Study of AT1a receptor silencing in autophagy and mitophagy in primary culture from skeletal muscle cells

• Grant number: 18/25661-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): March 01, 2019
• Effective date (End): December 31, 2019
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Roberta Sessa Stilhano Yamaguchi
• Grantee: Cynthia Silva Bartolomeo
• Host Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil

Abstract

Cells have their own mechanisms to maintain the homeostasis. Autophagy is based on self-destruction and selective elimination of dysfunctional intracellular components, in which the cell relocates unneeded nutrients to more essential processes. Mitophagy is the sequestration of the mitochondria by the autophagosome followed by its degradation in the lysosomes. Both autophagy and mitophagy are essential for the maintenance of myofibrous homeostasis, so it is very important to study these pathways in the muscle cell.In cases of deeper muscle injury, regeneration processes can occur imperfectly with scar tissue formation more fragile and less functional that can cause severe sequelae such as loss of locomotor activity and chronic pain. Thus, the search for factors that decrease the fibrosis process and allow greater muscle regeneration are of great clinical relevance. Signaling of Angiotensin II (Ang II) through its AT1 receptor (rAT1) has a pro-fibrotic role and the use of blockers from this receptor or its silencing by the RNA interference technique has shown benefits in muscle regeneration and fibrosis reduction. Fibroblasts and myoblasts are the main cells that participate in muscle regeneration and understand how the silencing of rAT1 acts on these cells in relation to proliferation, expression of fibrogenic and myogenic genes will clarify the fibrosis process. Autophagy and mitophagy are directly involved in the process of muscle regeneration and understanding the role of rAT1 in the modulation of these processes is one of the main objectives of this project. In addition, the discovery of the modulation mechanism of autophagy and mitophagy will open a window of opportunities in the development of future therapeutic targets in the context of muscle regeneration. Thus, the project aims to clarify the Ang II mechanisms of action in the modulation of autophagy and mitofagia in fibroblasts and myoblasts derived from murine skeletal muscle.