Abstract
Despite the emerging importance of protein arginine methyltransferases (PRMTs) in regulating skeletal muscle plasticity, PRMT biology during muscle development is complex and not completely understood. Therefore, our purpose was to investigate PRMT1, -4, and -5 expression and function in skeletal muscle cells during the phenotypic remodeling elicited by myogenesis. C2C12 muscle cell maturation, assessed during the myoblast (MB) stage, and during days 1, 3, 5, and 7 of differentiation, was employed as an in vitro model of myogenesis. We observed PRMT-specific patterns of expression and activity during myogenesis. PRMT4 and -5 gene expression was unchanged, while PRMT1 mRNA and protein content were significantly induced. Cellular monomethylarginines (MMAs) and symmetric dimethylarginines (SDMAs), indicative of global and type II PRMT activities, respectively, remained steady during development, while type I PRMT activity indicator asymmetric dimethylarginines (ADMAs) increased through myogenesis. Histone 4 arginine 3 (H4R3) and H3R17 contents were elevated coincident with the myonuclear accumulation of PRMT1 and -4. Collectively, this suggests that PRMTs are methyl donors throughout myogenesis and demonstrate specificity for their protein targets. Cells were then treated with TC-E 5003 (TC-E), a selective inhibitor of PRMT1 in order to specifically examine the enzymes role during myogenic differentiation. TC-E treated cells exhibited decrements in muscle differentiation, which were consistent with attenuated mitochondrial biogenesis and respiratory function. In summary, the present study increases our understanding of PRMT1, -4, and -5 biology during the plasticity of skeletal muscle development. Our results provide evidence for a role of PRMT1, via a mitochondrially mediated mechanism, in driving the muscle differentiation program.
Highlights
Protein arginine methyltransferases (PRMTs) are key regulators of important cellular events such as signal transduction, as well as transcriptional activation and repression [1,2,3]
To understand the potential mechanisms underlying the differentiation defects observed in PRMT1-inhibited cells, we examined the effects of TC-E 5003 (TC-E) on mitochondrial biogenesis and oxygen consumption
Complementary assessments of PRMT1, -4, and -5 function indicate that PRMT methyltransferase activity in muscle is substrate specific, depending in part, on the subcellular location of the protein target
Summary
Protein arginine methyltransferases (PRMTs) are key regulators of important cellular events such as signal transduction, as well as transcriptional activation and repression [1,2,3]. These enzymes methylate arginine residues by transferring methyl groups from S-adenosyl-l-methionine to terminal guanidino nitrogen atoms of targetted proteins [4]. Overexpression of PRMT1 is linked to lung cancer, while aberrant expression levels c 2018 The Author(s)
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