Heterogeneity of Satellite Cell Populations Play a Role in Improvements in PAD after Exercise Therapy

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Abstract Peripheral artery disease (PAD) is a major health problem worldwide. Patients with the disease have atherosclerotic lesions which impair blood flow to their limbs resulting in complications such as non-healing wounds and amputations as well as pain and decreased quality of life. While many medical therapies have been established to slow disease progression through controlling risk factors, the two most effective treatments at improving a patient’s status are surgical or endovascular repair and supervised exercise therapy. While exercise is an ideal treatment due to its lower cost and non-invasive nature, the mechanisms by which it improves patient outcomes are still not known preventing the development of an ideal therapeutic strategy. This proposal investigates a novel mechanism by which skeletal muscle satellite cells mediate these observed improvements. Preliminary data shows that satellite cells generate several different proteins which are associated with vascular growth and drive migration in vascular cells. Histological staining of human samples shows that satellite cells increase in patients that see improvements with exercise and the presence of satellite cells appears to be critical for recovery in an exercise preconditioning murine model. Aim 1 will investigate the causal relationship between satellite cells and exercise mediated recovery using an murine model in which satellite cells are selectively ablated. Aim 2 will use single cell sequencing to investigate the heterogeneity of satellite cells in response to exercise and determine which stimuli and which specific expression profiles are the most vasculogenic. Finally, Aim 3 will quantify the expression changes and heterogeneity in satellite cells from PAD patients isolated before and after supervised exercise therapy. The goal of this aim is to determine how differences in satellite cell populations correlate with clinical responses in the patients. The ultimate goal of this project is to understand the biology and response of satellite cells in response to exercise to help develop more effective exercise regimens for patients with PAD.