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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 9; pp. 1 - 12
• Main Authors: Ellwood, Rebecca A., Hewitt, Jennifer E., Torregrossa, Roberta, Philp, Ashleigh M., Hardee, Justin P., Hughes, Samantha, van de Klashorst, David, Gharahdaghi, Nima, Anupom, Taslim, Slade, Luke, Deane, Colleen S., Cooke, Michael, Etheridge, Timothy, Piasecki, Mathew, Antebi, Adam, Lynch, Gordon S., Philp, Andrew, Vanapalli, Siva A., Whiteman, Matthew, Szewczyk, Nathaniel J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02-03-2021
• Subjects: Animals; Biological Sciences; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Dystrophin - deficiency; Dystrophin - genetics; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation; Humans; Hydrogen Sulfide - metabolism; Hydrogen Sulfide - pharmacology; Locomotion - drug effects; Locomotion - genetics; Male; Mice; Mice, Inbred mdx; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - pathology; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Morpholines - metabolism; Morpholines - pharmacology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophy, Animal - drug therapy; Muscular Dystrophy, Animal - genetics; Muscular Dystrophy, Animal - metabolism; Muscular Dystrophy, Animal - pathology; Muscular Dystrophy, Duchenne - drug therapy; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - pathology; Organophosphorus Compounds - metabolism; Organophosphorus Compounds - pharmacology; Organothiophosphorus Compounds - metabolism; Organothiophosphorus Compounds - pharmacology; Prednisone - pharmacology; Sirtuins - genetics; Sirtuins - metabolism; Thiones - metabolism; Thiones - pharmacology; Transcription Factors - genetics; Transcription Factors - metabolism; Utrophin - deficiency; Utrophin - genetics; mouse; C. elegans; hydrogen sulfide; mitochondria; muscle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2018342118

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 (H₂S) supplementation has been suggested to modulate the effects of age-related decline in muscle function, and metabolic H2S deficiencies have been implicated in affecting muscle mass in conditions such as phenylketonuria. We therefore evaluated the use of sodium GYY4137 (NaGYY), a H₂S-releasing molecule, as a possible approach for DMD treatment. Using the dys-1(eg33) Caenorhabditis elegans 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 H₂S compound, also improved movement and strength in the dys-1(eg33) model, further implying that these improvements are mitochondria-based. Additionally, we found a decline in total sulfide and H₂S-producing enzymes in dystrophin/utrophin knockout mice. Overall, our results suggest that H₂S deficit may contribute to DMD pathology, and rectifying/overcoming the deficit with H₂S delivery compounds has potential as a therapeutic approach to DMD treatment.