Neural, hormonal and nutritional control of autophagy

• Grant number: 18/10089-2
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2019
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Isis Do Carmo Kettelhut
• Grantee: Isis Do Carmo Kettelhut
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Luciane Carla Alberici ; Luiz Carlos Carvalho Navegantes
• Associated researchers: Amanda Martins Baviera ; Fernando Silva Ramalho ; Marc R. Montminy ; Mariana Kiomy Osako ; Rubens Fazan Junior ; Rüdiger Rudolf
• Associated scholarship(s): 23/13306-2 - Role of Urocortin 2 in the maintenance of neuromuscular junction (NMJ) and muscle mass in skeletal muscles of atrophic and obese mice., BP.TT; 23/01030-2 - Molecular mechanisms involved in the control of hepatic neoglucogenesis in animals submitted to a high-protein diet: Role of CREB and branched-chain amino acids, BP.MS; 21/05848-4 - Sympathetic regulation of hepatic autophagy by CREB/CRTC-2, BP.DR; + associated scholarships 21/11527-6 - Drosophila melanogaster as a molecular modulation model for in vivo study of autophagy and its relationship with mitochondrial metabolism, BP.PD; 21/05868-5 - Liraglutide anti-atrophic mechanisms in an experimental model of Diabetes Mellitus, BP.DR; 19/22446-7 - Role of adrenaline in the protein metabolism regulation in cardiac muscle of rats, BP.IC; 19/19993-6 - Effects of maternal vitamin D deficiency on brown adipose tissue development and function in rat offspring, BP.IC; 19/20673-6 - The role of sympathetic nervous system and protein kinase A on muscle adaptations to exercise, BP.TT; 19/06517-1 - The effect of maternal vitamin D deficiency on offspring development and muscle protein metabolism, BP.DR; 19/05900-6 - Molecular mechanisms involved in the simpatic activation of hepatic gluconeogenesis, BP.MS; 19/10420-3 - Neural, hormonal and nutritional control of autophagy, BP.PD; 19/09814-7 - Effect of sexual dimorphism on adaptive responses of skeletal muscle in a model of neonatal Vitamin D deficiency in rats, BP.IC - associated scholarships

Abstract

Autophagy is a ubiquitous catabolic process that causes intracellular degradation through vesicular engulfment of dysfunctional, damaged, or harmful cytoplasmic components. Although it is well established that autophagy and the Ub-proteasome system regulate cellular homeostasis, the exacerbation of these processes leads to muscle atrophy and several pathologies. Previous work from our laboratory has demonstrated that activation of cAMP signaling plays an important role in the inhibition of proteolytic processes in different tissues including skeletal muscle, heart, brown adipose tissue as well as in the neuromuscular junction (NMJ) of rodents. The present project aims to investigate the mechanisms (transmission signals, transcription factors, degradation pathways and protein synthesis, etc.) through which the CNS, via the sympathetic nerves, hormones (glucocorticoids, glucagon, adrenaline and angiotensin II), peptides (CGRP) and dietary factors control autophagy in the setting of basal and energy demanding situations like fasting, exercise and cold. Moreover, we aim to investigate the effects of muscle transfection with Urocortin 2, a peptide that acts through cAMP, in the attenuation of muscle atrophy and loss of cholinergic receptors at the NMJ of denervated muscles and insulin sensitivity in obese animals. To this end, we will use biochemical, molecular and imaging methods for the evaluation of autophagic flow and protein metabolism turnover in tissues and cells. Also, we propose to use transgenic and mutant Drosophila melanogaster models of proteins of interest and carriers of fluorescent markers to estimate autophagy. The better understanding of the regulatory control of autophagy may contribute to the development of therapeutic strategies for metabolic and neuromuscular diseases. (AU)

Scientific publications

(23)

(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)

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, APR 2020. (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, AUG 2020. (18/10089-2, 12/18861-0, 12/24524-6)

LAUTHERBACH, NATALIA; GONCALVES, DAWIT A. P.; SILVEIRA, WILIAN A.; PAULA-GOMES, SILVIA; VALENTIM, RAFAEL ROSSI; ZANON, NEUSA M.; PEREIRA, MARCELO G.; MIYABARA, ELEN H.; NAVEGANTES, LUIZ C. C.; KETTELHUT, ISIS C.. Urocortin 2 promotes hypertrophy and enhances skeletal muscle function through cAMP and insulin/IGF-1 signaling pathways. MOLECULAR METABOLISM, v. 60, p. 16-pg., 2022-06-01. (11/11003-5, 18/10089-2, 12/24524-6, 12/18861-0)

PORTO DECHANDT, CARLOS ROBERTO; FERRARI, GUSTAVO DUARTE; DOS SANTOS, JONATHAS RODRIGO; CORTES DE OLIVEIRA, JOSE ANTONIO; PATRICIO SILVA-JR, RUI MILTON; SIQUEIRA CUNHA, ALEXANDRA OLIMPIO; GARCIA-CAIRASCO, NORBERTO; ALBERICI, LUCIANE CARLA. Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy. FRONTIERS IN NEUROLOGY, v. 10, OCT 1 2019. (14/03989-6, 18/10089-2, 16/23509-4, 15/22327-7, 19/00849-2)

DOS SANTOS, JONATHAS RODRIGO; BORTOLANZA, MARIZA; FERRARI, GUSTAVO DUARTE; LANFREDI, GUILHERME PAUPERIO; DO NASCIMENTO, GLAUCE CRIVELARO; CALEREIRO SEIXAS AZZOLINI, ANA ELISA; DEL BEL, ELAINE; DE CAMPOS, ALLINE CRISTINA; FACA, VITOR MARCEL; VULCZAK, ANDERSON; et al. One-Week High-Intensity Interval Training Increases Hippocampal Plasticity and Mitochondrial Content without Changes in Redox State. ANTIOXIDANTS, v. 9, n. 5, MAY 2020. (18/10089-2, 16/23509-4)

MORGAN, HENRIQUE J. N.; DELFINO, HEITOR B. P.; SCHAVINSKI, ALINE Z.; MALONE, SAMUEL A.; CHAROY, CAMILLE; REIS, NATANY G.; ASSIS, ANA P.; LAUTHERBACH, NATALIA; SILVEIRA, WILIAN A.; HECK, LILIAN C.; et al. Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 157, p. 17-pg., 2024-06-24. (19/26583-9, 18/10089-2, 19/05900-6)

VULCZAK, ANDERSON; ALBERICI, LUCIANE CARLA. Physical Exercise and Tumor Energy Metabolism. CANCER TREATMENT AND RESEARCH COMMUNICATIONS, v. 32, p. 5-pg., 2022-01-01. (16/23509-4, 18/10089-2)

NAVEGANTES, LUIZ; REIS, NATANY; TURATTI, JOAO; GONCALVES, DAWIT; SILVEIRA, WILLIAN; LAUTHERBACH, NATALIA; ALMEIDA, LUCAS; DE ASSIS, ANA; ZANON, NEUSA; HECK, LILIAN; et al. Sex-Specific Alterations on Muscle Plasticity and Myogenesis in Offspring Rats from Vitamin D Deficient Mothers. FASEB JOURNAL, v. 34, p. 2-pg., 2020-04-01. (18/10089-2, 19/06517-1)

DA COSTA, LUIS HENRIQUE ANGENENDT. Simvastatin Prevents Long-Term Cognitive Deficits in Sepsis Survivor Rats by Reducing Neuroinflammation and Neurodegeneration. NEUROTOXICITY RESEARCH, JUN 2020. (18/10089-2, 18/02854-0, 17/12462-0)

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. (09/54014-7, 11/11003-5, 12/24524-6, 18/10089-2, 12/18861-0)

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, APR 2019. (18/10089-2, 12/24524-6, 12/18861-0, 10/11015-0)

ALBERICI, LUCIANE C.; OLIVEIRA, HELENA C. F.. Mitochondrial Adaptive Responses to Hypertriglyceridemia and Bioactive Lipids. Antioxidants & Redox Signaling, v. 36, n. 13, p. 16-pg., 2021-12-31. (13/07607-8, 17/17728-8, 18/10089-2)

SCHAVINSKI, ALINE ZANATTA; MACHADO, JULIANO; NOVAES MORGAN, HENRIQUE JORGE; LAUTHERBACH, NATALIA; PAULA-GOMES, SILVIA; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ CARLOS C.. Calcitonin gene-related peptide exerts inhibitory effects on autophagy in the heart of mice. Peptides, v. 146, DEC 2021. (18/10089-2)

REIS, NATANY G.; ASSIS, ANA P.; LAUTHERBACH, NATALIA; GONCALVES, DAWIT A.; SILVEIRA, WILIAN A.; MORGAN, HENRIQUE J. N.; VALENTIM, RAFAEL R.; ALMEIDA, LUCAS F.; HECK, LILIAN C.; ZANON, NEUSA M.; et al. Maternal vitamin D deficiency affects the morphology and function of glycolytic muscle in adult offspring rats. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. N/A, p. 13-pg., 2022-05-18. (19/06517-1, 18/10089-2)

ABDALLA-SILVA, RONALDO L.; ZANETTI, GUSTAVO O.; LAUTHERBACH, NATALIA; SCHAVINSKI, ALINE ZANATTA; HECK, LILIAN C.; GONCALVES, DAWIT A. P.; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. C.; SILVEIRA, WILIAN A.. β₂-Adrenoceptors activation regulates muscle trophic-related genes following acute resistance exercise in mice. FRONTIERS IN PHYSIOLOGY, v. 15, p. 15-pg., 2024-01-22. (19/10420-3, 18/10089-2)

SCHAVINSKI, ALINE Z.; REIS, NATANY G.; MORGAN, HENRIQUE J. N.; ASSIS, ANA PAULA; MORO, MATHEUS L.; VALENTIM, RAFAEL R.; SENI-SILVA, ANA CAROLINA; RAMOS, ESTER S.; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ C. C.. Maternal Vitamin D Deficiency Impairs the Development of β Cells in Offspring Rats in a Sex-Dependent Manner. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 8, p. 16-pg., 2024-04-01. (18/10089-2)

CAVALCANTI DE ARAUJO, PAULO HENRIQUE; CEZINE, MARIA EDUARDA RAMOS; VULCZAK, ANDERSON; VIEIRA, LUIZ CARLOS; MATSUO, FLAVIA SAYURI; REMOTO, JULIA MARANGHETTI; SANTOS, AUDREI DOS REIS; MIYABARA, ELEN HARUKA; ALBERICI, LUCIANE CARLA; OSAKO, MARIANA KIOMY. RANKL signaling drives skeletal muscle into the oxidative profile. Journal of Bone and Mineral Research, v. 39, n. 6, p. 12-pg., 2024-04-15. (20/15959-5, 18/10089-2, 22/06359-0)

IVANILDO I.S. JÚNIOR; GUSTAVO O. ZANETTI; TALES S. VIEIRA; FLÁVIA P. ALBUQUERQUE; DAYANE A. GOMES; SILVA PAULA-GOMES; RAFAEL R. VALENTIM; FLAVIA A. GRAÇA; ISIS C. KETTLHUT; LUIZ C.C. NAVEGANTES; et al. Resveratrol directly suppresses proteolysis possibly via PKA/CREB signaling in denervated rat skeletal muscle. Anais da Academia Brasileira de Ciências, v. 95, 2023-12-01. (18/10089-2)

DOS SANTOS, JONATHAS RODRIGO; CATALAO, CARLOS HENRIQUE ROCHA; VULCZAK, ANDERSON; AZZOLINI, ANA ELISA CALEIRO SEIXAS; ALBERICI, LUCIANE CARLA. Voluntary wheel running decreases amyloidogenic pathway and rescues cognition and mitochondrial energy metabolism in middle-aged female 3xTg-AD mouse model of Alzheimer's disease. JOURNAL OF ALZHEIMER'S DISEASE, v. 102, n. 2, p. 13-pg., 2024-01-01. (18/10089-2)

RUDOLF, RUEDIGER; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ CARLOS C.. Sympathetic innervation in skeletal muscle and its role at the neuromuscular junction. JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY, v. N/A, p. 8-pg., 2024-02-17. (18/10089-2)

COUTO-LIMA, CARLOS ANTONIO; MACHADO, MAIARO CABRAL ROSA; ANHEZINI, LUCAS; OLIVEIRA, MARCOS TULIO; MOLINA, ROBERTO AUGUSTO DA SILVA; DA SILVA, RODRIGO RIBEIRO; LOPES, GABRIEL SARTI; TRINCA, VITOR; COLON, DAVID FERNANDO; PEIXOTO, PABLO M.; et al. EMC1 Is Required for the Sarcoplasmic Reticulum and Mitochondrial Functions in the Drosophila Muscle. BIOMOLECULES, v. 14, n. 10, p. 18-pg., 2024-10-01. (09/54014-7, 18/04017-9, 11/16666-2, 22/05632-4, 12/17890-6, 21/10032-3, 21/06711-2, 18/10089-2, 14/18189-5, 13/21242-2, 15/13396-5, 10/17259-9, 10/11812-8, 16/25325-8)

ROSSI, LEONARDO; MOTA, BARBARA I.; VALADAO, PRISCILA A. C.; MAGALHAES-GOMES, MATHEUS P. S.; OLIVEIRA, BRUNA S.; GUATIMOSIM, SILVIA; NAVEGANTES, LUIZ C. C.; MIRANDA, ALINE S.; PRADO, MARCO A. M.; PRADO, VANIA F.; et al. Influence of β₂-adrenergic selective agonist formoterol on the motor unit of a mouse model of a congenital myasthenic syndrome with complete VAChT deletion. Neuropharmacology, v. 260, p. 11-pg., 2024-08-30. (18/10089-2)

CATALAO, CARLOS HENRIQUE ROCHA; SANTOS-JUNIOR, NILTON NASCIMENTO; DA COSTA, LUIS HENRIQUE ANGENENDT; SOUZA, ANDERSON OLIVEIRA; CARNIO, EVELIN CAPELLARI; SEBOLLELA, ADRIANO; ALBERICI, LUCIANE CARLA; ROCHA, MARIA JOSE ALVES. Simvastatin Prevents Long-Term Cognitive Deficits in Sepsis Survivor Rats by Reducing Neuroinflammation and Neurodegeneration. NEUROTOXICITY RESEARCH, v. 38, n. 4, p. 16-pg., 2020-06-10. (18/10089-2, 17/12462-0, 18/02854-0)