FHL3 promotes the formation of fast glycolytic muscle fibers by interacting with YY1 and muscle glycolytic metabolism

被引:15
作者
Bai, Wei [1 ,2 ,3 ]
Zhang, Yunxia [4 ]
Ma, Jun [1 ,2 ,3 ]
Du, Mengmeng [1 ,2 ]
Xu, Haiyang [1 ,2 ]
Wang, Jian [1 ,2 ]
Zhang, Lu [1 ,2 ]
Li, Wentao [1 ,2 ]
Hou, Yunqing [1 ,2 ]
Liu, Xiaomeng [4 ,5 ]
Zhang, Xinyue [4 ]
Peng, Yaxin [1 ,2 ]
Li, Jianan [1 ,2 ]
Zhan, Xizhen [1 ,2 ]
Jiang, Wei [1 ,2 ]
Liu, Shengsi [1 ,2 ]
Liu, Xiao [1 ,2 ]
Li, Qinying [1 ,2 ]
Miao, Yang [1 ,2 ]
Sui, Mengru [4 ]
Yang, Yuhan [4 ]
Zhang, Shenghao [1 ]
Xu, Zaiyan [1 ,6 ]
Zuo, Bo [1 ,2 ,3 ]
机构
[1] Huazhong Agr Univ, Coll Anim Sci & Technol, Key Lab Swine Genet & Breeding, Minist Agr & Rural Affairs, Wuhan, Peoples R China
[2] Huazhong Agr Univ, Key Lab Agr Anim Genet Breeding & Reprod, Minist Educ, Wuhan, Peoples R China
[3] Hubei Hongshan Lab, Wuhan, Peoples R China
[4] Zhoukou Normal Univ, Inst Neurosci & Translat Med, Coll Life Sci & Agron, Zhoukou, Peoples R China
[5] Xinxiang Med Univ, Coll Publ Hlth, Dept Nutr & Food Hyg, Xinxiang 453003, Henan, Peoples R China
[6] Huazhong Agr Univ, Coll Vet Med, Dept Basic Vet Med, Wuhan, Peoples R China
基金
中国国家自然科学基金;
关键词
FHL3; Muscle fiber type; Glycolytic metabolism; YY1; EZH2; SKELETAL-MUSCLE; INSULIN-RESISTANCE; GENE-EXPRESSION; SLOW; MEAT; OVEREXPRESSION; ACTIVATION; CONVERSION; QUALITY; OBESITY;
D O I
10.1007/s00018-022-04680-w
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The proportions of the various muscle fiber types are important in the regulation of skeletal muscle metabolism, as well as animal meat production. Four-and-a-half LIM domain protein 3 (FHL3) is highly expressed in fast glycolytic muscle fibers and differentially regulates the expression of myosin heavy chain (MyHC) isoforms at the cellular level. Whether FHL3 regulates the transformation of muscle fiber types in vivo and the regulatory mechanism is unclear. In this study, muscle-specific FHL3 transgenic mice were generated by random integration, and lentivirus-mediated gene knockdown or overexpression in muscles of mice or pigs was conducted. Functional analysis showed that overexpression of FHL3 in muscles significantly increased the proportion of fast-twitch myofibers and muscle mass but decreased muscle succinate dehydrogenase (SDH) activity and whole-body oxygen consumption. Lentivirus-mediated FHL3 knockdown in muscles significantly decreased muscle mass and the proportion of fast-twitch myofibers. Mechanistically, FHL3 directly interacted with the Yin yang 1 (YY1) DNA-binding domain, repressed the binding of YY1 to the fast glycolytic MyHC2b gene regulatory region, and thereby promoted MyHC2b expression. FHL3 also competed with EZH2 to bind the repression domain of YY1 and reduced H3K27me3 enrichment in the MyHC2b regulatory region. Moreover, FHL3 overexpression reduced glucose tolerance by affecting muscle glycolytic metabolism, and its mRNA expression in muscle was positively associated with hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Therefore, FHL3 is a novel potential target gene for the treatment of muscle metabolism-related diseases and improvement of animal meat production.
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页数:24
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