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Study of the regenerative potential of satellite cells in centronuclear myopathy and myogenic capacity of its released microvesicles

Grant number: 15/18914-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2016
Effective date (End): February 28, 2019
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Mariz Vainzof
Grantee:Camila de Freitas Almeida
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID
Associated scholarship(s):17/07376-7 - Investigation of satellite cell behavior and extracellular vesicles in centronuclear myopathy, BE.EP.DR

Abstract

The adult muscle has an enormous regenerative capacity when damaged, growing new fibers or fixing the previous ones using progenitor cells with myogenic potential, named satellite cells. However, in neuromuscular disorders, both muscle development and regeneration are not efficient, causing muscle weakness and loss of motor ability.Among the many neuromuscular disorders, the centronuclear myopathies (CNM) comprise a subgroup characterized by the presence of muscle fibers with centralized nuclei. Three different forms are recognized, with mutations in the genes MTM1 (X-linked inheritance), BIN1 (autosomal recessive) and DNM2 (autosomal dominant). The knock-in murine model KI-Dnm2R465W bears the most frequent mutation found in CNM-AD patients and develops a mild myopathy, with modest muscle involvement and slight force reduction. This animal presents few centronucleated fibers and lack of an evident degeneration.A recent work showed alterations in satellite cells' quantity and behavior in a CNM mouse model with a mutation in MTM1. Thus, it is possible that regeneration in other CNM types could also be compromised. The regeneration process within the muscle affected by centronuclear myopathy with DNM2 mutations is not known, and its study is the main objective of this project. Satellite cell population and endocytosis process will be evaluated in CNM-AD-DNM2 patients and in its respective mouse model KI-Dnm2R465W. In the latter, muscle lesion will be induced by electroporation, to activate the degenerative-regenerative process. By using this approach, alterations are expected to be found in the regeneration which could help the search for new therapeutic targets.