Universität zu Köln

Ellwood, Rebecca A., Hewitt, Jennifer E., Torregrossa, Roberta, Philp, Ashleigh M., Hardee, Justin P., Hughes, Samantha ORCID: 0000-0001-8447-2563, van de Klashorst, David, Gharahdaghi, Nima, Anupom, Taslim ORCID: 0000-0001-8944-9004, Slade, Luke ORCID: 0000-0001-7660-7392, Deane, Colleen S., Cooke, Michael, Etheridge, Timothy ORCID: 0000-0002-3588-8711, Piasecki, Mathew ORCID: 0000-0002-7804-4631, Antebi, Adam, Lynch, Gordon S., Philp, Andrew, Vanapalli, Siva A., Whiteman, Matthew ORCID: 0000-0002-6583-6779 and Szewczyk, Nathaniel J. (2021). Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model. Proc. Natl. Acad. Sci. U. S. A., 118 (9). WASHINGTON: NATL ACAD SCIENCES. ISSN 1091-6490

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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 mu M) improved movement, strength, gait, and muscle mitochondrial structure, similar to the gold-standard therapeutic treatment, prednisone (370 mu M). 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ellwood, Rebecca A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hewitt, Jennifer E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Torregrossa, Roberta UNSPECIFIED UNSPECIFIED UNSPECIFIED Philp, Ashleigh M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hardee, Justin P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hughes, Samantha UNSPECIFIED orcid.org/0000-0001-8447-2563 UNSPECIFIED van de Klashorst, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Gharahdaghi, Nima UNSPECIFIED UNSPECIFIED UNSPECIFIED Anupom, Taslim UNSPECIFIED orcid.org/0000-0001-8944-9004 UNSPECIFIED Slade, Luke UNSPECIFIED orcid.org/0000-0001-7660-7392 UNSPECIFIED Deane, Colleen S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cooke, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Etheridge, Timothy UNSPECIFIED orcid.org/0000-0002-3588-8711 UNSPECIFIED Piasecki, Mathew UNSPECIFIED orcid.org/0000-0002-7804-4631 UNSPECIFIED Antebi, Adam UNSPECIFIED UNSPECIFIED UNSPECIFIED Lynch, Gordon S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Philp, Andrew UNSPECIFIED UNSPECIFIED UNSPECIFIED Vanapalli, Siva A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Whiteman, Matthew UNSPECIFIED orcid.org/0000-0002-6583-6779 UNSPECIFIED Szewczyk, Nathaniel J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-600729
DOI:	10.1073/pnas.2018342118
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	118
Number:	9
Date:	2021
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	1091-6490
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CAENORHABDITIS-ELEGANS; MUSCLE DEGENERATION; STRESS RESPONSES; BK CHANNEL; INTEGRITY; MYOPATHIES; DONOR; ONSET; TIME; AP39 Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60072