Author ORCID Identifier:
Date of Graduation
5-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Health, Sport and Exercise Science (PhD)
Degree Level
Graduate
Department
Health, Human Performance and Recreation
Advisor/Mentor
Murach, Kevin
Committee Member
Nelson, Christopher
Second Committee Member
Rosa-Caldwell, Megan
Third Committee Member
Greene, Nicholas
Keywords
Skeletal Muscle; MYC; Exercise
Abstract
Skeletal muscle is a remarkably plastic tissue, capable of remodeling its size, fiber type composition, and molecular architecture in response to contractile and non-contractile signals. MYC, canonically characterized as a proto-oncogene and one of the four Yamanaka reprogramming factors, has emerged from work in our laboratory as a central node in the skeletal muscle adaptive response to exercise. MYC transcript and protein are acutely induced in myonuclei following bouts of exercise in humans, and this response is attenuated with aging, coinciding with diminished hypertrophic plasticity and exercise responsiveness. Because skeletal muscle fibers are multinuclear and post-mitotic, they are resistant to the tumorigenic consequences of MYC elevation that occur in proliferating mononuclear cells, creating a unique platform in which the influence of MYC can be studied in isolation from oncogenic risk. Whether the pulsatile, exercise-mimetic induction of MYC in muscle fibers is sufficient to drive molecular and phenotypic outcomes across the lifespan, remained unresolved prior to the work presented in this dissertation. In Aim 1 (Chapter 3), I integrated whole-tissue bulk RNA-sequencing with reduced representation bisulfite sequencing (RRBS) to map transcriptomic and DNA methylation responses to a pulse of MYC in mouse skeletal muscle and compared these signatures to the transcriptomes of aged mice following progressive weighted wheel running (PoWeR) and to long-term exercise-trained human muscle. This work revealed that a single brief induction of MYC in skeletal muscle fibers recapitulates transcriptional changes of both the Yamanaka partial reprogramming and exercise response in aged mice, while also influencing the epigenome through regulation of DNA methylation. Key genes were commonly regulated across MYC induction, OKSM expression, and late-life exercise training, identifying MYC as a potential reprogramming factor through which exercise may combat sarcopenia. This work was published in The Journal of Physiology (Jones et al. 2021). In Aim 2 (Chapter 4), I present a multi-omics dissection of the human skeletal muscle response following a bout of resistance exercise across a 24-hour biopsy time course. This work, co-first authored with Sebastian Edman from the Karolinska Institute, demonstrated that MYC is the most influential transcription factor governing the late transcriptional response window between 8 and 24 hours after exercise in human skeletal muscle. Additionally, through periodic pulsing of MYC using our skeletal muscle-specific HSA-MYC mouse model over the course of four weeks, we were able to demonstrate increases in soleus mass and myofiber cross-sectional area, providing direct evidence that MYC induction alone is sufficient to induce hypertrophy. This work was published in EMBO Reports (Edman and Jones et al. 2024). In Aim 3 (Chapter 5), I employ the HSA-MYC doxycycline-inducible mouse model at multiple temporal resolutions, spanning acute induction, along with chronic four- and eight-week time courses, to mechanistically resolve how pulsatile MYC remodels skeletal muscle across transcriptomic, proteomic, single-nucleus, in vitro, and histological layers. These data reveal that transient MYC is sufficient to drive a combined hypertrophic, fiber type, and metabolic transition in the adult mouse soleus (Jones et al. manuscript in preparation).
Citation
Jones III, R. G. (2026). MYC in Skeletal Muscle: Regulation of Growth, Adaptation, and Fiber Type Remodeling. Graduate Theses and Dissertations Retrieved from https://scholarworks.uark.edu/etd/6259
