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

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.

Abstract

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.

Citation

Ellwood, R. A., Hewitt, J. E., Torregrossa, R., Philp, A. M., Hardee, J. P., Hughes, S., …Szewczyk, N. J. (2021). Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model. Proceedings of the National Academy of Sciences, 118(9), Article e2018342118. https://doi.org/10.1073/pnas.2018342118

• Journal Article Type: Article
• Acceptance Date: Jan 6, 2021
• Online Publication Date: Feb 24, 2021
• Publication Date: Mar 2, 2021
• Deposit Date: Feb 25, 2021
• Publicly Available Date: Apr 27, 2021
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 118
• Issue: 9
• Article Number: e2018342118
• DOI: https://doi.org/10.1073/pnas.2018342118
• Public URL: https://nottingham-repository.worktribe.com/output/5349750
• Publisher URL: https://www.pnas.org/content/118/9/e2018342118