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Role and mechanism of action of anabolic stimuli on neuromuscular trophicity

Grant number: 12/51456-1
Support Opportunities:Regular Research Grants
Duration: March 01, 2014 - February 29, 2016
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Convênio/Acordo: DFG
Principal Investigator:Isis Do Carmo Kettelhut
Grantee:Isis Do Carmo Kettelhut
Principal researcher abroad: Rüdiger Rudolf
Institution abroad: Hochschule Mannheim University of Applied Sciences, Germany
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Accumulating evidence suggests that the synapse between motoneurons and skeletal muscle fibers, the neuromuscular junction (NMJ), plays an integral role not only for muscle contraction but also for superior, metabolic muscle functions. This might be of particular relevance under a series of severe atrophic conditions, including age-related muscle loss (sarcopenia). The principal postsynaptic component is the nicotinic acetylcholine receptor (AChR), whose density in the synaptic membrane and metabolic stability are finely tuned in an activity-dependent manner. While agrin was identified as a factor inducing the clustering of AChR, the extracellular signals that regulate the metabolism of AChR are still elusive. Different lines of evidence indicate that postsynaptic cAMP/PKA-signaling and calpain activity play crucial roles in this process. Our published and preliminary data show that catecholamines as well as the neuropeptide, CGRP, inhibit calpain function via cAMP/PKA- dependent signaling in skeletal muscle. Furthermore, recent data highlight the beneficial effect of beta-agonists for the treatment of neuromuscular disease, suggesting that there is a direct mechanistic link. Notably, our data further demonstrate that catecholamines and CGRP are also important regulators of muscle protein metabolism indicating an intimate connection between the processes regulating protein turnover in both NMJ and fiber. This project aims to address 1) the role of catecholamines and CGRP under basal and catabolic conditions for the maintenance of the NMJ, 2) the mechanisms that underlie such function, and 3) whether the processes regulating protein turnover in the fiber are similar to those in the NMJ. To that end, the Brazilian and German groups will synergize with their respective expertises on muscle metabolism, in vivo-models and live animal microscopy. (AU)

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Scientific publications
(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)
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, . (12/51456-1, 12/05697-7, 12/24524-6, 10/11083-6)
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, . (12/51456-1, 11/11003-5, 12/05697-7, 12/24524-6, 12/18861-0)

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