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http://hdl.handle.net/11375/27281
Title: | The role of CARM1 during skeletal muscle atrophy |
Other Titles: | CARM1 and muscle atrophy |
Authors: | Stouth, Derek W. |
Advisor: | Ljubicic, Vladimir |
Department: | Kinesiology |
Keywords: | CARM1 skeletal muscle atrophy |
Publication Date: | 2021 |
Abstract: | 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. |
Description: | CARM1 and skeletal muscle atrophy |
URI: | http://hdl.handle.net/11375/27281 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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STOUTH_DEREK_W_202112_PhD.pdf | 36.65 MB | Adobe PDF | View/Open |
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