DHA alleviates diet-induced skeletal muscle fiber remodeling via FTO/m6A/DDIT4/PGC1α signaling

作者：Wei Chen, Yushi Chen, Ruifan Wu, Guanqun Guo, Youhua Liu, Botao Zeng, Xing Liao, Yizhen Wang, Xinxia Wang · 发表于：BMC Biology · 年份：2022 · DOI：10.1186/s12915-022-01239-w · 被引用次数：47 · 研究领域：RNA modifications and cancer、Cancer, Hypoxia, and Metabolism、Sirtuins and Resveratrol in Medicine

Abstract Background Obesity leads to a decline in the exercise capacity of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. Dietary intervention has been shown to be an important measure to regulate skeletal muscle function, and previous studies have demonstrated the beneficial effects of docosahexaenoic acid (DHA; 22:6 ω-3) on skeletal muscle function. At the molecular level, DHA and its metabolites were shown to be extensively involved in regulating epigenetic modifications, including DNA methylation, histone modifications, and small non-coding microRNAs. However, whether and how epigenetic modification of mRNA such as N6-methyladenosine (m6A) mediates DHA regulation of skeletal muscle function remains unknown. Here, we analyze the regulatory effect of DHA on skeletal muscle function and explore the involvement of m 6 A mRNA modifications in mediating such regulation. Results DHA supplement prevented HFD-induced decline in exercise capacity and conversion of muscle fiber types from slow to fast in mice. DHA-treated myoblasts display increased mitochondrial biogenesis, while slow muscle fiber formation was promoted through DHA-induced expression of PGC1α. Further analysis of the associated molecular mechanism revealed that DHA enhanced expression of the fat mass and obesity-associated gene (FTO), leading to reduced m6A levels of DNA damage-induced transcript 4 ( Ddit4 ). Ddit4 mRNA with lower m6A marks could not be recognized and boun...