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

This is the final version. Available on open access from the National Academy of Sciences via the DOI in this record. Data Availability: All study data are included in the article.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.Medical Research Council (MRC)NASABiotechnology and Biological Sciences Research Council (BBSRC)Medical Research Council (MRC)United Mitochondrial Disease FoundationMRC Versus Arthritis Centre for Musculoskeletal Ageing ResearchNational Health and Medical Research CouncilUniversity of Nottingham School of MedicineFulbright U.S. Student ProgramGermanistic Society of AmericaBrian Ridge ScholarshipUniversity of ExeterUniversity of New South WalesUniversity of MelbourneRebecca L. Cooper Medical Research FoundationOsteopathic Heritage Foundatio

Inter-population differences in the tolerance of a marsupial\ud folivore to plant secondary metabolites

Plant secondary metabolites (PSMs) strongly influence diet selection by mammalian herbivores. Concentrations of PSMs vary within and among plant species, and across landscapes. Therefore, local adaptations may cause different populations of herbivores to differ in their ability to tolerate PSMs. Here, we tested the food intake responses of three populations of a marsupial folivore, the common brushtail possum (Trichosurus vulpecula Kerr), from different\ud latitudes and habitat types, to four types of PSMs. We\ud found clear variation in the responses of northern and\ud southern Australian possums to PSMs. Brushtail possums\ud from southern Australia showed marked decreases in food\ud intake in response to all four PSMs, while the two populations from northern Australia were not as sensitive and their responses did not differ from one another. These results were unexpected, based on our understanding of the experiences of these populations with PSMs in the wild. Our\ud results suggest that geographically separated populations of\ud possums may have evolved differing abilities to cope with\ud PSMs, as a result of local adaptation to their natural environments. Our results provide the basis for future studies to investigate the mechanisms by which populations of mammalian species differ in their ability to tolerate PSMs