PRMTs and exercise. / Protein arginine methyltransferases (PRMTs) play an important role in muscle. Using three unique but complementary approaches across human and mouse models, we examined PRMT biology during conditions of exercise-induced skeletal muscle plasticity. In response to acute and chronic cues for muscle plasticity in human muscle, an array of PRMT-specific increases and reductions in expression and activity were observed. Following this we generated coactivator-associated arginine methyltransferase 1 (CARM1) skeletal muscle-specific knockout (mKO) mice to further examine the role of this enzyme. We discovered that the rate of arginine methylation is equivalent to that of phosphorylation and ubiquitination in healthy muscle. CARM1 mKO displayed altered transcriptome and arginine methylproteomic signatures, confirming remodelled muscle contractile and neuromuscular junction characteristics, which foreshadowed the animal’s decreased acute exercise tolerance. Removal of CARM1 reduced voluntary wheel running (VWR) performance in a sex-dependent manner and eliminated the strong, positive correlation between VWR distance and mitochondrial number observed in WT mice. While CARM1 was shown to regulate AMPK-PGC-1α signaling during acute conditions of activity-induced muscle plasticity, molecular measures of PRMT biology were mostly unaffected by VWR and the removal of this enzyme. In conclusion, these results indicate that changes to expression and activity are PRMT-specific and reveal the broad impact of CARM1 in the maintenance and remodelling of skeletal muscle biology. / Thesis / Doctor of Philosophy (PhD) / Skeletal muscle is a malleable tissue that can adapt to an array of physiological demands. Past research suggests that protein arginine methyltransferases (PRMTs) regulate skeletal muscle remodelling. However, their role in exercise-induced skeletal muscle plasticity is unknown. Therefore, the purpose of this work was to investigate PRMT biology during acute and chronic exercise. Our data demonstrate that in human muscle a variety of PRMT-specific alterations in expression and activity occur in response to cues for muscle plasticity. Using mice lacking coactivator-associated methyltransferase 1 (CARM1) in skeletal muscle, we studied the impact removal of CARM1 has on the acute and chronic muscle adaptations to training. Our data demonstrate that in addition to changing molecular signals and physiological function at rest, the deletion of CARM1 decreased acute exercise ability and altered chronic training performance in a sex-dependent manner. Altogether, these findings expand our knowledge of PRMTs in skeletal muscle biology.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/28883 |
| Date | January 2023 |
| Creators | vanLieshout, Tiffany |
| Contributors | Ljubicic, Vladimir, Kinesiology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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