EFFECTS OF EXERCISE AND OBESITY ON SKELETAL MUSCLE DAMAGE AND REPAIR
Obesity is associated with an increase in low grade systemic inflammation. Skeletal muscle of individuals with obesity undergo numerous biochemical and morphological alterations including an increase in ectopic lipid accumulation in skeletal muscle and increased macrophage infiltration. Increased intermuscular adipose tissue and macrophages contribute to skeletal muscle inflammation and insulin resistance by secreting elevated proinflammatory cytokines and lipids. This also contributes to reduction in skeletal muscle quality, increasing the susceptibility of muscle to damage and impairing the regenerative response to muscle. Exercise training can reduce inflammation and improve skeletal muscle quality. Importantly reductions in inflammation occur without change in adiposity. Peroxisome proliferator activated receptor g coactivator 1-a (PGC-1a) exerts protective effects on skeletal muscle against damaging insults and may improve muscle regeneration.
The primary aim of my dissertation was to determine the mechanisms that lead to deficits in skeletal muscle integrity and regeneration in persons with obesity. In Chapter 1, an introduction to the various physiological, pathological, and clinical topics is provided. In Chapter 2, we investigated how exercise training and obesity independently alter skeletal muscle extracellular vesicle (EV) miRNA (miR) content. We found that obesity alters EV miR content indicative of altered anabolic signaling, while exercise training altered EV miR content in a manner indicative of reduced inflammation. In Chapter 3, we report that overexpression of PGC-1a reduces cardiotoxin induced damage of primary human myotubes but limits the ability of undifferentiated cells to reenter the cell cycle and produce progeny that could aid in the restoration of myotubes. In Chapter 4, we demonstrate that exposure to an obesogenic environment increases cardiotoxin induced damage of primary human myotubes from obese donors. In this study we also found that the restoration of myotube fusion index was reduced in lean and obese subjects when incubated with obesogenic media. In Chapter 5 is a review and summary of the outcomes described in Chapters 2-4, a discussion of the limitations of these experiments, and a discussion of future directions.