Date of Degree
PhD (Doctor of Philosophy)
Molecular Physiology and Biophysics
Christopher M. Adams
Skeletal muscle atrophy is a common, debilitating consequence of muscle disuse, malnutrition, critical illness, musculoskeletal conditions, neurological disease, cancer, and organ failure. Despite its prevalence, little is known about the molecular pathogenesis of this devastating condition due in large part to an incomplete understanding of the molecular mechanisms that drive the atrophy process. In previous studies, we identified the transcription factor ATF4 as a critical mediator of skeletal muscle atrophy. We found that ATF4 is necessary and sufficient for skeletal muscle atrophy during limb immobilization. However, ATF4 mKO mice were only partially protected from skeletal muscle atrophy during limb immobilization, indicating the existence of another pro-atrophy factor that acts independently of the ATF4 pathway. Using mouse models, we identify p53 as this ATF4-independent factor. We show that skeletal muscle atrophy increases p53 expression in skeletal muscle fibers. In addition, overexpression of p53 causes skeletal muscle atrophy. Further, p53 mKO mice are partially resistant to muscle atrophy during limb immobilization. Taken together, these data indicate that like ATF4, p53 is sufficient and required for skeletal muscle atrophy during limb immobilization. Importantly, overexpression of p53 induces muscle atrophy in the absence of ATF4, whereas ATF4-mediated muscle atrophy does not require p53. Furthermore, overexpression of p53 and ATF4 induces greater muscle atrophy than p53 or ATF4 alone. Moreover, skeletal muscle lacking both p53 and ATF4 is more resistant to skeletal muscle atrophy than muscle lacking either p53 or ATF4 alone. Taken together, these data indicate that p53 and ATF4 mediate distinct and additive mechanisms to skeletal muscle atrophy. However, the precise mechanism by which p53 and ATF4 cause skeletal muscle atrophy remained unclear. Using genome-wide expression arrays, we identify p21 as a skeletal muscle mRNA that is highly induced by p53 and ATF4 during limb immobilization. Further, overexpression of p21 causes skeletal muscle atrophy. In addition, p21 is required for muscle atrophy due to limb immobilization, p53, and ATF4. Collectively, these results identify p53 and ATF4 as critical and complementary mediators of skeletal muscle atrophy during limb immobilization, and discover p21 as an essential downstream mediator of the p53 and ATF4 pathways.
Skeletal muscle atrophy is a very common condition that accompanies malnutrition, critical illness, aging, cancer, heart failure, diabetes, neurological disease, and musculoskeletal disorders. Skeletal muscle atrophy also occurs as a side effect of medicines such as high-dose steroids or anti-androgen prostate cancer regimens. Skeletal muscle atrophy leads to weakness, which limits activity, decreases quality of life and leads to subsequent falls, fractures, and loss of independent living. Skeletal muscle atrophy places tremendous burdens on patients, their families, and society in general. Despite its broad implications for health and human disease, skeletal muscle atrophy is poorly understood and lacks an effective therapy.
Our current study therefore focuses on identifying novel mechanisms of skeletal muscle atrophy. In previous work we identified a cellular protein called ATF4, which we found served as a critical regulator of the atrophy process. However, in subsequent studies, it became clear that other factors must exist that act independently of ATF4. Therefore, the focus of this study was to identify this novel factor that regulates skeletal muscle mass. We identified p53 as this ATF4-independent factor inasmuch as p53 serves as an essential and causative factor in the development of skeletal muscle atrophy. Further studies identified the cellular protein p21 as a critical downstream regulator of the p53 and ATF4 pathways. Understanding these mechanisms at a deeper level may help us identify novel therapeutic approaches, a critical step towards our long-term goal of identifying a therapy to prevent or reverse muscle atrophy in those who are ill or aged.
publicabstract, ATF4, Immobilization, p21, p53, Skeletal muscle, Skeletal muscle atrophy
Copyright 2016 Daniel Fox