Prodh2 inhibition alleviates muscle atrophy and restores strength in COPD mice

In a study examining sarcopenic COPD patients and mouse models, researchers found that the mitochondrial enzyme Prodh2 mediates inflammation-driven muscle wasting. Prodh2 was significantly elevated in both patients and diseased mice. In myoblasts, the inflammatory cytokine TNF-α stimulated Prodh2 transcription through a p53-dependent pathway. Elevated Prodh2 provoked excess mitochondrial reactive oxygen species, triggering the release of mitochondrial DNA into the cytosol. This cytosolic DNA activated the cGAS/STING innate immune pathway, resulting in myoblast apoptosis, proliferation arrest, and cellular atrophy. Knocking down Prodh2 reversed these defects in vitro. Moreover, muscle-specific knockdown of Prodh2 in mice reduced muscle atrophy and restored muscle strength, establishing a metabolic-immune mechanism connecting chronic inflammation to sarcopenia.