文献类型： 外文期刊

作者： Chen, Ming-Ming ¹ ; Zhao, Yue ¹ ; Yu, Kun ¹ ; Xu, Xue-Ling ¹ ; Zhang, Xiao-Sheng ² ; Zhang, Jin-Long ² ; Wu, Su-Jun ¹ ; Liu, Zhi-Mei ¹ ; Yuan, Yi-Ming ¹ ; Guo, Xiao-Fei ² ; Qi, Shi-Yu ¹ ; Yi, Guang ¹ ; Wang, Shu-Qi ¹ ; Li, Huang-Xiang ¹ ; Wu, Ao-Wu ¹ ; Liu, Guo-Shi ¹ ; Deng, Shou-Long ³ ; Han, Hong-Bing ¹ ; Lv, Feng-Hua ¹ ; Lian, Di ⁵ ; Lian, Zheng-Xing ¹ ;

作者机构： 1.China Agr Univ, Coll Anim Sci & Technol, Key Lab Anim Genet & Breeding, State Key Lab Anim Biotech Breeding,Beijing Key L, Beijing, Peoples R China

2.Tianjin Acad Agr Sci, Inst Anim Husb & Vet Med, Tianjin, Peoples R China

3.Chinese Acad Med Sci, Inst Lab Anim Sci, Natl Ctr Technol Innovat Anim model, NHC Key Lab Human Dis Comparat Med, Beijing, Peoples R China

4.Peking Union Med Coll, Comparat Med Ctr, Beijing, Peoples R China

5.Chinese Peoples Liberat Army Gen Hosp, Coll Pulm & Crit Care Med, Beijing, Peoples R China

关键词： MSTN; FGF5; dual-gene biallelic mutation; FOSL1; myogenesis

期刊名称：ELIFE

ISSN： 2050-084X

年卷期： 2024 年 12 卷

页码：

收录情况： SCI

摘要： Mutations in the well-known Myostatin (MSTN) produce a 'double-muscle' phenotype, which makes it commercially invaluable for improving livestock meat production and providing high-quality protein for humans. However, mutations at different loci of the MSTN often produce a variety of different phenotypes. In the current study, we increased the delivery ratio of Cas9 mRNA to sgRNA from the traditional 1:2 to 1:10, which improves the efficiency of the homozygous mutation of biallelic gene. Here, a MSTNDel73C mutation with FGF5 knockout sheep, in which the MSTN and FGF5 dual-gene biallelic homozygous mutations were produced via the deletion of 3-base pairs of AGC in the third exon of MSTN, resulting in cysteine-depleted at amino acid position 73, and the FGF5 double allele mutation led to inactivation of FGF5 gene. The MSTNDel73C mutation with FGF5 knockout sheep highlights a dominant 'double-muscle' phenotype, which can be stably inherited. Both F0 and F1 generation mutants highlight the excellent trait of high-yield meat with a smaller cross-sectional area and higher number of muscle fibers per unit area. Mechanistically, the MSTNDel73C mutation with FGF5 knockout mediated the activation of FOSL1 via the MEK-ERK-FOSL1 axis. The activated FOSL1 promotes skeletal muscle satellite cell proliferation and inhibits myogenic differentiation by inhibiting the expression of MyoD1, and resulting in smaller myotubes. In addition, activated ERK1/2 may inhibit the secondary fusion of myotubes by Ca2+-dependent CaMKII activation pathway, leading to myoblasts fusion to form smaller myotubes.