Liraglutide anti-atrophic mechanisms in an experimental model of Diabetes Mellitus

• Grant number: 21/05868-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): October 01, 2021
• Effective date (End): February 28, 2025
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Luiz Carlos Carvalho Navegantes
• Grantee: Gabriel Hunzicker Skiba
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/10089-2 - Neural, hormonal and nutritional control of autophagy, AP.TEM

Abstract

The loss of muscle mass is a consequence of neuromuscular and metabolic diseases and remain untreated. Previous experiments in our laboratory have shown that the Sympathetic Nervous System, by activating the cAMP cascade, positively modulates the protein balance in skeletal muscle by stimulating synthesis and inhibiting proteolytic pathways such as lysosomal/autophagic, dependent on Ca++ and Ubiquitin-Proteasome (UPS). Liraglutide is an analogue of GLP-1 (Glucagon Like Peptide Type I) that stimulates the release of insulin by the pancreas through the induction of cAMP and has been used for the glycemic control of diabetic patients. However, nothing is known about its impact on muscle mass balance. Therefore, the aim of this study will be to investigate the intracellular mechanisms that participate in changes in protein metabolism in skeletal muscle in an experimental model of Diabetes Mellitus treated with Liraglutide. The direct effects of the drug will be studied on C2C12 muscle cells. More specifically, the activities of enzymes and metabolic pathways, gene expression (RtPCR), protein content and levels of protein phosphorylation (Western Blot) related to protein synthesis and proteolysis involved with cAMP signaling will be evaluated. In vivo gene transfection methods will be used to elucidate the role of PKA in the possible anti-atrophic effect of Liraglutide. The understanding of these new mechanisms of action of GLP-1 analogues in the muscle may contribute to the fight against muscular atrophy. (AU)