Prodh2‐Mediated Mitochondrial Stress Drives TNF ‐α‐Induced Myoblast Dysfunction and Sarcopenia in COPD

Sarcopenia in chronic obstructive pulmonary disease (COPD) is driven by elevated tumor necrosis factor-alpha (TNF-α), yet the underlying mechanism remains unclear. Here, we identify the mitochondrial metabolic enzyme Prodh2 as a pivotal mediator. Prodh2 was significantly upregulated in sarcopenic COPD patients and a corresponding mouse model. Mechanistically, TNF-α induced Prodh2 transcription in myoblasts via a p53-dependent pathway. This upregulation triggered excessive mitochondrial reactive oxygen species, leading to the release of mitochondrial DNA (mtDNA). Cytosolic mtDNA subsequently activated the cGAS/STING innate immune pathway, causing myoblast apoptosis, proliferation arrest, and atrophy. While Prodh2 knockdown reversed these effects in vitro, muscle-specific knockdown of Prodh2 in vivo critically ameliorated muscle atrophy and restored strength. Our study unveils a novel TNF-α-p53-Prodh2-cGAS/STING axis that links chronic inflammation to sarcopenia through metabolic-immune crosstalk, validating Prodh2 as a promising therapeutic target.