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<p>Skeletal muscle is a major organ for maintaining whole-body energy balance, yet how it adapts its transcriptional and metabolic programs to environmental cues remains unclear. Here, we report that histone mono-methyltransferase mixed lineage leukemia 4 (MLL4), a key enhancer regulator, directs muscle metabolic adaptation and systemic metabolism through AMPK signaling. Nutrient availability modulates MLL4 expression, and skeletal muscle-specific ablation of MLL4 in male mice protects against diet-induced obesity and improves glucose homeostasis despite reduced exercise endurance. These effects arise from enhanced fuel catabolism caused by marked activation of AMPK in MLL4-depleted muscles. Mechanistically, MLL4 cooperates with myocyte enhancer factor 2 to induce AMP-metabolizing enzymes cytosolic 5’-nucleotidase 1A and AMP-deaminase 3, which suppress AMPK activity. Pharmacologic inhibition of AMP-metabolizing pathway by Pentostatin activates muscle AMPK, confers resistance to obesity and improves metabolic health. These findings identify an enhancer regulator limiting AMPK-mediated muscle fuel catabolism, offering a potential strategy for treating obesity-related disorders.</p>

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Enhancer regulator MLL4 controls skeletal muscle metabolic efficiency by limiting AMPK-mediated fuel catabolism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Likun Yang,
  • Lin Liu,
  • Wen Wang,
  • Chenyun Ding,
  • Aneesh K. Asokan,
  • Tingze Feng,
  • Danxia Zhou,
  • Zhisheng Xu,
  • Tingting Fu,
  • Qiqi Guo,
  • Zheng Zhou,
  • Shaojun Pei,
  • Gonghao Shen,
  • Liwei Xiao,
  • Yujing Yin,
  • Zongchao Sun,
  • Yan Mao,
  • Wanping Sun,
  • Jinjie Li,
  • Jiacheng Xue,
  • Min-Sheng Zhu,
  • Kai Ge,
  • K. Sreekumaran Nair,
  • Hai-Long Piao,
  • Zhenji Gan

摘要

Skeletal muscle is a major organ for maintaining whole-body energy balance, yet how it adapts its transcriptional and metabolic programs to environmental cues remains unclear. Here, we report that histone mono-methyltransferase mixed lineage leukemia 4 (MLL4), a key enhancer regulator, directs muscle metabolic adaptation and systemic metabolism through AMPK signaling. Nutrient availability modulates MLL4 expression, and skeletal muscle-specific ablation of MLL4 in male mice protects against diet-induced obesity and improves glucose homeostasis despite reduced exercise endurance. These effects arise from enhanced fuel catabolism caused by marked activation of AMPK in MLL4-depleted muscles. Mechanistically, MLL4 cooperates with myocyte enhancer factor 2 to induce AMP-metabolizing enzymes cytosolic 5’-nucleotidase 1A and AMP-deaminase 3, which suppress AMPK activity. Pharmacologic inhibition of AMP-metabolizing pathway by Pentostatin activates muscle AMPK, confers resistance to obesity and improves metabolic health. These findings identify an enhancer regulator limiting AMPK-mediated muscle fuel catabolism, offering a potential strategy for treating obesity-related disorders.