The role of CARM1 in skeletal muscle regeneration and repair

Abstract

The skeletal muscle regenerative process is primarily driven by myogenic stem cells, termed satellite cells. The presence of coactivator-associated arginine methyltransferase 1 (CARM1) in satellite cells is necessary for myogenic repair. However, the requirement of skeletal muscle CARM1 for muscle regeneration remains unknown. This project investigated the role of skeletal muscle-specific CARM1 expression in the regenerative response to acute muscle trauma. We hypothesized that the absence of CARM1 in muscle would attenuate its regeneration and repair. The tibialis anterior (TA) and gastrocnemius (GAST) muscles in one hindlimb of 12-week-old adult, male and female wild-type (WT) and CARM1 skeletal muscle-specific knockout (mKO) mice (n = 6 - 10) were injected with cardiotoxin (CTX). The contralateral hindlimb was injected with saline to serve as an uninjured control (Ctrl). Muscles were harvested at 7-, 14-, and 28-days post-injury (DPI) and processed for morphological and biochemical analyses. While we observed no changes in CARM1 protein content up to 28 days following CTX-induced injury, we saw a transient upregulation in the arginine methylation of its downstream target in both genotypes. Morphological indicators of muscle remodeling were evident in histological assays of TA muscles following injury and largely restored by the end of the study period in both cohorts. We observed increased collagen deposition in WT mice at 7DPI, accompanied by greater interstitial area in both WT and mKO mice. Embryonic myosin heavy chain peaked in both cohorts at 7DPI. Finally, satellite cell analysis revealed increased Pax7 positive cells, as well as Pax7/Antigen Kiel 67 (Ki67) positive cells, in mKO mice at 7DPI, alongside an elevation in Ki67 positive cells in WT mice at 7DPI. Collectively, these results suggest that the skeletal muscle-specific deletion of CARM1 induces early alterations, primarily in satellite cell behaviour, that do not impair overall skeletal muscle regeneration and repair.