CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise
Jin Ma,
Ping-yuan Wang,
Jie Zhuang,
Annie Y. Son,
Alexander K. Karius,
Abu Mohammad Syed,
Masahiro Nishi,
Zhichao Wu,
Mateus P. Mori,
Young-Chae Kim,
Paul M. Hwang
Affiliations
Jin Ma
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Ping-yuan Wang
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Jie Zhuang
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA; School of Medicine, Nankai University, Tianjin 300071, China
Annie Y. Son
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Alexander K. Karius
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Abu Mohammad Syed
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Masahiro Nishi
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Zhichao Wu
Laboratory of Pathology, National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA
Mateus P. Mori
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Young-Chae Kim
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA
Paul M. Hwang
Cardiovascular Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA; Corresponding author
Summary: 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.
