fto依赖的m6A以NFATC1-YTHDF2依赖的方式调节肌纤维重塑。

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-07-05 DOI:10.1186/s13148-023-01526-5
Wengang Wang, Xueming Du, Ming Luo, Ningning Yang
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引用次数: 1

摘要

背景:青少年特发性脊柱侧凸(AIS)的特点是低瘦块无椎体畸形。脊柱侧凸与脊柱旁肌肉失衡的因果关系一直困扰着研究者。虽然FTO已被确定为AIS的易感基因,但其在棘旁肌肉不对称中的潜在作用尚未完全阐明。方法:研究Fto在小鼠成肌细胞增殖、迁移和成肌分化中的作用。我们在体外和体内研究了其对小鼠肌纤维重塑的精确调控作用。我们通过筛选小鼠肌纤维重塑的关键调控因子,确定了Fto的下游靶基因,并鉴定了其m6A读取器。采用或不采用Schroth运动的AIS患者的凹侧和凸侧采集深棘旁肌样本,并以先天性脊柱侧凸为对照组。我们比较了I型纤维的含量、快型和慢型基因的表达模式以及FTO的表达水平。结果:FTO在体外和体内均有助于维持小鼠慢肌纤维的形成。这些作用是由FTO的去甲基化活性介导的,它特异性地去甲基化NFATC1并阻止YTHDF2降解它。我们发现I型纤维、MYH7和MYH7B mRNA水平以及AIS凹侧FTO的表达显著减少。I型纤维百分比与FTO表达水平呈正相关。在AIS中观察到的不对称模式与先天性脊柱侧凸一致,并且通过Schroth运动在很大程度上恢复了AIS中FTO表达和纤维类型的不对称。结论:FTO以依赖于NFATC1-YTHDF2的方式支持小鼠慢肌纤维的形成。AIS和先天性脊柱侧凸中一致的棘旁肌特征,以及AIS中肌纤维的可逆模式和FTO的表达提示FTO可能参与脊柱侧凸继发的肌纤维重塑。
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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.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, 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.
期刊最新文献
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