biostudies-literatureChen CNatural Science Foundation of Fujian Province41https://www.ebi.ac.uk/biostudies/studies/S-EPMC12911173biostudies-literatureUnknown24(1)<h4>Background</h4>The dynamic change of N6-methyladenosine (m⁶A) modification on substrate RNA molecules plays a critical role in different biological processes and disease pathogenesis. Although the beneficial effects of exercise training (ET) on skeletal muscle insulin resistance (IR) are well-established, the contribution of RNA m⁶A modification in ET-related adaptations in high-fat diet (HFD)-induced IR remains unclear.<h4>Results</h4>In this study, we show that exercise stimulation triggers a dynamic shift in skeletal muscle m⁶A modification levels during HFD consumption. As a key m⁶A methyltransferase, METTL16 was downregulated in HFD-fed mice and upregulated by ET at both the mRNA and protein levels. In vitro, METTL16 knockdown disrupted BMC biologyMETTL16-m&lt;sup&gt;6&lt;/sup&gt;A-PGC-1α axis contributes to exercise-induced mitochondrial adaptations in skeletal muscle of high-fat diet-fed insulin-resistant mice.PMC129111732025J01959Xiang QHou MHuang CHu YHan XJiang CChen CZhou HWu HXu YLiu WfalseMETTL16-m&lt;sup&gt;6&lt;/sup&gt;A-PGC-1α axis contributes to exercise-induced mitochondrial adaptations in skeletal muscle of high-fat diet-fed insulin-resistant mice.<h4>Background</h4>The dynamic change of N6-methyladenosine (m⁶A) modification on substrate RNA molecules plays a critical role in different biological processes and disease pathogenesis. Although the beneficial effects of exercise training (ET) on skeletal muscle insulin resistance (IR) are well-established, the contribution of RNA m⁶A modification in ET-related adaptations in high-fat diet (HFD)-induced IR remains unclear.<h4>Results</h4>In this study, we show that exercise stimulation triggers a dynamic shift in skeletal muscle m⁶A modification levels during HFD consumption. As a key m⁶A methyltransferase, METTL16 was downregulated in HFD-fed mice and upregulated by ET at both the mRNA and protein levels. In vitro, METTL16 knockdown disrupted 2026-01-01T00:00:00Z2026 Jan2026-07-16T00:50:01.654Z2026-07-09T13:10:05.133ZS-EPMC129111734157227610.1186/s12915-026-02519-5