Regulation of Skeletal Muscle Plasticity by Protein Arginine Methyltransferases and Their Potential Roles in Neuromuscular Disorders

Abstract

Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the methylation of arginine residues on target proteins, thereby mediating a diverse set of intracellular functions that are indispensable for survival. Indeed, full-body knockouts of specific PRMTs are lethal and PRMT dysregulation has been implicated in the most prevalent chronic disorders, such as cancers and cardiovascular disease (CVD). PRMTs are now emerging as important mediators of skeletal muscle phenotype and plasticity. Since their first description in muscle in 2002, a number of studies employing wide varieties of experimental models support the hypothesis that PRMTs regulate multiple aspects of skeletal muscle biology, including development and regeneration, glucose metabolism, as well as oxidative metabolism. Furthermore, investigations in non-muscle cell types strongly suggest that proteins, such as peroxisome proliferator-activated receptor-γ coactivator-1α, E2F transcription factor 1, receptor interacting protein 140, and the tumor suppressor protein p53, are putative downstream targets of PRMTs that regulate muscle phenotype determination and remodeling. Recent studies demonstrating that PRMT function is dysregulated in Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS) suggests that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders (NMDs). This review summarizes our understanding of PRMT biology in skeletal muscle, and identifies uncharted areas that warrant further investigation in this rapidly expanding field of research.

CARM1 Regulates AMPK Signaling in Skeletal Muscle

“…In summary, this study reveals a CARM1-AMPK mechanism that impacts the maintenance and remodeling of muscle mass via altered downstream autophagic and atrophic signaling. Given the emerging roles for CARM1 in muscle biology ( Stouth et al., 2017 ; vanLieshout et al., 2019 ), as well as the established functions for AMPK in maintaining and remodeling skeletal muscle phenotype ( Mounier et al., 2015 ; Dial et al., 2018 ; Kjøbsted et al., 2018 ; Steinberg and Carling, 2019 ), targeting this interplay between CARM1-AMPK may therefore provide therapeutic strategies for myopathies such as disuse atrophy, the sarcopenia of aging, or cancer cachexia.…”

“…CARM1 has emerged as an important player in skeletal muscle biology. Work from our laboratory indicates that the methyltransferase is a novel regulator of skeletal muscle remodeling in rodents and humans ( Ljubicic et al., 2012 ; Stouth et al., 2017 , 2018 ; Vanlieshout et al., 2018 ; Shen et al., 2018 ; vanLieshout and Ljubicic, 2019 ; vanLieshout et al., 2019 ). Moreover, a series of elegant studies demonstrate that CARM1 governs myogenesis during development and regeneration, as well as plays a role in muscle glycogen metabolism ( Chen et al., 2002 ; Kawabe et al., 2012 ; Wang et al., 2012 ; Chang et al., 2018 ).…”

Protein arginine methyltransferase expression and activity during myogenesis

“…Protein arginine methyltransferases (PRMTs) are key regulators of important cellular events such as signal transduction, as well as transcriptional activation and repression [ 1 – 3 ]. These enzymes methylate arginine residues by transferring methyl groups from S-adenosyl- l -methionine to terminal guanidino nitrogen atoms of targetted proteins [ 4 ].…”

“…Though the presence of arginine methylation in skeletal muscle was first reported almost five decades ago [ 11 ], only recently have studies emerged implicating roles for PRMTs in muscle. A number of mechanistic papers have provided a basis for knowledge of PRMT biology in skeletal muscle [ 3 ]. For example, PRMT expression, activity, and subcellular localization are dynamic and contribute to the early processes that drive both disuse- and exercise-induced skeletal muscle plasticity in vivo [ 12 , 13 ].…”

Posttranslational regulation of PGC‐1α and its implication in cancer metabolism

“…PRMT1 is the major protein arginine methyltransferase (PRMT) family member in mammalian cells. It serves as a coactivator for NRs and other DNA‐binding transcription factors, such as p53 and initiator element binding factor (YY1) and mediates chromatin remodeling and initiation of transcription . PGC‐1α has been confirmed to be methylated by PRMT1 at arginines 665, 667 and 669.…”