KLF4 regulates skeletal muscle development and regeneration by directly targeting P57 and Myomixer

• Published in: Cell death & disease Vol. 14; no. 9; p. 612
• Main Authors: Cai, Shufang, Wang, Xiaoyu, Xu, Rong, Liang, Ziyun, Zhu, Qi, Chen, Meilin, Lin, Zhuhu, Li, Chenggan, Duo, Tianqi, Tong, Xian, Li, Enru, He, Zuyong, Liu, Xiaohong, Chen, Yaosheng, Mo, Delin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-09-2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/31; 38/77; 38/79; 42/109; 42/44; 631/136/142; 631/80/641/1655; 64/60; 82/80; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell cycle; Cell differentiation; Cell proliferation; Embryogenesis; Immunology; KLF4 protein; Krueppel-like factor; Life Sciences; Muscle strength; Musculoskeletal system; Myoblasts; Ontogeny; Physical activity; Skeletal muscle; Zinc finger proteins
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-06136-w

Krüppel-like factor 4 (KLF4) is an evolutionarily conserved zinc finger-containing transcription factor that regulates diverse cellular processes such as cell proliferation, apoptosis, and differentiation. Our previous study showed that KLF4 expression is upregulated in skeletal muscle ontogeny during embryonic development in pigs, suggesting its importance for skeletal muscle development and muscle function. We revealed here that KLF4 plays a critical role in skeletal muscle development and regeneration. Specific knockout of KLF4 in skeletal muscle impaired muscle formation further affecting physical activity and also defected skeletal muscle regeneration. In vitro, KLF4 was highly expressed in proliferating myoblasts and early differentiated cells. KLF4 knockdown promoted myoblast proliferation and inhibited myoblast fusion, while its overexpression showed opposite results. Mechanically, in proliferating myoblasts, KLF4 inhibits myoblast proliferation through regulating cell cycle arrest protein P57 by directly targeting its promoter; while in differentiated myoblasts, KLF4 promotes myoblast fusion by transcriptionally activating Myomixer. Our study provides mechanistic information for skeletal muscle development, reduced muscle strength and impaired regeneration after injury and unveiling the mechanism of KLF4 in myogenic regulation.