CARM1 Regulates AMPK Signaling in Skeletal Muscle

Derek W Stouth; Tiffany L vanLieshout; Sean Y Ng; Erin K Webb; Alexander Manta; Zachary Moll; Vladimir Ljubicic

doi:10.1016/j.isci.2020.101755

CARM1 Regulates AMPK Signaling in Skeletal Muscle

iScience. 2020 Nov 2;23(11):101755. doi: 10.1016/j.isci.2020.101755. eCollection 2020 Nov 20.

Authors

Derek W Stouth¹, Tiffany L vanLieshout¹, Sean Y Ng¹, Erin K Webb¹, Alexander Manta¹, Zachary Moll¹, Vladimir Ljubicic¹

Affiliation

¹ Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada.

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1) is an emerging 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, during muscle disuse. CARM1 methylated AMPK during the early stages of muscle inactivity, whereas CARM1 mKO mitigated progression of denervation-induced atrophy and was accompanied by attenuated phosphorylation of AMPK targets such as unc-51 like autophagy-activating kinase 1^Ser555. Lower acetyl-coenzyme A corboxylase^Ser79 phosphorylation, as well as reduced peroxisome proliferator-activated receptor-γ coactivator-1α, was also observed in mKO animals following acute administration of the direct AMPK activator MK-8722. Our study suggests that targeting CARM1-AMPK interplay may have broad impacts on neuromuscular health and disease.

Keywords: Biochemistry; Biological Sciences; Genetics; Molecular Biology.