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<p>Skeletal muscles are composed of multinucleated fibers with distinct metabolic and contractile properties. Skeletal muscles support locomotion and systemic metabolism, and their dysfunction underlies the pathogenesis of muscular dystrophies. The MyoD family inhibitor (Mdfi) has been implicated in muscle biology, yet its function in muscle development and muscle fiber type conversion remains largely unclear. Here, we developed the first tamoxifen (TMX)-inducible, skeletal muscle-specific Mdfi overexpression mouse model using CRISPR/Cas9 and Cre<sup>ERT2</sup> integration, enabling spatiotemporal control of Mdfi activity to mimic therapeutic modulation. This model revealed that Mdfi exerts dual-phase regulatory roles: suppressing early postnatal myogenesis while driving glycolytic-to-oxidative fiber switching in mature muscle. Mechanistically, elevated Mdfi activates the calcium signaling pathway to enhance mitochondrial oxidative phosphorylation, directly linking its function to improved muscle fatigue resistance. These Mdfi overexpression-induced phenotypic alterations exhibit stable transgenerational inheritance patterns. Our findings establish Mdfi as a key regulator of muscle plasticity and metabolic adaptation, providing a genetically tractable model for investigating muscle development and energy metabolism. Importantly, this study opens new avenues for understanding and potentially modulating fiber-type composition in muscular dystrophies and other disorders involving metabolic insufficiency, offering a conceptual framework for future therapeutic interventions aimed at improving muscle health.</p>

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Mdfi overexpression promotes oxidative muscle fiber formation without affecting muscle development in mature skeletal muscles

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月1日

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  • Tingting Lu,
  • Xulong Liu,
  • Chao Wang,
  • Bo Huang,
  • Ziyuan Mo,
  • Jiali Guo,
  • Xuezhu Gong,
  • Yifan Zhu,
  • Xiong Tong,
  • Ching Yuan Hu,
  • Chong Wang

摘要

Skeletal muscles are composed of multinucleated fibers with distinct metabolic and contractile properties. Skeletal muscles support locomotion and systemic metabolism, and their dysfunction underlies the pathogenesis of muscular dystrophies. The MyoD family inhibitor (Mdfi) has been implicated in muscle biology, yet its function in muscle development and muscle fiber type conversion remains largely unclear. Here, we developed the first tamoxifen (TMX)-inducible, skeletal muscle-specific Mdfi overexpression mouse model using CRISPR/Cas9 and CreERT2 integration, enabling spatiotemporal control of Mdfi activity to mimic therapeutic modulation. This model revealed that Mdfi exerts dual-phase regulatory roles: suppressing early postnatal myogenesis while driving glycolytic-to-oxidative fiber switching in mature muscle. Mechanistically, elevated Mdfi activates the calcium signaling pathway to enhance mitochondrial oxidative phosphorylation, directly linking its function to improved muscle fatigue resistance. These Mdfi overexpression-induced phenotypic alterations exhibit stable transgenerational inheritance patterns. Our findings establish Mdfi as a key regulator of muscle plasticity and metabolic adaptation, providing a genetically tractable model for investigating muscle development and energy metabolism. Importantly, this study opens new avenues for understanding and potentially modulating fiber-type composition in muscular dystrophies and other disorders involving metabolic insufficiency, offering a conceptual framework for future therapeutic interventions aimed at improving muscle health.