Date on Master's Thesis/Doctoral Dissertation
Physiology and Biophysics
Physiology and Biophysics, PhD
Committee Co-Chair (if applicable)
mitochondria; antioxidants; SOD-2; PGC-1a; oxidative stress; mitochondrial transcription factor A
This dissertation is an analysis of skeletal muscle atrophy and a molecular assessment of potential preventative treatments. Chapter I begins with a background of skeletal muscle atrophy along with an analysis of associated molecular pathways. Here, we discuss how skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis and can occur when a muscle is abnormally disused. The development of therapies prior to skeletal muscle atrophy settings to diminish protein degradation is scarce and could be useful to prevent negative clinical outcomes of patients who must unload and disuse musculature over extended periods. Mitochondrial dysfunction is associated with skeletal muscle atrophy and contributes to the induction of protein degradation and cell apoptosis through increased levels of ROS. This damages mtDNA, leading to its degradation and mutation resulting in dysfunctional mitochondria. Mitochondrial transcription factor A (TFAM) protects mtDNA from ROS and degradation while increasing mitochondrial function and the transcription of mitochondrial proteins. Exercise stimulates mitochondrial function by activating cell signaling pathways that converge on and increase PGC-1α, a well-known activator of the transcription of TFAM and mitochondrial biogenesis. Therefore, we first hypothesize exercise training prior to muscle unloading and disuse will prevent skeletal muscle atrophy. Additionally, we hypothesize this protective effect of exercise in preventing skeletal muscle atrophy is associated with increased mitochondrial markers. In Chapter II, we test these hypotheses by first inducing skeletal muscle atrophy using hindlimb suspension (HLS) and exercising mice prior to this suspension. The results indicated exercising prior to HLS reduced many of the morphological and molecular changes within the muscle associated with atrophy. Also in Chapter II, we follow up these findings through mitochondrial molecular analyses with results showing exercise increasing mitochondrial-associated markers and redox balance. We also find decreases in TFAM after HLS, which led to further analyses through the use of a TFAM overexpression transgenic mouse model in HLS. We reason if HLS induces excessive ROS accumulation and decreases TFAM, overexpressing this gene may prevent mitochondrial dysfunction mechanisms associated with atrophy. Therefore, we hypothesize the overexpression of TFAM diminishes skeletal muscle atrophy and, secondarily, TFAM overexpression combined with exercise training will synergistically prevent atrophy caused by HLS. To assess these hypotheses, in Chapter III we subject TFAM mice to HLS as well as exercising TFAM mice prior to entering HLS. Results here reveal TFAM overexpression diminishes skeletal muscle atrophy caused by HLS and combining exercise and TFAM overexpression resulted in no significant difference compared to exercising prior to HLS in wild-type mice. Collectively, the data indicate an important role for exercise and TFAM in diminishing skeletal muscle atrophy.
Theilen, Nicholas Todd, "Exercise preconditioning and TFAM overexpression diminish skeletal muscle atrophy." (2018). Electronic Theses and Dissertations. Paper 2986.