Proteasomal regulation of rDNA transcription and skeletal muscle hypertrophy
Open Access
- Author:
- Chandler, Paige Nicole
- Graduate Program:
- Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 23, 2018
- Committee Members:
- Gustavo Alberto Nader, Dissertation Advisor/Co-Advisor
Gustavo Alberto Nader, Committee Chair/Co-Chair
Craig Eugene Cameron, Committee Member
Kenneth Charles Keiler, Committee Member
Rudolf Johannes Schilder, Outside Member
Leonard Jefferson, Committee Member - Keywords:
- proteasome
ribosome
rDNA transcription
hypertrophy - Abstract:
- Muscle growth is advantageous not only because of its roles in mobility and breathing, but because increases in muscle mass increase physical strength, reduces the risk of injury, increases bone strength, and promotes immune function. Given the various roles of skeletal muscle, it is clear that inadequately maintaining muscle mass and function is a threat to an individual’s quality of life and health. Muscle atrophy is a debilitating condition that commonly occurs in conjunction with disuse due to injury, aging, and chronic illness. In 2012, more than 54% of US adults suffered from a musculoskeletal disorder (MSDs), the vast majority of which are caused by traumatic illness. As a result, MSDs represent the second highest cause of disability. As for the aging population, the US Census Bureau has predicted that 20% (80 million) of the population will be > 65 years of age by 2050. The economic burden of age-related muscle loss is so great that a 10% reduction in age-related muscle loss would save the US $1 billion in health costs per year. Finally, 60% of US adults are living with one chronic illness while 42% are living with two. Given the alarming incidence of conditions which promote muscle atrophy, it is imperative to fully understand the biological underpinnings of muscle growth. Skeletal muscle hypertrophy occurs when rates of protein synthesis exceed rates of protein degradation. Most studies centered on the regulation of muscle mass emphasize the role of protein synthesis while there is less emphasis placed on the role of protein degradation. However, protein degradation is required for the quick and efficient removal of not only damaged proteins, but ~20% of the cellular proteome. Indeed, the ubiquitin-proteasome system (UPS), one of the predominant proteolytic systems in muscle, controls the expression of regulatory factors like cell cycle proteins, transcription factors, and signaling molecules. This means that the UPS can selectively control gene expression, and signal transduction. Unfortunately, because one of the hallmarks of muscle atrophy is hyperactive proteolysis by the UPS, proteolysis generally has a negative connotation in muscle. Nonetheless, the UPS is necessary for muscle hypertrophy because inhibition of the UPS in various rodent and human models causes defects in muscle growth, architecture, and function. Therefore, we propose that the UPS is crucially involved in skeletal muscle growth. The goal of my dissertation research was to identify a precise role for the UPS during hypertrophy. We hypothesized that UPS inhibition would impair growth by blocking ribosomal DNA (rDNA) transcription and ribosome production. In order to study the role of the proteasome in skeletal muscle growth, we used the reversible but potent 26S proteasome inhibitor MG-132. We found that inhibition of the proteasome, but not other prominent proteolytic systems, blocked hypertrophy by impairing rDNA transcription and ribosome production. We further hypothesized that proteasome inhibition would lead to the accumulation of p53, a negative regulatory factor of rDNA transcription. Indeed, p53 accumulated upon proteasome inhibition, which impaired rDNA transcription by reducing RNA Pol I recruitment to the rDNA promoter. Collectively, my dissertation work highlights the role of the UPS in the transcriptional regulation of muscle hypertrophy. Specifically, this work demonstrates that the UPS is not a passive participant in growth but has precise molecular roles in the regulation of muscle mass. Furthermore, this study is important for the development of therapeutics for those individuals suffering from chronic muscle loss. We can conclude that inhibition of the UPS may not be the best target for those individuals suffering from muscle atrophy as UPS inhibition might exacerbate muscle loss.