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Background <p>The dynamic change of N6-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A modification in ET-related adaptations in high-fat diet (HFD)-induced IR remains unclear.</p> Results <p>In this study, we show that exercise stimulation triggers a dynamic shift in skeletal muscle m<sup>6</sup>A modification levels during HFD consumption. As a key m<sup>6</sup>A methyltransferase, METTL16 was downregulated in HFD-fed mice and upregulated by ET at both the mRNA and protein levels. In vitro, METTL16 knockdown disrupted mitochondrial ultrastructure, reduced electron transport chain complex activities, and decreased the NAD<sup>+</sup>/NADH ratio, ATP content, and mitochondrial membrane potential, indicating impaired mitochondrial function. Concomitantly, METTL16 loss lowered m<sup>6</sup>A on <i>PGC-1α</i> mRNA, reducing its stability and protein abundance and blunting insulin signalling, whereas PGC-1α overexpression partially reversed these defects.</p> Conclusions <p>In conclusion, METTL16 functions as an exercise-responsive m<sup>6</sup>A methyltransferase that may modulate PGC-1α, mitochondrial function, and insulin-related signalling in HFD skeletal muscle, implicating the METTL16-m<sup>6</sup>A-PGC-1α axis in exercise-induced metabolic adaptations.</p>

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METTL16-m6A-PGC-1α axis contributes to exercise-induced mitochondrial adaptations in skeletal muscle of high-fat diet-fed insulin-resistant mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月22日

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  • Cong Chen,
  • Cai Jiang,
  • Qing Xiang,
  • Yue Hu,
  • Huijuan Wu,
  • Chunxiu Huang,
  • Huanghao Zhou,
  • Ying Xu,
  • Meijin Hou,
  • Weilin Liu,
  • Xiao Han

摘要

Background

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.

Results

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 mitochondrial ultrastructure, reduced electron transport chain complex activities, and decreased the NAD+/NADH ratio, ATP content, and mitochondrial membrane potential, indicating impaired mitochondrial function. Concomitantly, METTL16 loss lowered m6A on PGC-1α mRNA, reducing its stability and protein abundance and blunting insulin signalling, whereas PGC-1α overexpression partially reversed these defects.

Conclusions

In conclusion, METTL16 functions as an exercise-responsive m6A methyltransferase that may modulate PGC-1α, mitochondrial function, and insulin-related signalling in HFD skeletal muscle, implicating the METTL16-m6A-PGC-1α axis in exercise-induced metabolic adaptations.