ERRγ 促进 PGC1α/β 缺陷肌肉中的血管生成、线粒体生物发生和氧化重塑。
ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle.
机构信息
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
出版信息
Cell Rep. 2018 Mar 6;22(10):2521-2529. doi: 10.1016/j.celrep.2018.02.047.
PGC1α is a pleiotropic co-factor that affects angiogenesis, mitochondrial biogenesis, and oxidative muscle remodeling via its association with multiple transcription factors, including the master oxidative nuclear receptor ERRγ. To decipher their epistatic relationship, we explored ERRγ gain of function in muscle-specific PGC1α/β double-knockout (PKO) mice. ERRγ-driven transcriptional reprogramming largely rescues muscle damage and improves muscle function in PKO mice, inducing mitochondrial biogenesis, antioxidant defense, angiogenesis, and a glycolytic-to-oxidative fiber-type transformation independent of PGC1α/β. Furthermore, in combination with voluntary exercise, ERRγ gain of function largely restores mitochondrial energetic deficits in PKO muscle, resulting in a 5-fold increase in running performance. Thus, while PGC1s can interact with multiple transcription factors, these findings implicate ERRs as the major molecular target through which PGC1α/β regulates both innate and adaptive energy metabolism.
PGC1α 是一种多效共因子，通过与多个转录因子（包括主要的氧化核受体 ERRγ）结合，影响血管生成、线粒体生物发生和氧化肌肉重塑。为了解析它们的上位性关系，我们探索了肌肉特异性 PGC1α/β 双敲除（PKO）小鼠中 ERRγ 的功能获得。ERRγ 驱动的转录重编程在很大程度上挽救了 PKO 小鼠的肌肉损伤并改善了肌肉功能，诱导了线粒体生物发生、抗氧化防御、血管生成以及与 PGC1α/β 无关的糖酵解到氧化纤维型转变。此外，与自愿运动相结合，ERRγ 的功能获得在很大程度上恢复了 PKO 肌肉中的线粒体能量缺陷，导致跑步性能提高了 5 倍。因此，虽然 PGC1s 可以与多个转录因子相互作用，但这些发现表明 ERRs 是 PGC1α/β 调节先天和适应性能量代谢的主要分子靶标。
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