Regulation of myogenesis and skeletal muscle function by bioactive lipid class switching

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Rationale: The formation of new muscle tissue, named myogenesis, is a tightly regulated process that plays a vital role in skeletal muscle development and growth. During that process, muscle stem cells (MuSCs) enter the cell cycle to become proliferating myoblasts, which eventually self-renew or differentiate and fuse to form new muscle fibers. How the cell fate decision of MuSCs is regulated during myogenesis is of great interest in the field. Our research project proposes that bioactive lipids class switching is a central process regulating the cell fate decision of MuSCs. Lipid mediator class switching is a process during which fatty acids (such as omega-3 or -6) are initially transformed into pro-inflammatory lipids; and thereafter into pro-resolving lipids. This process plays a key role in the regulation of inflammation; however, its impact on MuSCs has never been investigated. A better comprehension of the mechanisms regulating MuSC decision-making during myogenesis will open new possibilities to regulate their cell fate decision in vitro, which is a great challenge in the field. Objective and hypothesis: The overall goal of this research project is to characterize the impact of lipid mediator class switching on MuSC and skeletal muscle function. We hypothesize that there is a switch during myogenesis that favours the biosynthesis of pro-resolving lipids, which promote late myogenic events (such as cell differentiation and fusion). This proposal is divided in 3 aims: Aim 1: Define the bioactive lipid mediator class switching during myogenesis. Using biomolecular techniques (mass spec, RT-qPCR, western blot), we will assess the expression of bioactive lipids and their receptors by MuSCs at different stages of myogenesis. Aim 2: Determine the mechanism of action and the impact of lipid mediator class switching on cell cycle regulation of myogenic cells. Using MuSC deficient in the enzymes responsible for bioactive lipid biosynthesis, we will determine the impact and the mechanism of action of lipid mediator class switching on the cell fate decision of MuSCs. Aim 3: Determine the effect of bioactive lipids class switching on myotube and skeletal muscle function. Using in vitro and in vivo experiments we will assess the impact of bioactive lipid class switching on the function of newly-formed muscle fiber and skeletal muscles. Relevance: We expect that this research project will uncover a completely novel mechanism regulating MuSC decision-making during myogenesis, which is of broad and current interest in the field. This research project will set the foundation stone of our research program aiming to develop novel methods to regulate stem cell fate. Particularly, the maintenance of cell stemness in vitro is of wide interest for bioengineers, investigators, and life science industries, which will lead to the development of strong partnerships with academia and industries in Canada.