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Control of muscle mass by cAMP signaling pathway


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)

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Scientific publications (14)
(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)
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, . (12/24524-6, 08/06694-6, 10/11083-6, 09/07584-2, 10/11015-0)
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; et al. 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, . (12/24524-6, 18/10089-2, 12/18861-0, 10/11015-0)
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, . (10/11015-0, 12/24524-6, 12/18861-0, 13/08553-9)
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, . (08/06694-6, 12/24524-6)
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, . (12/24524-6, 10/18287-6, 12/18861-0, 12/15276-9, 09/17667-2)
KHAN, MUZAMIL MAJID; LUSTRINO, DANILO; SILVEIRA, WILLIAN A.; WILD, FRANZISKA; STRAKA, TATJANA; ISSOP, YASMIN; O'CONNOR, EMILY; COX, DAN; REISCHL, MARKUS; MARQUARDT, TILL; et al. 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, . (12/24524-6, 10/11083-6, 12/51456-1, 12/05697-7)
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, . (08/06694-6, 12/05697-7, 12/24524-6)
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, . (09/54014-7, 11/11003-5, 12/24524-6, 18/10089-2, 12/18861-0)
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, . (12/24524-6, 08/06694-6, 12/18861-0, 10/11083-6, 10/11015-0)
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, . (12/24524-6, 12/05697-7)
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, . (08/06694-6, 12/24524-6, 12/18861-0)
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, . (11/11003-5, 12/24524-6, 12/05697-7, 12/51456-1, 12/18861-0)
PRZYGODDA, FRANCIELE; LAUTHERBACH, NATALIA; BUZELLE, SAMYRA LOPES; GONCALVES, DAWIT ALBIEIRO; ASSIS, ANA PAULA; PAULA-GOMES, SILVIA; RISSATO GAROFALO, MARIA ANTONIETA; HECK, LILIAN CARMO; MATSUO, FLAVIA SAYURI; MOTA, RYERSON FONSECA; et al. Sympathetic innervation suppresses the autophagic-lysosomal system in brown adipose tissue under basal and cold-stimulated conditions. Journal of Applied Physiology, v. 128, n. 4, p. 855-871, . (12/24524-6, 18/10089-2, 16/00508-2, 15/26088-7, 14/11092-6, 13/17111-0, 12/18861-0)
SILVEIRA, WILIAN A.; GONCALVES, DAWIT A.; MACHADO, JULIANO; LAUTHERBACH, NATALIA; LUSTRINO, DANILO; PAULA-GOMES, SILVIA; PEREIRA, MARCELO G.; MIYABARA, ELEN H.; SANDRI, MARCO; KETTELHUT, ISIS C.; et al. cAMP-dependent protein kinase inhibits FoxO activity and regulates skeletal muscle plasticity in mice. FASEB JOURNAL, v. 34, n. 9, . (18/10089-2, 12/18861-0, 12/24524-6)

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