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

Abstract

ABSTRACT 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.