H2S inhibition of xanthine dehydrogenase to xanthine oxidase conversion reduces uric acid levels and improves myoblast functions.

Hydrogen sulfide (H2S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H2S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H2S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H2S at physiologically relevant concentration. In addition, H2S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H2S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H2S-generating enzyme) and suppressed endogenous H2S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H2S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H2S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.