Nature Metabolism ( IF 18.9 ) Pub Date : 2025-01-27 , DOI: 10.1038/s42255-024-01210-9
Yuhan Wang, Hao Xie, Qianrui Liu, Na Wang, Xi Luo, Fei Sun, Jinghan Zhu, Ruihan Dong, Yi Wang, Jia Gao, Zhichao Gao, Teng Huang, Xin Liu, Qilin Yu, Ting Wang, Yang Li, Danni Song, Shiwei Liu, Shu Zhang, Hao Yin, Wen Kong, Cong-Yi Wang
Skeletal muscle is a critical organ in maintaining homoeostasis against metabolic stress, and histone post-translational modifications are pivotal in those processes. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homoeostasis have yet to be elucidated. Here, we report that mitochondria-rich slow-twitch myofibers are characterized by significantly higher levels of H3K36me2 along with repressed expression of Kdm2a, an enzyme that specifically catalyses H3K36me2 demethylation. Deletion or inhibition of Kdm2a shifts fuel use from glucose under cold challenge to lipids under obese conditions by increasing the proportion of mitochondria-rich slow-twitch myofibers. This protects mice against cold insults and high-fat-diet-induced obesity and insulin resistance. Mechanistically, Kdm2a deficiency leads to a marked increase in H3K36me2 levels, which then promotes the recruitment of Mrg15 to the Esrrg locus to process its precursor messenger RNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Collectively, our data support the role of Kdm2a as a viable target against metabolic stress.
中文翻译:
骨骼肌中的 Kdm2a 抑制提高了肥胖患者的代谢灵活性
骨骼肌是维持对抗代谢应激的稳态的关键器官,组蛋白翻译后修饰在这些过程中至关重要。然而,骨骼肌中组蛋白甲基化的复杂性及其对代谢稳态的影响尚未阐明。在这里,我们报道了富含线粒体的慢肌纤维的特征是 H3K36me2 水平显着升高,并且 Kdm2a 的表达受到抑制,Kdm2a 是一种特异性催化 H3K36me2 去甲基化的酶。Kdm2a 的缺失或抑制通过增加富含线粒体的慢肌纤维的比例,将燃料使用从寒冷攻击下的葡萄糖转移到肥胖条件下的脂质。这可以保护小鼠免受寒冷侮辱和高脂肪饮食诱导的肥胖和胰岛素抵抗。从机制上讲,Kdm2a 缺陷导致 H3K36me2 水平显着增加,然后促进 Mrg15 募集到 Esrrg 基因座以处理其前体信使 RNA 剪接,从而重塑骨骼肌代谢谱以诱导慢肌纤维转换。总的来说,我们的数据支持 Kdm2a 作为对抗代谢应激的可行靶标的作用。