INTRACELLULAR AND CIRCULATING METABOLIC MEDIATORS OF SKELETAL MUSCLE PROGENITOR CELL FUNCTION
Skeletal muscle progenitor cells (MPCs) are essential to repair muscle tissue damage after injury and maintain muscle composition with advancing age. Metabolism, including glucose uptake and breakdown, and mitochondrial substrate interconversion, is increasingly recognized as a key contributor to MPC function. Additionally, circulating factors (e.g., hormones, nutrients, peptides in the blood) regulate muscle regenerative capacity. Metabolic pathway use and circulating factors are altered in MPCs from populations with impairment. Thus, furthering understanding of the role of intracellular and circulating metabolic mediators may lead to therapies to improve MPC function. This dissertation explores the role of two metabolic proteins in MPCs: pyruvate kinase M2 (PKM2) and Sirtuin 5 (SIRT5). MPCs from PKM2 null mice were previously shown to have severely impaired proliferation. PKM2 is the enzyme responsible for the conversion of phosphoenolpyruvate into pyruvate (canonical activity) and interacts with other proteins to control a variety of cellular functions (non-canonical activity). We attribute the non-canonical function of PKM2 to its role in MPC proliferation and further identify glutamate dehydrogenase (GLUD1) as a PKM2 binding partner. SIRT5, an enzyme that removes succinyl- post-translational modifications, regulates proliferation in numerous cancer cells but had never been explored in MPCs. We identified that SIRT5 levels increase during MPC differentiation. We further show that serine hydroxymethyltransferase (SHMT2) is desuccinylated during MPC differentiation. Lastly, we test the capacity of a dietary intervention, consumption of freeze-dried blueberries to modify MPC function, and find beneficial effects in young but not old adults.
Thalacker-Mercer, Anna E.
Field, Martha S.; Gu, Zhenglong; Rasmussen, Kathleen Maher
Ph. D., Nutrition
Doctor of Philosophy
dissertation or thesis