PDF(Pubmed)
Abstract：
Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation. Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle. VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging. The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.
摘要：
运动训练可以刺激脂肪酸氧化性慢抽搐的骨骼肌纤维的形成,与肥胖呈负相关，但是这种转化的分子机制需要进一步阐明。这里,我们报告说，通过运动训练下调线粒体二硫化物中继载体CHCHD4降低了TP53调节的凋亡抑制剂1（TRIAP1）向线粒体的导入，可以降低心磷脂水平，促进骨骼肌VDAC寡聚化。VDAC低聚,已知促进mtDNA释放，可以激活cGAS-STING/NFKB先天免疫信号并下调骨骼肌中的MyoD，从而促进氧化慢抽搐纤维的形成。在老鼠身上,CHCHD4单倍体不足足以激活该途径，导致氧化性肌纤维增加，脂肪积累随着年龄的增长而减少。调节肌纤维转化的特定介质的鉴定提供了进一步理解复杂代谢病症如肥胖的分子基础的机会,并且可能具有治疗意义。
