CARM1 Regulates AMPK Signalling in Skeletal Muscle

Coactivator-associated arginine methyltransferase 1 (CARM1) is emerging as an important mediator of skeletal muscle plasticity. We employed genetic, physiologic, and pharmacologic approaches to determine whether CARM1 regulates the master neuromuscular phenotypic modifier AMP-activated protein kinase (AMPK). CARM1 skeletal muscle-specific knockout (mKO) mice displayed reduced muscle mass and dysregulated autophagic and atrophic processes downstream of AMPK. We observed altered interactions between CARM1 and AMPK and its network, including forkhead box protein O1 and transcription factor EB, during chronic neurogenic muscle disuse. CARM1 methylated AMPK during the early stages of muscle inactivity, while CARM1 mKO mitigated the progression of denervation-induced muscle atrophy and was accompanied by attenuated AMPK signalling. Attenuated acetyl-coenzyme A corboxylaseSer79 phosphorylation, as well as reduced peroxisome proliferator-activated receptor-γ coactivator-1α and muscle RING finger 1 expression were also observed in mKO animals following acute administration of the direct, pan-AMPK activator MK-8722. Overall, loss of CARM1 in skeletal muscle altered AMPK signalling under physiologic and pharmacologic conditions. Our study suggests that targeting the interplay between CARM1-AMPK may have broad impacts on neuromuscular health and disease.