THE ROLE OF MG53 IN AVOIDANCE OF DISUSE-INDUCED MUSCLE ATROPHY - PROJECT SUMMARY Extended periods of inactivity accelerate the progression of age-related loss of muscle mass, clinically known as sarcopenia, and contribute to frailty. While antioxidant administration has been proven to reduce disuse- induced atrophy, prolonged use is correlated with negative outcomes, including reduced mitochondrial biogenesis in skeletal muscle, demonstrating a need for novel approaches to mitigate muscle loss during conditions of disuse. A promising approach in this regard involves investigating the unique strategies that hibernating mammals employ to maintain muscle integrity and function following 4-5 months of inactivity. Seasonal-specific muscle proteomics of naturally hibernating thirteen-lined ground squirrels revealed an increase in mitsugumin 53 (MG53) expression, a protein associated with mitochondrial protection in the presence of reactive oxygen species (ROS). Of note, ROS have been shown to be a key factor associated with disuse-induced atrophy, as they increase muscle protein breakdown (MPB) and depress muscle protein synthesis (MPS). Although evidence clearly demonstrates the importance of inactivity-induced mitochondrial ROS production, the mechanisms involved in its regulation are not well-understood. The exciting possibility that upregulation of MG53 in hibernating mammals can improve mitochondrial health, reduce mitochondrial ROS production, and prevent disuse-induced atrophy warrants investigation in a non-hibernating model system. Informed by these findings, the overall goal of this research is to advance the understanding of MG53’s role in muscle mass regulation during disuse-induced atrophy and lay a foundation for exploring its role in sarcopenia and myopathies. The central hypothesis is that elevated MG53 reduces damaged mitochondria through upregulation of autophagy beclin 1 regulator 1 (AMBRA1) expression, which lowers ROS accumulation, leading to reduced MPB and allowing an increase in MPS during muscle disuse. To test this, two specific aims will be pursued: (1) determine if MG53 is necessary to ameliorate disuse-induced muscle atrophy; and (2) determine if MG53 is required for muscle regrowth following immobilization-induced muscle atrophy. Expected results of the proposed studies will demonstrate that MG53 is a critical protein for skeletal muscle recovery via improved mitochondrial function and AMBRA1 regulation. Ultimately, this work will advance knowledge of the role of MG53 in mitochondrial ROS production and provide new therapeutic opportunities for preventing muscle loss and dysfunction—ultimately improving quality of life among elderly populations in the United States.
