Administrative Supplement: The Role of Satellite Cells in Skeletal Muscle Hypertrophy with Aging

SUMMARY The strong relationship between the occurrence of sarcopenia and Alzheimer’s disease in the geriatric population suggests these diseases may share a common underlying genetic component. A recent meta- analysis seeking to identify genetic variants that contribute to the development of sarcopenia found individuals carrying the apolipoprotein E (APOE) ε4 allele variant have less skeletal muscle mass and worse physical performance with aging. We have acquired single-cell RNA-sequencing data showing that Apoe is a marker of mouse quiescent satellite cells and dramatically down-regulated upon activation. Given the importance of satellite cells in the maintenance of muscle mass with age through their ability to effectively repair muscle injury, we hypothesize that satellite cell function and ability to regenerate muscle will be impaired in mice harboring the human APOE ε4 variant. To test this hypothesis, we will use mice harboring one of the three APOE variants (ε2, ε3 or ε4) to pursue the following three aims: 1) determine the ability of APOE variant mice to regenerate skeletal muscle following injury, 2) determine if satellite cell proliferation and differentiation is altered in the APOE variant mice and 3) determine if APOE is a target gene of miR-206. Similar to the parent grant, the current supplement is focused on the role of satellite cells in skeletal muscle plasticity. If satellite cell function and muscle regeneration is impaired in the APOE e4 mice, this would provide some of the first evidence to support the hypothesis that sarcopenia and Alzheimer’s disease share a common genetic link. Establishing a link between APOE and satellite cell function will lay the foundation for future studies focused on the interaction between the APOE variants, the maintenance of muscle function, and physical activity. These studies hold great promise given that exercise is currently one of the only effective interventions to slow the progression of Alzheimer’s disease, particularly in high-risk APOE ε4 individuals.