BGG Student Tom O’Conner Successfully Defends Thesis!
Friday, July 14, 2023
On Wednesday July 12th BGG student Tom O’Connor successfully defended his thesis. Tom earned his B.S. in Biotechnology from the University of Buffalo in 2017. As a Ph.D. student Tom pursued his doctoral research in Dr. Robert T. Dirksen’s laboratory. Tom is currently a Scientist at Roswell Park Comprehensive Cancer Center.
Tom’s Thesis is titled ‘Adaptive and Protective Responses of Skeletal Muscle to Endurance Exercise in the Context of Aging, Juvenile Radiotherapy, and Tubular Aggregate Myopathy’.You can read his thesis abstract below.
Congratulations Tom!
Abstract: Endurance exercise elicits a multitude of adaptive and protective responses to skeletal muscle in response to prolonged training. These include renewal and contribution of muscle stem cells (or satellite cells, SCs) to growing and repairing myofibers, improved proteostasis, adapted calcium handling and mitochondrial dynamics, and scavenging of elevated reactive oxygen species. In this work, endurance exercise was implemented as a therapeutic intervention in mouse models of aging, juvenile irradiation, and congenital myopathy to assess whether the adaptive responses of skeletal muscle to endurance exercise would confer protective and/or restorative effects in the context of disease. Frailty is an extremely common condition in both elderly individuals and juvenile cancer survivors, characterized by reductions in muscle mass (sarcopenia) and strength (dynapenia). Individuals born with rhabdomyosarcoma, a common form of childhood cancer that primarily affects skeletal muscle, are often treated by surgical resection of the tumor and subsequent ionizing radiation therapy. Due to recent medical advancements, pediatric cancer survivorship is improving. However, these individuals often suffer into adulthood from the cytotoxic effects of radiation therapy received during development. Using aged mice and a clinically relevant juvenile irradiation protocol, we assessed the impact that one month of voluntary wheel running (VWR) exercise had on aged and irradiated skeletal muscle. Regarding SCs, we found that exercise activated the muscle stem cell pool in aged mice in a similar manner to what was observed in adult mice. Although aged SCs were able to activate, they were unable to terminally commit and fuse to the myofiber to maintain and repair skeletal muscle tissue, as observed in the adult cohort. This observation was consistent with an elevated autoregulatory inflammatory signature observed in aged SCs post-endurance exercise ince SC activation and commitment was observed in the adult cohort, we hypothesized that post-juvenile irradiation endurance exercise would elicit SC contribution to the myofiber and minimize the deficits seen in irradiated muscle. While we did not observe significant contribution of SCs to irradiated muscle post-endurance exercise, we found that adapted calcium handling, scavenging of reactive oxygen and nitrogen species, and adapted mitochondrial dynamics was consistent with improved irradiated muscle function and contractile kinetics. Based on these observed adaptations of skeletal muscle to endurance exercise in the context of irradiation, we implemented a prolonged endurance exercise regimen as a preventative intervention in a novel mouse model of tubular aggregate myopathy (TAM). TAM is a congenital myopathy typically caused by gain of function mutations in the store- operated calcium machinery STIM1 and ORAI1 and can be characterized by the formation of tubular aggregates (TAs) in skeletal muscle. TAM patients commonly present with progressive muscle weakness, cramps, and myalgia. In our TAM mouse model, we observed robust formation of TAs and disrupted skeletal muscle function. However, prolonged endurance exercise reduced the presence of TAs and improved muscle function consistent with adapted calcium handling, proteostasis, metabolism and mitochondrial dynamics.