Date of Graduation
School of Medicine
Microbiology, Immunology, and Cell Biology
Emidio E Pistilli
Stephen E Alway
John M Hollander
Altering interleukin-15 (IL-15) signaling through ablation of interleukin receptor alpha (IL-15Ralpha) in the IL-15Ralpha global KO mouse has been shown to result in an oxidative shift in skeletal muscle characterized by enhanced fatigue resistance and increases in mitochondrial density. However, the mechanism of this phenomenon is unclear, as IL-15 signaling in skeletal muscle has been virtually unexplored. It has been previously suggested that loss of IL-15Ralpha in the global KO mouse directly results in an increase in muscle IL-15 secretion, and this increase in secreted IL-15 acts on skeletal muscle in an autocrine fashion, directly stimulating pro-oxidative remodeling. Thus, the purpose of this study was to examine the effects of muscle IL-15Ralpha loss on the ability of muscle to secrete and respond to IL-15, and also to determine whether IL-15 has the ability to act directly on skeletal muscle to induce pro-oxidative changes. These aims were addressed through the generation of C2C12 myogenic cell lines lacking IL-15Ralpha, as well as a through the development of a novel muscle-specific IL-15Ralpha KO mouse. Myogenic cell cultures lacking IL-15Ralpha failed to exhibit the capacity to respond to exogenously provided IL-15. Furthermore, IL-15Ralpha-null cultures displayed a depressed ability to secrete IL-15, even in the presence of pro-inflammatory stress. In support of this observation, mice lacking IL-15Ralpha conditionally in skeletal muscle exhibited no changes in circulating IL-15. However, acute treatment of wild type myogenic cultures with IL-15 resulted in induction of the pro-oxidative genes PGC-1alpha and PPARdelta. These results provide evidence that IL-15 has the capacity to act directly on skeletal muscle in a pro-oxidative manner, and that loss of IL-15Ralpha ablates the ability of skeletal muscle to secrete and respond to IL-15. Collectively, these results suggest that the muscle changes observed in the IL-15Ralpha KO mouse are driven by increased muscle response to IL-15, but that the ability to secrete and respond to IL-15 is enhanced in the global IL-15Ralpha KO mouse due to a confound such as immunodeficiency.
O'Connell, Grant C., "IL-15 Signaling in Skeletal Muscle: Implications in Modulation of PGC-1alpha and Mitochondrial Biogenesis" (2014). Graduate Theses, Dissertations, and Problem Reports. 6337.