Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity

Abstract

Maintenance of skeletal muscle function is critical for metabolic health and the disruption of which exacerbates many chronic diseases such as obesity and diabetes. Skeletal muscle responds to exercise or metabolic demands by a fiber-type switch regulated by signaling-transcription networks that remains to be fully defined. Here, we report that protein arginine methyltransferase 7 (Prmt7) is a key regulator for skeletal muscle oxidative metabolism. Prmt7 is expressed at the highest levels in skeletal muscle and decreased in skeletal muscles with age or obesity. Prmt7−/− muscles exhibit decreased oxidative metabolism with decreased expression of genes involved in muscle oxidative metabolism, including PGC-1α. Consistently, Prmt7−/− mice exhibited significantly reduced endurance exercise capacities. Furthermore, Prmt7−/− mice exhibit decreased energy expenditure, which might contribute to the exacerbated age-related obesity of Prmt7−/− mice. Similarly to Prmt7−/− muscles, Prmt7 depletion in myoblasts also reduces PGC-1α expression and PGC-1α–promoter driven reporter activities. Prmt7 regulates PGC-1α expression through interaction with and activation of p38 mitogen-activated protein kinase (p38MAPK), which in turn activates ATF2, an upstream transcriptional activator for PGC-1α. Taken together, Prmt7 is a novel regulator for muscle oxidative metabolism via activation of p38MAPK/ATF2/PGC-1α.

PRMT7 deficiency causes dysregulation of the HCN channels in the CA1 pyramidal cells and impairment of social behaviors

“…Prmt7 mice were originally purchased from the Sanger Institute. Mice were backcrossed onto C67BL/6J background for at least six generations and maintained on C67BL/6J background, and wild-type littermates were used as controls for the phenotype studies of the PRMT7 knockout mice 25 . All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Sungkyunkwan University School of Medicine (IACUC2019-07-11-3).…”

The N-terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation.

“…PRMT7, like NRMT2, is also found less broadly expressed than other PRMT family members, and its highest expression is in skeletal muscle (Jeong et al, 2016). It is also notably found in mouse embryonic stem cells and is thought to regulate pluripotency and differentiation.…”

“…PRMT7-null mice show reduced oxidative metabolism and increased agerelated obesity, indicating a distinct functional role of monomethylation in skeletal muscle metabolism (Jeong et al, 2016). In another function, similar to that of the NRMT family, PRMT7 and its associated monomethylation activity are associated with genes associated with DNA damage repair (Karkhanis et al, 2012).…”

Identification, expression and functional analysis of prmt7 in medaka Oryzias latipes

“…PRMT7 expression was upregulated in some cancers and may have a significant role in promoting cell invasions (Baldwin et al, 2015; Cheng et al, 2018; Geng et al, 2017). PRMT7 was also a key regulator for the stemness of mouse embryonic and muscle stem cells (Blanc, Vogel, Chen, Crist, & Richard, 2016; Jeong et al, 2016; Lee et al, 2016; Wang, Pfeiffer, Drexler, Fuellen, & Boiani, 2016). It was also reported that PRMT7 was associated with late B cell differentiation in the spleen and germinal center formation after immunization (Ying et al, 2015).…”