Grant: Travel Awards - Institute Community Support

Canada's population is aging, with one in five Canadians now over 65. As we age, our cells and tissues lose function, leading to muscle weakness, frailty, and increased risk of falls-issues that cost our healthcare system billions each year. To better understand why this happens, we study how mitochondria, the energy-producing and signaling hubs of cells, become defective with age and contribute to muscle decline. Cells normally follow a regulated cycle of growth and division, with built-in "pause points" to ensure quality control. When chronic low-grade damage is not resolved, cells can permanently stop dividing, a process known as senescence. While this prevents harmful cells from multiplying, it also reduces tissue regeneration as we age. One trigger of senescence is mitochondrial dysfunction. Mitochondria constantly change shape to meet cellular demands, and a protein called OPA1 helps maintain their structure. However, OPA1 levels drop during aging, impairing mitochondrial function. Our research shows that long-term loss of OPA1 in muscle stem cells (MuSCs)-the cells responsible for muscle repair-causes mitochondrial dysfunction, cell cycle arrest, and senescence. These cells fail to effectively regenerate muscle, become depleted, and have global changes in signaling and energy molecules called metabolites. In turn, the whole muscle eventually shows signs of degeneration and fatigue. Encouragingly, restoring certain metabolites partially improved MuSC cell cycle progression. This work highlights how maintaining healthy mitochondrial structure is crucial for muscle regeneration and suggests that targeting OPA1-related pathways could help combat muscle decline with age.