Myonuclear dynamics in muscle plasticity and the transcriptional regulation of resistance training induced hypertrophy.

Skeletal muscle is highly responsive to changes in mechanical load or activity and can adjust its morphological, metabolic, and contractile properties accordingly. The remodeling of these characteristics is controlled by the reprogramming of the transcriptional output of the myonuclei along the length of the muscle fiber. To meet the transcriptional demands of growth and increased activity, myonuclei can be added to the existing cytoplasm through the fusion of satellite cells, to support synthetic activity. This project utilises improved methodologies including automated, high-throughput immunohistochemical analysis and bulk RNA-sequencing of skeletal muscle. With these techniques, we define the temporal patterns of myonuclear dynamics and how they correspond to fiber-type specific adaptations in response to loading, unloading, reloading and changes in activity and how the acute transcriptional response is altered, dependent on the training status of the muscle. To induce these modalities of activity or inactivity, we utilised in-vivo models from our lab including, (1) programmed exercise delivered through miniature implanted pulse generators (IPGs) to induce muscle hypertrophy or metabolic adaptation and (2) disuse by means of tetrodotoxin-induced nerve silencing to induce muscle atrophy. We report that the genes that most closely track with changes in muscle mass are controlled centrally by the basic-helix-loop-helix transcription factor Myc, that functions to bind to E-box containing DNA sequences. In addition, we identify 10 other genes that appear as important regulators across species and modalities of exercise that warrant further investigation. Lastly, we investigate a promising marker for specifically identifying myonuclei, pericentriolar material-1 (PCM1), which would allow for deconvolution of mRNA signals from bulk skeletal muscle mRNA analysis, allowing for identification of myogenic and non-myogenic transcriptional changes. In summary, our aim is to provide key mechanistic insights into myonuclear dynamics and how adaptation of skeletal muscle is regulated at the transcriptional level