Regulation of Myonuclear Turnover Dynamics in Multinucleated Muscle Cells

Abstract Skeletal muscle health is important for longevity. Skeletal muscle is comprised of post-mitotic, multi-nucleated cells that are long-lived and must be maintained for the lifespan of the animal. Effective tissue maintenance requires turnover of damaged proteins and organelles, including the nucleus. Muscle cells can add new myonuclei through the activation, differentiation, and fusion of resident muscle stem cells known as satellite cells. Recent findings clearly demonstrate that satellite continue to fuse into muscle fibers throughout adulthood, yet the number of myonuclei remains constant across the lifespan, suggesting that there must be an opposing mechanism to degrade myonuclei. However, no mechanism to selectively target and degrade a myonucleus has yet been identified, leading to the longstanding debate over whether entire myonuclei can be degraded and turned over. Novel model systems are required to elucidate the molecular players and regulatory mechanisms involved in targeting an entire nucleus for degradation within a syncytium. Using a unique mouse model that undergoes significant myonuclear and DNA damage, our preliminary data demonstrates that nuclear damage promotes myonuclear turnover, with damaged myonuclei being enriched in autophagic markers, but not apoptotic markers. This proposal will 1) re-examine the role of myonuclear turnover in muscle fiber homeostasis, 2) the regulatory mechanisms controlling this process, and 3) the potential connection between nuclear degradation and muscle stem cell function. This proposal will address a major knowledge gap in muscle biology regarding the mechanisms regulating myonuclear turnover, with broader implications for furthering our understanding of nucleophagy in mammalian cells. Findings from this project could fundamentally change how we think about myonuclear and genomic maintenance during skeletal muscle aging, with additional relevance for the long-term effectiveness of gene therapy treatments for muscular diseases.