Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA.
Department of Anesthesiology, Perioperative Care, and Pain Medicine at New York University Grossman School of Medicine, New York, New York, USA; Department of Cell Biology at New York University Grossman School of Medicine, New York, New York, USA.
J Biol Chem. 2023 Mar;299(3):102978. doi: 10.1016/j.jbc.2023.102978. Epub 2023 Feb 4.
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.
线粒体磷脂心磷脂 (CL) 对于许多重要的生物学过程至关重要，包括线粒体动力学和能量代谢。CL 重塑酶 TAFAZZIN 的突变会导致巴德-希利综合征，这是一种危及生命的遗传疾病，会导致严重的生理缺陷，包括心肌病、骨骼肌病和嗜中性粒细胞减少症。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分析。我们的数据表明，TAZ-KO 细胞中心脏和肌肉发育途径高度降低，与该细胞系中肌生成缺陷的先前报道一致。有趣的是，肌肉转录因子成肌决定蛋白 1 (MyoD1) 在 TAZ-KO 细胞和 TAZ-KO 小鼠心脏中显著受到抑制。MyoD1 的外源性表达挽救了 TAZ-KO 细胞中先前观察到的成肌缺陷。我们的数据表明，MyoD1 的抑制是由 MyoD1 负调节剂同源盒蛋白 Mohawk 的上调和 Wnt 信号的降低引起的。我们的发现首次表明，CL 代谢通过 MyoD1 调节肌肉分化，并确定了 CL 缺乏细胞中 MyoD1 被抑制的机制。
