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Updated: Nov 16, 2025
Comparative Analysis of Experimental Methods to Quantify Animal Activity in Caenorhabditis elegans Models of Mitochondrial Disease
Published on: April 4, 2021
Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model
Rebecca A Ellwood1,2, Jennifer E Hewitt3,4,5, Roberta Torregrossa6
1Medical Research Council (MRC) Versus Arthritis Centre for Musculoskeletal Ageing Research, Royal Derby Hospital, University of Nottingham, Derby DE22 3DT, United Kingdom.
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.
Insights
Hydrogen sulfide (H2S) delivery compounds like NaGYY show promise for treating Duchenne muscular dystrophy (DMD). These treatments improved muscle function and mitochondrial health in a DMD model, suggesting H2S deficiency contributes to DMD.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) involves progressive muscle degeneration linked to dystrophin gene mutations.
- DMD symptoms resemble accelerated aging, and hydrogen sulfide (H2S) plays a role in age-related muscle decline.
- Metabolic H2S deficiencies are implicated in muscle mass reduction in certain conditions.
Purpose of the Study:
- To investigate sodium GYY4137 (NaGYY), an H2S-releasing molecule, as a potential therapeutic for DMD.
- To explore the role of H2S in DMD pathology using a Caenorhabditis elegans model and dystrophin/utrophin knockout mice.
Main Methods:
- Treatment of the dys-1(eg33) Caenorhabditis elegans DMD model with NaGYY (100 µM) and prednisone (370 µM).
- Assessment of movement, strength, gait, and muscle mitochondrial structure.
- Investigated the involvement of JNK-1, SKN-1, SIR-2.1, and DAF-16.
- Tested mitochondria-targeted H2S compound AP39 (100 pM).
- Analyzed sulfide levels and H2S-producing enzymes in dystrophin/utrophin knockout mice.
Main Results:
- NaGYY treatment significantly improved movement, strength, gait, and muscle mitochondrial structure in the DMD model.
- These improvements were comparable to prednisone treatment and required JNK-1, SKN-1, and SIR-2.1.
- DAF-16 was essential for NaGYY benefits but not prednisone.
- Mitochondria-targeted AP39 also enhanced movement and strength, indicating mitochondrial involvement.
- Dystrophin/utrophin knockout mice exhibited reduced sulfide levels and H2S-producing enzymes.
Conclusions:
- H2S deficit may contribute to the pathology of Duchenne muscular dystrophy.
- H2S-releasing compounds, such as NaGYY, demonstrate therapeutic potential for DMD.
- Targeting H2S pathways offers a promising avenue for future DMD treatment strategies.
