{"title":"fto依赖的m6A以NFATC1-YTHDF2依赖的方式调节肌纤维重塑。","authors":"Wengang Wang, Xueming Du, Ming Luo, Ningning Yang","doi":"10.1186/s13148-023-01526-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Adolescent idiopathic scoliosis (AIS) is characterized by low lean mass without vertebral deformity. The cause-and-effect relationship between scoliosis and paraspinal muscle imbalance has long puzzled researchers. Although FTO has been identified as a susceptibility gene for AIS, its potential role in the asymmetry of paraspinal muscles has not been fully elucidated.</p><p><strong>Methods: </strong>We investigated the role of Fto in murine myoblast proliferation, migration, and myogenic differentiation. We examined its precise regulatory influence on murine muscle fiber remodeling in vitro and in vivo. We identified the downstream target gene of Fto by screening key regulators of murine muscle fiber remodeling and identified its m<sup>6</sup>A reader. Deep paraspinal muscle samples were obtained from the concave and convex sides of AIS patients with or without Schroth exercises, and congenital scoliosis served as a control group. We compared the content of type I fibers, expression patterns of fast- and slow-type genes, and levels of FTO expression.</p><p><strong>Results: </strong>FTO contributed to maintain the formation of murine slow-twitch fibers both in vitro and in vivo. These effects were mediated by the demethylation activity of FTO, which specifically demethylated NFATC1 and prevented YTHDF2 from degrading it. We found a significant reduction in type I fibers, mRNA levels of MYH7 and MYH7B, and expression of FTO on the concave side of AIS. The percentage of type I fibers showed a positive correlation with the expression level of FTO. The asymmetric patterns observed in AIS were consistent with those seen in congenital scoliosis, and the asymmetry of FTO expression and fiber type in AIS was largely restored by Schroth exercises.</p><p><strong>Conclusions: </strong>FTO supports the formation of murine slow-twitch fibers in an NFATC1-YTHDF2 dependent manner. The consistent paraspinal muscle features seen in AIS and congenital scoliosis, as well as the reversible pattern of muscle fibers and expression of FTO in AIS suggest that FTO may contribute to the muscle fiber remodeling secondary to scoliosis.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":"15 1","pages":"109"},"PeriodicalIF":5.7000,"publicationDate":"2023-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320966/pdf/","citationCount":"1","resultStr":"{\"title\":\"FTO-dependent m<sup>6</sup>A regulates muscle fiber remodeling in an NFATC1-YTHDF2 dependent manner.\",\"authors\":\"Wengang Wang, Xueming Du, Ming Luo, Ningning Yang\",\"doi\":\"10.1186/s13148-023-01526-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Adolescent idiopathic scoliosis (AIS) is characterized by low lean mass without vertebral deformity. The cause-and-effect relationship between scoliosis and paraspinal muscle imbalance has long puzzled researchers. Although FTO has been identified as a susceptibility gene for AIS, its potential role in the asymmetry of paraspinal muscles has not been fully elucidated.</p><p><strong>Methods: </strong>We investigated the role of Fto in murine myoblast proliferation, migration, and myogenic differentiation. We examined its precise regulatory influence on murine muscle fiber remodeling in vitro and in vivo. We identified the downstream target gene of Fto by screening key regulators of murine muscle fiber remodeling and identified its m<sup>6</sup>A reader. Deep paraspinal muscle samples were obtained from the concave and convex sides of AIS patients with or without Schroth exercises, and congenital scoliosis served as a control group. We compared the content of type I fibers, expression patterns of fast- and slow-type genes, and levels of FTO expression.</p><p><strong>Results: </strong>FTO contributed to maintain the formation of murine slow-twitch fibers both in vitro and in vivo. These effects were mediated by the demethylation activity of FTO, which specifically demethylated NFATC1 and prevented YTHDF2 from degrading it. We found a significant reduction in type I fibers, mRNA levels of MYH7 and MYH7B, and expression of FTO on the concave side of AIS. The percentage of type I fibers showed a positive correlation with the expression level of FTO. The asymmetric patterns observed in AIS were consistent with those seen in congenital scoliosis, and the asymmetry of FTO expression and fiber type in AIS was largely restored by Schroth exercises.</p><p><strong>Conclusions: </strong>FTO supports the formation of murine slow-twitch fibers in an NFATC1-YTHDF2 dependent manner. The consistent paraspinal muscle features seen in AIS and congenital scoliosis, as well as the reversible pattern of muscle fibers and expression of FTO in AIS suggest that FTO may contribute to the muscle fiber remodeling secondary to scoliosis.</p>\",\"PeriodicalId\":48652,\"journal\":{\"name\":\"Clinical Epigenetics\",\"volume\":\"15 1\",\"pages\":\"109\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2023-07-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10320966/pdf/\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Epigenetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13148-023-01526-5\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Epigenetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13148-023-01526-5","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
FTO-dependent m6A regulates muscle fiber remodeling in an NFATC1-YTHDF2 dependent manner.
Background: Adolescent idiopathic scoliosis (AIS) is characterized by low lean mass without vertebral deformity. The cause-and-effect relationship between scoliosis and paraspinal muscle imbalance has long puzzled researchers. Although FTO has been identified as a susceptibility gene for AIS, its potential role in the asymmetry of paraspinal muscles has not been fully elucidated.
Methods: We investigated the role of Fto in murine myoblast proliferation, migration, and myogenic differentiation. We examined its precise regulatory influence on murine muscle fiber remodeling in vitro and in vivo. We identified the downstream target gene of Fto by screening key regulators of murine muscle fiber remodeling and identified its m6A reader. Deep paraspinal muscle samples were obtained from the concave and convex sides of AIS patients with or without Schroth exercises, and congenital scoliosis served as a control group. We compared the content of type I fibers, expression patterns of fast- and slow-type genes, and levels of FTO expression.
Results: FTO contributed to maintain the formation of murine slow-twitch fibers both in vitro and in vivo. These effects were mediated by the demethylation activity of FTO, which specifically demethylated NFATC1 and prevented YTHDF2 from degrading it. We found a significant reduction in type I fibers, mRNA levels of MYH7 and MYH7B, and expression of FTO on the concave side of AIS. The percentage of type I fibers showed a positive correlation with the expression level of FTO. The asymmetric patterns observed in AIS were consistent with those seen in congenital scoliosis, and the asymmetry of FTO expression and fiber type in AIS was largely restored by Schroth exercises.
Conclusions: FTO supports the formation of murine slow-twitch fibers in an NFATC1-YTHDF2 dependent manner. The consistent paraspinal muscle features seen in AIS and congenital scoliosis, as well as the reversible pattern of muscle fibers and expression of FTO in AIS suggest that FTO may contribute to the muscle fiber remodeling secondary to scoliosis.
Clinical EpigeneticsBiochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍:
Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.