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

Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model
Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans 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 (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.
0027-8424
Ellwood, Rebecca A.
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Hewitt, Jennifer E.
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Torregrossa, Roberta
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Philp, Ashleigh M.
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Hardee, Justin P.
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Hughes, Samantha
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van de Klashorst, David
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Gharahdaghi, Nima
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Anupom, Taslim
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Slade, Luke
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Deane, Colleen S.
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Cooke, Michael
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Etheridge, Timothy
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Philp, Andrew
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Vanapalli, Siva A.
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Whiteman, Matthew
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Szewczyk, Nathaniel
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Ellwood, Rebecca A.
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Hewitt, Jennifer E.
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Torregrossa, Roberta
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Philp, Ashleigh M.
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Hardee, Justin P.
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Hughes, Samantha
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van de Klashorst, David
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Gharahdaghi, Nima
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Anupom, Taslim
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Slade, Luke
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Deane, Colleen S.
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Cooke, Michael
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Etheridge, Timothy
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Piasecki, Mathew
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Antebi, Adam
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Lynch, Gordon S.
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Philp, Andrew
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Vanapalli, Siva A.
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Whiteman, Matthew
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Szewczyk, Nathaniel
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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 and Szewczyk, Nathaniel (2021) Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model. Proceedings of the National Academy of Sciences of the United States of America, 118 (9), [e2018342118]. (doi:10.1073/pnas.2018342118).

Record type: Article

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.

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Accepted/In Press date: 6 January 2021
e-pub ahead of print date: 24 February 2021
Published date: 2 March 2021

Identifiers

Local EPrints ID: 483348
URI: http://eprints.soton.ac.uk/id/eprint/483348
ISSN: 0027-8424
PURE UUID: 11dca04b-421a-4f23-bba3-ecd56a0174a8
ORCID for Colleen S. Deane: ORCID iD orcid.org/0000-0002-2281-6479

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Date deposited: 30 Oct 2023 07:58
Last modified: 17 Mar 2024 04:15

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Contributors

Author: Rebecca A. Ellwood
Author: Jennifer E. Hewitt
Author: Roberta Torregrossa
Author: Ashleigh M. Philp
Author: Justin P. Hardee
Author: Samantha Hughes
Author: David van de Klashorst
Author: Nima Gharahdaghi
Author: Taslim Anupom
Author: Luke Slade
Author: Colleen S. Deane ORCID iD
Author: Michael Cooke
Author: Timothy Etheridge
Author: Mathew Piasecki
Author: Adam Antebi
Author: Gordon S. Lynch
Author: Andrew Philp
Author: Siva A. Vanapalli
Author: Matthew Whiteman
Author: Nathaniel Szewczyk

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