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

BMC Biology

Yushi Chen¹  Xinxia Wang¹  Ruifan Wu¹  Xing Liao¹  Guanqun Guo¹  Botao Zeng¹  Wei Chen¹  Yizhen Wang¹  Youhua Liu¹ 

[1] College of Animal Sciences, Zhejiang University, No. 866 Yuhangtang Road, 310058, Hangzhou, Zhejiang province, China;Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, 310058, Hangzhou, China;Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, 310058, Hangzhou, China;Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, 310058, Hangzhou, China;

关键词: DHA;    FTO;    Muscle fiber;    Obesity;    PGC1α;   

DOI  :  10.1186/s12915-022-01239-w

来源: Springer

【 摘 要 】

BackgroundObesity 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 m6A mRNA modifications in mediating such regulation.ResultsDHA 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 bound by the cytoplasmic m6A reader YTH domain family 2 (YTHDF2), thereby blocking the decay of Ddit4 mRNA. Accumulated Ddit4 mRNA levels accelerated its protein translation, and the consequential increased DDIT4 protein abundance promoted the expression of PGC1α, which finally elevated mitochondria biogenesis and slow muscle fiber formation.ConclusionsDHA promotes mitochondrial biogenesis and skeletal muscle fiber remodeling via FTO/m6A/DDIT4/PGC1α signaling, protecting against obesity-induced decline in skeletal muscle function.

【 授权许可】

CC BY