Mdfi overexpression promotes oxidative muscle fiber formation without affecting muscle development in mature skeletal muscles.
6 affiliations
- 1National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Laboratory for Lingnan Modern Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong, China.
- 2Heyuan Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Heyuan, Heyuan, 517000, China.
- 3State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong, China.
- 4Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, 510640, China.
- 5Department of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, Honolulu, HI, 96822, USA.
- 6National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Laboratory for Lingnan Modern Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong, China. [email protected].
Abstract
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.
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BibTeX
@article{lu2026mdfi,
title = {{Mdfi overexpression promotes oxidative muscle fiber formation without affecting muscle development in mature skeletal muscles.}},
author = {Tingting Lu and Xulong Liu and Chao Wang and Bo Huang and Ziyuan Mo and Jiali Guo and Xuezhu Gong and Yifan Zhu and Xiong Tong and Ching Yuan Hu and Chong Wang},
journal = {Cellular and molecular life sciences : CMLS},
year = {2026},
month = aug,
doi = {10.1007/s00018-026-06279-x},
url = {https://europepmc.org/article/MED/42955098},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Mdfi overexpression promotes oxidative muscle fiber formation without affecting muscle development in mature skeletal muscles.
AU - Tingting Lu
AU - Xulong Liu
AU - Chao Wang
AU - Bo Huang
AU - Ziyuan Mo
AU - Jiali Guo
AU - Xuezhu Gong
AU - Yifan Zhu
AU - Xiong Tong
AU - Ching Yuan Hu
AU - Chong Wang
PY - 2026
DA - 2026/08/01
JO - Cellular and molecular life sciences : CMLS
DO - 10.1007/s00018-026-06279-x
UR - https://europepmc.org/article/MED/42955098
AB - 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.
SN - 1420-682X
SN - 1420-9071
ER -