Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model
dc.contributor.author | Ellwood, RA | |
dc.contributor.author | Hewitt, JE | |
dc.contributor.author | Torregrossa, R | |
dc.contributor.author | Philp, AM | |
dc.contributor.author | Hardee, JP | |
dc.contributor.author | Hughes, S | |
dc.contributor.author | van de Klashorst, D | |
dc.contributor.author | Gharahdaghi, N | |
dc.contributor.author | Anupom, T | |
dc.contributor.author | Slade, L | |
dc.contributor.author | Deane, CS | |
dc.contributor.author | Cooke, M | |
dc.contributor.author | Etheridge, T | |
dc.contributor.author | Piasecki, M | |
dc.contributor.author | Antebi, A | |
dc.contributor.author | Lynch, GS | |
dc.contributor.author | Philp, A | |
dc.contributor.author | Vanapalli, SA | |
dc.contributor.author | Whiteman, M | |
dc.contributor.author | Szewczyk, NJ | |
dc.date.accessioned | 2021-03-03T09:20:20Z | |
dc.date.issued | 2021-02-24 | |
dc.description.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. | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | NASA | en_GB |
dc.description.sponsorship | Biotechnology and Biological Sciences Research Council (BBSRC) | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | United Mitochondrial Disease Foundation | en_GB |
dc.description.sponsorship | MRC Versus Arthritis Centre for Musculoskeletal Ageing Research | en_GB |
dc.description.sponsorship | National Health and Medical Research Council | en_GB |
dc.description.sponsorship | University of Nottingham School of Medicine | en_GB |
dc.description.sponsorship | Fulbright U.S. Student Program | en_GB |
dc.description.sponsorship | Germanistic Society of America | en_GB |
dc.description.sponsorship | Brian Ridge Scholarship | en_GB |
dc.description.sponsorship | University of Exeter | en_GB |
dc.description.sponsorship | University of New South Wales | en_GB |
dc.description.sponsorship | University of Melbourne | en_GB |
dc.description.sponsorship | Rebecca L. Cooper Medical Research Foundation | en_GB |
dc.description.sponsorship | Osteopathic Heritage Foundation | en_GB |
dc.identifier.citation | Vol. 118, No. 9, article e2018342118 | en_GB |
dc.identifier.doi | 10.1073/pnas.2018342118 | |
dc.identifier.grantnumber | MR/T026014/1 | en_GB |
dc.identifier.grantnumber | NNX15AL16G | en_GB |
dc.identifier.grantnumber | BB/N015894/1 | en_GB |
dc.identifier.grantnumber | MR/S002626/1 | en_GB |
dc.identifier.grantnumber | PI-19-0985 | en_GB |
dc.identifier.grantnumber | MR/P021220/1 | en_GB |
dc.identifier.grantnumber | MR/R502364/1 | en_GB |
dc.identifier.grantnumber | GNT1124474 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/124987 | |
dc.language.iso | en | en_GB |
dc.publisher | National Academy of Sciences | en_GB |
dc.rights | © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). | en_GB |
dc.subject | C. elegans | en_GB |
dc.subject | muscle | en_GB |
dc.subject | mitochondria | en_GB |
dc.subject | hydrogen sulfide | en_GB |
dc.subject | mouse | en_GB |
dc.title | Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2021-03-03T09:20:20Z | |
dc.identifier.issn | 0027-8424 | |
dc.description | This is the final version. Available on open access from the National Academy of Sciences via the DOI in this record. | en_GB |
dc.description | Data Availability: All study data are included in the article. | en_GB |
dc.identifier.journal | Proceedings of the National Academy of Sciences | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2021-01-06 | |
exeter.funder | ::Medical Research Council (MRC) | en_GB |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2021-02-24 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2021-03-03T09:06:57Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2021-03-03T09:20:27Z | |
refterms.panel | C | en_GB |
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Except where otherwise noted, this item's licence is described as © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).