Abstract
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.
Highlights
Obesity leads to a decline in the exercise capacity of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks
docosahexaenoic acid (DHA) alleviates diet‐induced obesity and metabolic dysfunctions To assess the effect of DHA on skeletal muscle function in a diet-induced obesity (DIO), we fed the mice with normal fat diet (NFD), high-fat diet (HFD), or high-fat diet supplemented with DHA (HFD+DHA) for 10 weeks
We found that the final body weight of mice in HFD group was significantly higher than those fed NFD, and this showed that our obesity model is successfully constructed (Fig. 1A)
Summary
Obesity leads to a decline in the exercise capacity of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. Chen et al BMC Biology (2022) 20:39 as muscular atrophy, insulin resistance, and a shift from slow to fast muscle fiber types, thereby reducing mobility and further increasing the health risks associated with obesity [2, 3]. The transition of muscle fiber type from slow-twitch to fast-twitch caused by obesity leads to the change of metabolism mode and the decrease of insulin sensitivity in skeletal muscle, which exacerbates the systemic metabolic imbalance in turn [5]. Recent studies have reported that exercise and nutrition regulation can reverse the transition of skeletal muscle fiber type caused by obesity and restore its exercise and metabolic function, so as to improve systemic metabolism [6, 7]. It is meaningful to improve the function of skeletal muscle in obesity by nutritional pathway
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