FTO 依赖性 mA 通过 NFATC1-YTHDF2 依赖性方式调节肌纤维重塑。
FTO-dependent mA regulates muscle fiber remodeling in an NFATC1-YTHDF2 dependent manner.
机构信息
Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
Department of Gynaecology and Obstetrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China.
出版信息
Clin Epigenetics. 2023 Jul 5;15(1):109. doi: 10.1186/s13148-023-01526-5.
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 mA 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.
背景
青少年特发性脊柱侧凸（AIS）的特征是瘦体重低而无椎体畸形。脊柱侧凸和脊柱旁肌失衡之间的因果关系长期以来一直困扰着研究人员。尽管 FTO 已被确定为 AIS 的易感基因，但它在脊柱旁肌无力的不对称性中的潜在作用尚未得到充分阐明。
方法
我们研究了 Fto 在鼠成肌细胞增殖、迁移和肌生成分化中的作用。我们检查了它在体外和体内对鼠肌纤维重塑的精确调节作用。我们通过筛选影响鼠肌纤维重塑的关键调节因子来鉴定 Fto 的下游靶基因，并鉴定其 mA 读取器。从 AIS 患者（有或没有施罗特练习）的凹侧和凸侧以及先天性脊柱侧凸获得深部脊柱旁肌肉样本，并将其作为对照组。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 表达水平。
结果
FTO 有助于维持体外和体内鼠慢肌纤维的形成。这些作用是通过 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 AIS 的凹侧 I 型纤维、MYH7 和 MYH7B 的 mRNA 水平以及 FTO 的表达显著降低。AIS 中 I 型纤维的百分比与 FTO 的表达水平呈正相关。在 AIS 中观察到的不对称模式与先天性脊柱侧凸中观察到的模式一致，AIS 中 FTO 表达和纤维类型的不对称性在施罗特练习后得到了很大程度的恢复。
结论
FTO 以 NFATC1-YTHDF2 依赖的方式支持鼠慢肌纤维的形成。AIS 和先天性脊柱侧凸中一致的脊柱旁肌肉特征，以及 AIS 中肌纤维和 FTO 表达的可逆模式表明，FTO 可能有助于继发于脊柱侧凸的肌纤维重塑。
Zotero 插件