gonçalves
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:12/24524-6 - Control of muscle mass by cAMP signaling pathway, AP.TEM
Associated scholarship(s):15/12740-4 - FOXO hyperacetylation as a mechanism of suppression of atrophy gene program induced by beta2-adrenergic signaling in rodent skeletal muscle, BE.EP.PD

Abstract

The knowledge of therapeutic strategies able to counteract skeletal muscle atrophy is an important issue for human health. In previous studies, we have showed that b2-adrenoceptors (AR) activation regulates muscle protein metabolism through the suppression of the activity of ubiquitin (Ub)-proteasome system, the major proteolytic system involved in muscle wasting, and the expression of atrophy-related genes (atrogenes). Multiple signaling pathways, such as cAMP/PKA, ERK1/2 and Akt, have been associated with the antiproteolytic effects of b2-agonists. However, the precise molecular mechanism by which these kinases suppress atrogenes expression is unclear. Preliminary results from our lab indicate that pharmacological activation of b2AR induces acetylation, and possibly inactivation, of Foxo, a family of transcription factors responsible for atrogenes expression. Thus, the project aims to investigate the in vivo involvement of histone deacetilases (HDAC) and histone acetyltransferases (HAT) p300/CBP in Foxo acetylation and downregulation of atrophy gene program induced by b2-adrenergic signaling in skeletal muscle. For that, 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 atrophic muscles from 2-days-fasted mice treated with formoterol, a potent b2-agonist. To investigate further the signaling pathways involved in the anticatabolic action of b2-agonist, skeletal muscles will be transfected with dominant negative forms of PKA, CREB, ERK2 or Akt. In addition, we will test whether in vivo transfection of CREB and Sik1, a kinase downstream of CREB and an inhibitor of HDACs, is able to regulate the activity and the acetylation level of Foxo and prevent muscle wasting.

Scientific publications (8)
(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.
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.
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: 17.
PAULA-GOMES, S.; GONCALVES, D. A. P.; BAVIERA, A. M.; ZANON, N. M.; NAVEGANTES, L. C. C.; KETTELHUT, I. C. Insulin Suppresses Atrophy- and Autophagy-related Genes in Heart Tissue and Cardiomyocytes Through AKT/FOXO Signaling. Hormone and Metabolic Research, v. 45, n. 12, p. 849-855, NOV 2013. Web of Science Citations: 31.

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