Functional interaction between cholinergic and adrenergic systems in the maintenance of muscle mass and motor endplate

• Grant number: 12/05697-7
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): June 01, 2012
• Effective date (End): July 31, 2015
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal researcher: Luiz Carlos Carvalho Navegantes
• Grantee: Danilo Lustrino Borges
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 08/06694-6 - Neural control of protein metabolism, AP.TEM

Abstract

Although previous studies have revealed a major role of cAMP signaling in controlling the stabilization of the nicotinic acetylcholine receptors (AchRs) at the neuromuscular junction, the physiological regulators of this pathway remain elusive. We have recently demonstrated that the Sympathetic Nervous System (SNS) plays an important role in controlling the skeletal muscle protein metabolism through the activation of ²2-adrenoceptors and cAMP/PKA signaling. Thus, we hypothesize that beyond protective effects on muscle mass, the SNS mediates the stabilization of AchRs at motor endplate. For this purpose, mice will be treated with clenbuterol, a selective ²2-agonist and the kinetics of AchRs lifetimes upon pulse labeling of mouse muscles with ¹²uI-±-bungarotoxin in vivo (using innervated and denervated muscles). Additionaly, we will employ in vivo imaging of mouse neuromuscular synapses. To elucidate the molecular mechanisms related to these effects we will quantitate the PKA activity, cAMP content, and the expression of genes and proteins related to atrophy (atrogin-1 and MuRF1) and autophagy (GABARAP and LC3). In parallel, the phosphorylation levels of Akt, a key protein in the control of protein metabolism, will be estimated. We aim to further define the role of the cholinergic innervation in the control of protein metabolism. Following addition of cholinergic agonists in isolated rat muscles, we shall measure the activity of diverse proteolytic pathways and rates of protein synthesis, in the presence or absence of ²2-agonists. These results will contribute to a better understanding of the functional interaction between cholinergic and adrenergic systems in the maintenance of muscle mass and motor endplate. (AU)

Scientific publications

(4)

(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)

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.

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: 9.

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: 32.

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.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

BORGES, Danilo Lustrino. Functional interaction between Cholinergic and Adrenergic systems in the maintenance of muscle mass and motor endplate. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto Ribeirão Preto.