CARM1 and skeletal muscle atrophy / Coactivator-associated arginine methyltransferase 1 (CARM1) is emerging as an important player in skeletal muscle biology. We sought to elucidate the role of CARM1 in mediating muscle mass and function, as well as in the induction and progression of the muscle atrophy program. To this end, we engineered CARM1 skeletal muscle-specific knockout (mKO) mice and employed distinct, but complementary models of muscle atrophy, including neurogenic muscle disuse, food deprivation, and the sarcopenia of aging. CARM1 mKO resulted in reduced muscle mass and myofiber cross-sectional area concomitant with dysregulated autophagic and atrophic signaling, which indicates the requirement of CARM1 for the maintenance of muscle biology. Interestingly, CARM1 deletion mitigated the progression of both denervation- and fasting-induced skeletal muscle atrophy as compared to wild-type (WT) mice. Key mechanistic findings revealed that CARM1 interacts with the master neuromuscular regulator AMPK and attenuates the expression and activity of its downstream autophagy and atrophy networks. Surprisingly, both male and female mKO mice have a significantly shorter lifespan versus their WT littermates, revealed by a ~50% reduction in survival at 22-months-old, which is equivalent to ~70 years-old in humans. As such, we observed significantly reduced functional outcomes of integrative physiology in old mKO mice compared to old WT animals, such as strength and motor performance. Taken together, these results indicate that skeletal muscle CARM1 is indispensable for maintaining muscle mass, function, and lifespan. Targeting the interplay between CARM1 and AMPK may offer a viable therapeutic strategy for combating life-limiting muscle wasting conditions. / Thesis / Doctor of Philosophy (PhD) / While muscle wasting and weakness remains a widespread issue, the mechanisms that control muscle atrophy are not entirely understood. Previous evidence suggests that coactivator-associated arginine methyltransferase 1 (CARM1) regulates skeletal muscle remodeling. However, the role of CARM1 during muscle atrophy is unknown. Therefore, the purpose of this work was to investigate the function of CARM1 during muscle wasting. We generated mice with CARM1 deleted in skeletal muscle and studied the impact of CARM1 deficiency on the loss of skeletal muscle mass during muscle disuse, food deprivation, and aging. We found that CARM1 is required to maintain muscle mass under basal conditions. Interestingly, knocking out CARM1 in muscle attenuated the progression of denervation- and fasting-induced atrophy. However, CARM1 deletion in muscle resulted in lower muscle strength and a reduced lifespan. CARM1 deficiency did not prevent aging-induced muscle loss. Overall, these findings advance our understanding of CARM1 in skeletal muscle biology.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27281 |
| Date | January 2021 |
| Creators | Stouth, Derek W. |
| Contributors | Ljubicic, Vladimir, Kinesiology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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