Xia Wei, Qiu Jiamin, Peng Ying, Snyder Madigan M, Gu Lijie, Huang Kuilong, Luo Nanjian, Yue Feng, Kuang Shihuan
College of Animal Science and Technology, Hebei Agricultural University, Baoding, 071000, China.
Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
Cell Regen. 2022 Apr 1;11(1):14. doi: 10.1186/s13619-022-00111-0.
The Chchd10 gene encodes a coiled-coil-helix-coiled-coil-helix-domain containing protein predicted to function in the mitochondrion and nucleus. Mutations of Chchd10 are associated with ALS, dementia and myopathy in humans and animal models, but how knockout of Chchd10 (Chchd10) affects various tissues especially skeletal muscle and adipose tissues remains unclear. Here we show that Chchd10 expression increases as myoblasts and preadipocytes differentiate. During myogenesis, CHCHD10 interacts with TAR DNA binding protein 43 (TDP-43) in regenerating myofibers in vivo and in newly differentiated myotubes ex vivo. Surprisingly, Chchd10 mice had normal skeletal muscle development, growth and regeneration, with moderate defects in grip strength and motor performance. Chchd10 similarly had no effects on development of brown and white adipose tissues (WAT). However, Chchd10 mice had blunted response to acute cold and attenuated cold-induced browning of WAT, with markedly reduced UCP1 levels. Together, these results demonstrate that Chchd10 is dispensable for normal myogenesis and adipogenesis but is required for normal motility and cold-induced, mitochondrion-dependent browning of adipocytes. The data also suggest that human CHCHD10 mutations cause myopathy through a gain-of-function mechanism.
Chchd10基因编码一种含有卷曲螺旋-螺旋-卷曲螺旋-螺旋结构域的蛋白质，预计其在线粒体和细胞核中发挥作用。Chchd10的突变与人类和动物模型中的肌萎缩侧索硬化症、痴呆症和肌病有关，但Chchd10基因敲除（Chchd10−/−）如何影响各种组织，尤其是骨骼肌和脂肪组织仍不清楚。在这里，我们表明Chchd10的表达随着成肌细胞和前脂肪细胞的分化而增加。在肌肉生成过程中，CHCHD10在体内再生肌纤维和体外新分化的肌管中与TAR DNA结合蛋白43（TDP-43）相互作用。令人惊讶的是，Chchd10−/−小鼠的骨骼肌发育、生长和再生正常，但握力和运动性能存在中度缺陷。Chchd10−/−同样对棕色和白色脂肪组织（WAT）的发育没有影响。然而，Chchd10−/−小鼠对急性寒冷的反应减弱，WAT的冷诱导褐变减弱，UCP1水平明显降低。总之，这些结果表明，Chchd10对于正常的肌肉生成和脂肪生成是可有可无的，但对于正常的运动能力以及冷诱导的、线粒体依赖性的脂肪细胞褐变是必需的。数据还表明，人类CHCHD10突变通过功能获得机制导致肌病。
