The Role of Coactivator‐associated Arginine Methyltransferase 1 (CARM1) During Sarcopenia

Abstract

CARM1 is emerging as an important regulator of skeletal muscle plasticity. We recently reported reduced muscle mass, along with aberrant autophagic and atrophic signaling in CARM1 skeletal muscle-specific knockout (mKO) mice. Notably, CARM1 interacts with forkhead box O1 (FOXO1), a master transcriptional regulator of the atrophy program, and knockout of CARM1 in skeletal muscle results in elevated FOXO1 protein content. Although CARM1 appears to be indispensable for preserving muscle mass, the impact of CARM1 deletion during the sarcopenia of aging remains to be elucidated. The purpose of this study was to more comprehensively understand the function of CARM1 during the progressive loss of skeletal muscle mass and strength with age. Survival analysis revealed that mKO mice have a significantly shorter lifespan compared to their wild type (WT) littermates. For instance, the survival rate of mKO and WT animals at 22 months is 17% and 33%, respectively. In order to assess functional and physiological adaptations to aging, grip strength and tibialis anterior (TA) muscle weights were assessed in 3 month (young) and 22 month (old) animals. We detected main effects (p < 0.05) of aging and genotype on forelimb grip strength. In particular, grip strength was significantly lower by 24% in old mKO versus old WT mice. Main effects (p < 0.05) of aging and genotype were also observed for TA muscle weight normalized to body weight. Relative to old WT mice, TA muscle weight was significantly lower by 7% in old mKO animals. We also employed Western blot analyses to assess FOXO1Ser256 activation status (phosphorylated/total), as well as the mammalian target of rapamycin complex 1 (mTORC1)Ser2448, a key regulator of muscle protein synthesis. The phosphorylation status of FOXO1Ser256 was lower (p = 0.07) in old mKO versus old WT mice, suggesting that CARM1 deletion leads to greater FOXO1 nuclear entry and transcription of atrogenes with aging. Compared to old WT animals, phosphorylation levels of mTORC1Ser2448 were also lower (p < 0.05) in old mKO mice, suggesting that CARM1 is important for driving muscle protein synthesis throughout the lifespan. Collectively, these results highlight the importance of CARM1 for combating the progressive and generalized loss of skeletal muscle mass and strength that occurs with age. Manipulating the expression and/or activity of CARM1 in skeletal muscle may offer a viable therapeutic strategy for mitigating sarcopenia.