GYY4137, a Slow-Releasing Hydrogen Sulfide Donor, Attenuates Skeletal Muscle Abnormalities in a Murine Model of Duchenne Muscular Dystrophy

<b><i>Aims:</i></b> Duchenne muscular dystrophy (DMD) is a severe, incurable X-linked genetic disorder caused by mutations in the <i>DMD</i> gene, leading to a deficiency of the muscle structural protein, dystrophin, which results in damage to skeletal and cardiac muscles. Altered expression of enzymes that generate hydrogen sulfide (H₂S) has been demonstrated in dystrophic muscles, however, the exact role of this gasotransmitter in DMD remains elusive. Here, we investigated the effect of the slow-releasing H₂S donor (GYY4137) on the skeletal muscles of the dystrophin-deficient <i>mdx</i> mice. <b><i>Methods and Results:</i></b> Grip strength assay and the treadmill exhaustion test showed that administering the GYY4137 donor to <i>mdx</i> mice improved DMD-related decline in motor functions. Additionally, the H₂S donor decreased the level of muscle damage markers such as lactate dehydrogenase, creatine kinase, and osteopontin (OPN). Histological, gene, and protein analyses of the dystrophic gastrocnemius and diaphragm muscles revealed reduced inflammation and fibrosis after treatment with the H₂S donor. Moreover, we showed decreased necrosis with improved muscle regeneration and angiogenesis. We demonstrated that GYY4137 upregulates the levels of phosphorylated AMPKα, as well as the cytoprotective and antioxidant heme oxygenase-1, mitochondrial superoxide dismutase, and glutamate-cysteine ligase modifier subunit (<i>Gclm</i>). Finally, it exerted an anti-apoptotic effect by reducing cleaved caspase-3 and caspase-3 and increasing AKT phosphorylation. <b><i>Innovation and Conclusion:</i></b> The administration of GYY4137 improves exercise capacity and ameliorates the markers of inflammation, fibrosis, oxidative stress, apoptosis, and necrosis in the skeletal muscles of <i>mdx</i> animals pointing out its possible therapeutic use in DMD pathology. <i>Antioxid. Redox Signal.</i> 43, 115-137.