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CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise

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 in skeletal muscle by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which reduces cardiolipin levels and promotes VDAC oligomerization. The subsequent release of mtDNA into the cytosol activates innate immune signaling through cGAS and NFKB, downregulating MyoD and promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency was 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE245760 | GEO | 2024/01/04

REPOSITORIES: GEO

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