Role of autophagy in neurogenic myopathy

• Grant number: 17/24836-1
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): February 01, 2018
• Effective date (End): January 31, 2020
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Nikolas Dresch Ferreira
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo, SP, Brazil

Abstract

Sustained loss of skeletal muscle mass and function occurs mainly during degenerative processes. Increased proteolytic activity (i.e. autophagy) has been extensively associated with muscle atrophy. However, proteolysis is also crucial for the maintenance of cellular homeostasis. In fact, autophagy serves as a protective system against non-functional proteins/organelles through a sophisticated intracellular signaling that ends up in a lysosomal degradation. Preliminary data from our laboratory have shown that autophagic degradation flux is impaired in a neurogenic myopathy rat model, where skeletal muscle atrophy/dysfunction is induced by a permanent sciatic nerve constriction (SNC). Of interest, accumulation of cytotoxic proteins was observed in this model. In this context, the aim of this project is to investigate the real contribution of autophagy in skeletal muscle morphology and function. Therefore, transgenic mice displaying compromised autophagy in skeletal muscle (ATG7-/- conditional knockout - Cre/LoxP system), kindly provided by Roberta Gottlieb (Cedars-Sinai MC, USA), will be submitted to SNC surgery to induce skeletal myopathy. The trophism (histology, H&E), contractile function (ex vivo, isolated tissue bath) and autophagic flux (western blotting) will be evaluated in skeletal muscle of ATG7-/- (knockout) and ATG7+/+ (control) animals 14 days after sham or SNC surgery. The opportunity to use this genetic tool to inhibit autophagy in vivo will be of great value to validate the phenotype previously found in our laboratory, providing a cause-effect relationship. Moreover, it will help a better understanding of the key mechanisms involved in the pathophysiology of neurogenic myopathy. It should also be pointed out that the animal's colony has already been established in our laboratory. Finally, this study will be supported by Roberta Gottlieb (Cedars-Sinai MC, USA) and postdoctoral Juliane Cruz Campos (ICB-USP). (AU)