The CARM1 transcriptome and arginine methylproteome mediate skeletal muscle integrative biology

Tiffany L vanLieshout; Derek W Stouth; Nicolas G Hartel; Goutham Vasam; Sean Y Ng; Erin K Webb; Irena A Rebalka; Andrew I Mikhail; Nicholas A Graham; Keir J Menzies; Thomas J Hawke; Vladimir Ljubicic

doi:10.1016/j.molmet.2022.101555

The CARM1 transcriptome and arginine methylproteome mediate skeletal muscle integrative biology

Mol Metab. 2022 Oct:64:101555. doi: 10.1016/j.molmet.2022.101555. Epub 2022 Jul 21.

Affiliations

¹ Department of Kinesiology, McMaster University, Hamilton, ON, L8S 4L8, Canada.
² Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, 90089, USA.
³ Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
⁴ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada.
⁵ Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON, K1H 8M5, Canada; Ottawa Institute of Systems Biology and the Centre for Neuromuscular Disease, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Rd, K1H 8M5, Ottawa, Canada.
⁶ Department of Kinesiology, McMaster University, Hamilton, ON, L8S 4L8, Canada. Electronic address: ljubicic@mcmaster.ca.

Abstract

Objective: Coactivator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of arginine residues on target proteins to regulate critical processes in health and disease. A mechanistic understanding of the role(s) of CARM1 in skeletal muscle biology is only gradually emerging. The purpose of this study was to elucidate the function of CARM1 in regulating the maintenance and plasticity of skeletal muscle.

Methods: We used transcriptomic, methylproteomic, molecular, functional, and integrative physiological approaches to determine the specific impact of CARM1 in muscle homeostasis.

Results: Our data defines the occurrence of arginine methylation in skeletal muscle and demonstrates that this mark occurs on par with phosphorylation and ubiquitination. CARM1 skeletal muscle-specific knockout (mKO) mice displayed altered transcriptomic and arginine methylproteomic signatures with molecular and functional outcomes confirming remodeled skeletal muscle contractile and neuromuscular junction characteristics, which presaged decreased exercise tolerance. Moreover, CARM1 regulates AMPK-PGC-1α signalling during acute conditions of activity-induced muscle plasticity.

Conclusions: This study uncovers the broad impact of CARM1 in the maintenance and remodelling of skeletal muscle biology.

Keywords: AMPK; Mitochondria; Muscle plasticity; Neuromuscular junction; PGC-1α.

MeSH terms

Animals
Arginine* / metabolism
Biology
Mice
Muscle, Skeletal / metabolism
Protein-Arginine N-Methyltransferases
Transcriptome*

Substances

Arginine
Protein-Arginine N-Methyltransferases
coactivator-associated arginine methyltransferase 1