线粒体磷脂心磷脂(CL)对于许多基本的生物过程至关重要,包括线粒体动力学和能量代谢。CL重塑酶TAFAZZIN的突变引起Barth综合征(BTHS),导致严重生理缺陷的危及生命的遗传疾病,包括心肌病,骨骼肌病,和中性粒细胞减少症.为了研究CL缺乏导致骨骼肌病的分子机制,我们对TAFAZZIN敲除(TAZ-KO)小鼠成肌细胞C2C12细胞系进行了转录组学分析。我们的数据表明,TAZ-KO细胞中的心脏和肌肉发育途径高度减少,与以前关于该细胞系中肌生成缺陷的报道一致。有趣的是,在TAZ-KO细胞和TAZ-KO小鼠心脏中,肌肉转录因子成肌细胞决定蛋白1(MyoD1)被显着抑制。MyoD1的外源表达挽救了先前在TAZ-KO细胞中观察到的肌生成缺陷。我们的数据表明,MyoD1抑制是由MyoD1负调节因子的上调引起的,同源盒蛋白莫霍克(MKX),和减少的Wnt信号。我们的发现显示,第一次,CL代谢通过MyoD1调节肌肉分化,并确定了在CL缺陷细胞中抑制MyoD1的机制。
The mitochondrial phospholipid cardiolipin (CL) is critical for numerous essential biological processes, including mitochondrial dynamics and energy metabolism. Mutations in the CL remodeling enzyme TAFAZZIN cause Barth syndrome, a life-threatening genetic disorder that results in severe physiological defects, including cardiomyopathy, skeletal myopathy, and neutropenia. To study the molecular mechanisms whereby CL deficiency leads to skeletal myopathy, we carried out transcriptomic analysis of the TAFAZZIN-knockout (TAZ-KO) mouse myoblast C2C12 cell line. Our data indicated that cardiac and muscle development pathways are highly decreased in TAZ-KO cells, consistent with a previous report of defective myogenesis in this cell line. Interestingly, the muscle transcription factor myoblast determination protein 1 (
MyoD1) is significantly repressed in TAZ-KO cells and TAZ-KO mouse hearts. Exogenous expression of
MyoD1 rescued the myogenesis defects previously observed in TAZ-KO cells. Our data suggest that
MyoD1 repression is caused by upregulation of the
MyoD1 negative regulator, homeobox protein Mohawk, and decreased Wnt signaling. Our findings reveal, for the first time, that CL metabolism regulates muscle differentiation through
MyoD1 and identify the mechanism whereby
MyoD1 is repressed in CL-deficient cells.