Mettl21e, a member of the newly classified nonhistone methyltransferases, is enriched in type IIb myofibers. It functions to maintain myofiber size by inhibiting proteasome-mediated protein degradation, specifically by methylating valosin-containing protein (Vcp/p97), a key component of the ubiquitin-proteasome system [1].

Knockdown (KD) of Mettl21e in cultured myotubes led to atrophy, and targeted mutation of Mettl21e in mice reduced the size of IIb myofibers without affecting myofiber type composition. KD or knockout of Mettl21e resulted in elevated 26S proteasome activity, and inhibiting proteasome activity prevented atrophy of Mettl21e KD myotubes [1]. In Callipyge sheep, Mettl21e was co-expressed with DLK1, and its expression was significantly increased in DLK1-treated myoblasts but reduced in DLK1-treated myotubes. Also, its expression increased Myh7 and decreased Myh4 luciferase activity [2]. In pupfishes, the gene (mettl21e) was misexpressed in lab-reared hybrids, suggesting a potential intrinsic genetic incompatibility [3].

In conclusion, Mettl21e is crucial for maintaining myofiber size through its role in inhibiting proteasome-mediated protein degradation. Studies in mouse models have revealed its significance in muscle-related processes. Although not directly related to diseases in the given references, its misexpression in pupfish hybrids indicates potential implications in genetic compatibility and evolution-related phenomena [1,2,3].

References:

1. Wang, Chao, Zhang, Bin, Ratliff, Anna C, Sun, Xiaobo, Kuang, Shihuan. 2019. Methyltransferase-like 21e inhibits 26S proteasome activity to facilitate hypertrophy of type IIb myofibers. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 9672-9684. doi:10.1096/fj.201900582R. https://pubmed.ncbi.nlm.nih.gov/31162944/

2. Yu, Hui, Waddell, Jolena N, Kuang, Shihuan, Cockett, Noelle E, Bidwell, Christopher A. 2018. Identification of genes directly responding to DLK1 signaling in Callipyge sheep. In BMC genomics, 19, 283. doi:10.1186/s12864-018-4682-1. https://pubmed.ncbi.nlm.nih.gov/29690867/

3. Patton, Austin H, Richards, Emilie J, Gould, Katelyn J, Buie, Logan K, Martin, Christopher H. 2022. Hybridization alters the shape of the genotypic fitness landscape, increasing access to novel fitness peaks during adaptive radiation. In eLife, 11, . doi:10.7554/eLife.72905. https://pubmed.ncbi.nlm.nih.gov/35616528/