Mitochondrial hydrogen sulfide supplementation improves health in the Duchenne muscular dystrophy model.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle degeneration and weakness due to mutations in the dystrophin gene. The symptoms of DMD share similarities with those of accelerated aging. Recently, hydrogen sulfide (HS) supplementation has been suggested to modulate the effects of age-related decline in muscle function, and metabolic HS deficiencies have been implicated in affecting muscle mass in conditions such as phenylketonuria. We therefore evaluated the use of sodium GYY4137 (NaGYY), a HS-releasing molecule, as a possible approach for DMD treatment. Using the 33 DMD model, we found that NaGYY treatment (100 µM) improved movement, strength, gait, and muscle mitochondrial structure, similar to the gold-standard therapeutic treatment, prednisone (370 µM). The health improvements of either treatment required the action of the kinase JNK-1, the transcription factor SKN-1, and the NAD-dependent deacetylase SIR-2.1. The transcription factor DAF-16 was required for the health benefits of NaGYY treatment, but not prednisone treatment. AP39 (100 pM), a mitochondria-targeted HS compound, also improved movement and strength in the 33 model, further implying that these improvements are mitochondria-based. Additionally, we found a decline in total sulfide and HS-producing enzymes in dystrophin/utrophin knockout mice. Overall, our results suggest that HS deficit may contribute to DMD pathology, and rectifying/overcoming the deficit with HS delivery compounds has potential as a therapeutic approach to DMD treatment.