The Skeletal Muscle Proteomic Signature of Long-Term Repeated Transient MYC Induction

Our recent work shows that MYC is one of the most influential transcription factors driving gene expression in response to resistance exercise in human skeletal muscle. Using a murine genetic doxycycline-inducible recombination-independent skeletal muscle-specific pulsatile model called HSA-MYC, we showed that weekly transient bursts of MYC – mimicking bouts of exercise - are sufficient to drive significant muscle hypertrophy of the soleus. To gain insight on how MYC controls adult muscle hypertrophy, we performed exploratory data-independent acquisition (DIA) proteomics on the soleus following 8 weeks of weekly transient MYC pulses (repeating 2 days of induction then 5 days off, n=5). Soleus muscles from doxycycline-treated age-matched (6-8 months) non-MYC mice were used for comparison (n=5). Repeated MYC induction causes large shifts in metabolism-related (PFKL, TPI1, PGAM2, ALDOC, ALDOA, and ENO3) and structural proteins (TPM3, ACTA1, TNNC2, TNNT1, MYL3, PDLIM3), as revealed by differential expression analysis (adj. p<0.05), indicative of metabolic reprogramming and cytoskeletal remodeling, respectively. MYC also caused upregulation in proteins and signaling pathways associated with ribosome biogenesis, rRNA processing, and ribosomal quality control. MYC’s regulation of ribosome function supports the hypothesis that enhanced translational efficiency is one of the primary mechanisms by which MYC regulates skeletal muscle growth. These findings collectively suggest a powerful regulatory role of MYC on the skeletal muscle proteome and provide information on potential therapeutic targets for mitigating muscle wasting conditions and/or enhancing skeletal muscle health. National Institutes of Health: Kevin A. Murach, R01 AG080047; IDeA National Resource for Quantitative Proteomics Voucher Award: Kevin A. Murach, R24GM137786 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.