Grant: Discovery Grants Program - Individual

Skeletal muscle is a dynamic and essential tissue that plays a central role in movement, posture, and energy metabolism. The long-term objectives of my research program are to understand the mechanical and physiological signals regulating skeletal muscle integrity. My research program will be devoted to the study of signaling pathways that control protein breakdown and protein synthesis, with a particular emphasis on the discovery and characterization of novel genes that are involved in the autophagy-lysosomal system. Currently, most of the scientific literature focuses on a limited number of genes and, as such, there are still many genes with no known function. In this proposal, I will use a combination of genetic, molecular, cellular, and physiological approaches to investigate how two previously uncharacterized autophagy genes, Mytho and Bcas3, contribute to cellular homeostasis under basal and stress conditions. Based on preliminary results and recently published data (Leduc-Gaudet et al. 2023, Nat Commun.), we will test the central hypothesis that MYTHO and BCAS3 are 2 interacting partners that regulates autophagy and we will characterize their roles in skeletal muscle physiology, whole-body metabolism, and longevity. For the upcoming 5 years, my research program will be organized around 3 short-term objectives that address several key questions in the autophagy field. These objectives are the following: Objective 1: To determine the impact of MYTHO deficiency in various vital organs under basal and stress conditions. To achieve this objective, we recently generated MYTHO floxed mice that use conditional knockout strategies to "turn off" MYTHO in adulthood, after the developmental period. This unique mouse model systems that I generated during my post-doc will be used to delineate MYTHO's roles in various tissues, and will address the role played by MYTHO in the regulation of whole-body metabolism and longevity. We anticipate that inducible deletion of MYTHO ubiquitously will result in lethal phenotype characterized by major metabolic defects. Objective 2: To determine the impact of MYTHO deficiency in skeletal muscle on exercise adaptation, whole-body metabolism and longevity using an inducible muscle-specific MYTHO knockout mouse model. We anticipate that MYTHO deficiency in skeletal muscle will progressively develop metabolic impairments, exercise intolerance and, ultimately, will have reduced lifespan. Objective 3: To determine the functional roles of BCAS3 on skeletal muscle autophagy and integrity using loss- and gain-of-function approaches. We anticipate that BCAS3 depletion will significantly attenuate basal and starvation-induced autophagy, whereas BCAS3 overexpression will increase autophagy. The proposed research will further our understanding of the regulatory mechanisms that control autophagy and may provide insights into other important biological processes that control skeletal muscle physiology and vital organ function.