Effects of acute exercise and training on gene expression and regulatory proteins in human skeletal muscle

Regular physical activity affects all tissues in the human body, not least skeletal muscle. The skeletal muscle adaptation involves changes that help the muscle to handle perturbations of the intracellular homeostasis during exercise and thereby gradually improve the exercise capacity. Skeletal muscle has a remarkable ability to dynamically remodel and its adaptive process depends on e.g. exercise intensity and the training status of the individual performing the exercise. An important aerobic adaptive process is mitochondrial biogenesis, a process regulated by a complex network of transcriptional regulators inside the muscle cell. Using three different exercise interventions in humans, acute aerobic- and resistance exercise, and three weeks of HIIT, and obtaining skeletal muscle biopsies at various time points, the overall aim of this thesis was to expand the knowledge of molecular mechanisms involved in human skeletal muscle adaptation to exercise and exercise training, with a special emphasis on mitochondrial biogenesis. With three weeks of HIIT there was an overall attenuation of the transcriptional response to a single exercise bout. However, the response pattern was strikingly reproducible and independent of training status since the vast majority of differentially expressed genes at the last exercise bout were regulated at the first bout, albeit to a lesser degree. Additionally, there were different genes and pathways responding to acute exercise compared to training. At least four variants of the ‘master regulator’ of mitochondrial biogenesis, PGC-1a, were present in human skeletal muscle. All PGC-1a variants were increased by aerobic- and resistance exercise and there was no support for an exercise-modality specific variant. Moreover, PGC-1a-ex1b protein was induced earlier than PGC-1a protein after acute aerobic exercise. The transcriptional repressors RIP140 and p107 were affected by acute exercise and training, respectively.

In conclusion, the acute transcriptional response in skeletal muscle after exercise is blunted as the muscle adapts to training, supporting the fundamental concept that ‘trained’ muscle can maintain the cellular homeostasis better than ‘untrained’ muscle and thereby is exposed to a lower stimulus during acute exercise. Also, it seems like there are generally other genes orchestrating the remodelling process than those coordinating the maintenance of skeletal muscle adaptation. The control of both hypertrophy and aerobic adaptations are most likely coordinated through a much broader array of transcription factors, and other molecular mechanisms, than a single coactivator of transcription. Also, more emphasis should be put on the importance of transcriptional repressors in the regulation of skeletal muscle adaptation to exercise training.

List of scientific papers

I. Ydfors M, Fischer H, Mascher H, Blomstrand E, Norrbom J, Gustafsson T. The truncated splice variants, NT-PGC-1α and PGC-1α4, increase with both endurance and resistance exercise in human skeletal muscle. Physiol Rep. 2013 Nov;1(6):e00140.
https://doi.org/10.1002/phy2.140

II. Gidlund E-K, Ydfors M, Appel S, Rundqvist H, Sundberg CJ, Norrbom J. Rapidly elevated levels of PGC-1α-b protein in human skeletal muscle after exercise: exploring regulatory factors in a randomized controlled trial. J Appl Physiol. 2015 Aug 15;119(4):374–84.
https://doi.org/10.1152/japplphysiol.01000.2014

III. Bhattacharya D, Ydfors M, Hughes MC, Norrbom J, Perry CGR, Scimè A. Decreased transcriptional corepressor p107 is associated with exercise-induced mitochondrial biogenesis in human skeletal muscle. Physiol Rep. 2017 Mar;5(5):e13155.
https://doi.org/10.14814/phy2.13155

IV. Ydfors M, Sundberg CJ, Perry CGR, Rullman E, Norrbom J. Human skeletal muscle transcriptome in response to high-intensity interval training. [Manuscript]