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<p>Skeletal muscle fiber-type composition is key determinant of systemic metabolism and health. However, how fiber-type-specific gene expression patterns are established and maintained to specify myofiber identity remains unclear. Here we show that BRD4 is a crucial regulator for muscle fiber identity and metabolism. In humans, <i>BRD4</i> expression correlates with muscle contractile properties, and is notably altered in individuals with obesity. In mice, HFD feeding elevates BRD4 protein levels, preceding body weight changes, while muscle-specific <i>Brd4</i> deletion induces a slow-oxidative fiber shift, enhances energy expenditure, and protects against diet-induced obesity and insulin resistance. Mechanistically, BRD4 cooperates with MEF2 and CHD4 to regulate fast-twitch myofiber gene expression. CHD4 deletion mirrors the metabolic benefits seen with BRD4 loss. Importantly, BRD4 inhibition with JQ1 replicates these effects in mice and human myotubes. These findings establish BRD4 axis as a critical determinant of myofiber identity and metabolism, offering a potential therapeutic strategy for metabolic disorders.</p>

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BRD4 directs myofiber identity and metabolic adaptation through CHD4 cooperation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月9日

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  • Zheng Zhou,
  • Lin Liu,
  • Zhisheng Xu,
  • Danxia Zhou,
  • Anqi Liu,
  • Jiachen Yuan,
  • Gonghao Shen,
  • Qiqi Guo,
  • Yujing Yin,
  • Yan Mao,
  • Wanping Sun,
  • Liwei Xiao,
  • Cheng Lv,
  • Abdukahar Kiram,
  • Likun Yang,
  • Yuhuan Jia,
  • Lu Ke,
  • Lei Fang,
  • Weiqin Li,
  • Tingting Fu,
  • Zhenji Gan

摘要

Skeletal muscle fiber-type composition is key determinant of systemic metabolism and health. However, how fiber-type-specific gene expression patterns are established and maintained to specify myofiber identity remains unclear. Here we show that BRD4 is a crucial regulator for muscle fiber identity and metabolism. In humans, BRD4 expression correlates with muscle contractile properties, and is notably altered in individuals with obesity. In mice, HFD feeding elevates BRD4 protein levels, preceding body weight changes, while muscle-specific Brd4 deletion induces a slow-oxidative fiber shift, enhances energy expenditure, and protects against diet-induced obesity and insulin resistance. Mechanistically, BRD4 cooperates with MEF2 and CHD4 to regulate fast-twitch myofiber gene expression. CHD4 deletion mirrors the metabolic benefits seen with BRD4 loss. Importantly, BRD4 inhibition with JQ1 replicates these effects in mice and human myotubes. These findings establish BRD4 axis as a critical determinant of myofiber identity and metabolism, offering a potential therapeutic strategy for metabolic disorders.