Aging Skeletal Muscle Plasticity in Exercise and Injury

Sarcopenia—progressive loss of muscle mass and strength—diminishes quality of life and longevity. In addition to progressive atrophy, older adults exhibit impaired regeneration after muscular injury. Activity of muscle stem cells, termed satellite cells, is dysregulated with aging which impairs skeletal muscle remodeling and limits plasticity of aged muscle. Aim 1 (Chapter 2) of this dissertation seeks to clarify the debated requirement of satellite cells for overload-induced hypertrophy in aging muscle via a common surgical overload model, with the original hypothesis that while aging satellite cells contribute to overload-induced hypertrophy to mitigate sarcopenia, growth can occur in the absence of satellite cells via expansion of the myonuclear domain. In light of Aim 1 results demonstrating no overload-induced hypertrophy in aging skeletal muscle with surgical overload, Aim 2 (Chapter 3) examines the efficacy of a novel and translatable murine resistance exercise model to elicit satellite cell expansion with myonuclear accretion and hypertrophy in aging skeletal muscle, with the hypothesis that this novel exercise model would result in expansion of the satellite cell pool along with hypertrophy not observed in old mice with the surgical overload model. Indeed, PoWeR (Progressive Weighted wheel Running) elicited hypertrophy in old mice, likely supported by a robust angiogenic response in hind limb muscles. Lastly, Aim 3 (Chapter 4) examines the efficacy of a novel NNMT inhibitor to enhance regeneration of aging skeletal muscle after injury by enhancement of satellite cell proliferation and fusion to myofibers, confirming the hypothesis that NNMT inhibition would rescue age-related deficits in satellite cell activity to promote superior regeneration of muscular injury of old mice.