Sulfur amino acid supplementation displays therapeutic potential in a C. elegans model of Duchenne muscular dystrophy

Abstract

Mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD), a common muscle disease that manifests with muscle weakness, wasting, and degeneration. An emerging theme in DMD pathophysiology is an intramuscular deficit in the gasotransmitter hydrogen sulfide (H2S). Here we show that the C. elegans DMD model displays reduced levels of H2S and expression of genes required for sulfur metabolism. These reductions can be offset by increasing bioavailability of sulfur containing amino acids (L-methionine, L-homocysteine, L-cysteine, L-glutathione, and L-taurine), augmenting healthspan primarily via improved calcium regulation, mitochondrial structure and delayed muscle cell death. Additionally, we show distinct differences in preservation mechanisms between sulfur amino acid vs H2S administration, despite similarities in required health-preserving pathways. Our results suggest that the H2S deficit in DMD is likely caused by altered sulfur metabolism and that modulation of this pathway may improve DMD muscle health via multiple evolutionarily conserved mechanisms.

Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans

“…Approximately 20 to 30 animals per condition were placed in 20 µL M9 on a microscope slide and immobilized with a cover slip. Images were taken of myofibers or mitochondria in body-wall muscle from both head and tail regions of every animal and visually classified as either well-networked, moderately fragmented, or severely fragmented (for mitochondrial quantification), or organized, moderately disorganized, and severely disorganized (for myofibrillar quantification) as previously described ( 26 , 86 ). The overall proportion of mitochondrial or myofibrillar classifications was obtained by normalizing to the total muscle cell count within each treatment condition (~150 to 300 muscle cells per condition from 30 to 60 animals per time point) across two biological replicates.…”

“…Samples were snap-frozen in 40 µL M9 and stored at −80 °C until analysis (within 1 wk). Sulfide content was assessed as described previously ( 13 , 86 ) as described in SI Appendix , Supplemental Methods section.…”

Bisphosphonates attenuate age‐related muscle decline inCaenorhabditis elegans

“…Images of the body wall muscles were captured from the head and tail region of each animal (avoiding the mid‐animal/vulva region that exhibits frequent egg‐laying induced tissue disruption) using an Orca‐spark camera (Hamamatsu, Japan) set to 50 ms exposure rate and a gain of 3.4 dB for all acquired images. Approximately 10 individual muscle cells were scored per animal equating to ~300 muscle cells per condition/replicate and scored as either well networked, moderately fragmented or severely fragmented muscle sarcomere or mitochondria structures as previously described 26 (see Figure S1 for representative images of each class of structural defect). Analysis was carried out in ImageJ, and the number of well networked, moderately fragmented or severely fragmented muscles were expressed as a percentage of total muscle cells visible and analysed within each animal.…”

The Role of Gasotransmitter-Dependent Signaling Mechanisms in Apoptotic Cell Death in Cardiovascular, Rheumatic, Kidney, and Neurodegenerative Diseases and Mental Disorders

“…In model organisms C. elegans with Duchenne muscular dystrophy, the level of H 2 S and the expression of genes necessary for sulfur metabolism are reduced. This decrease may be offset by an increase in the bioavailability of sulfur-containing amino acids, which increases lifespan, primarily by improving calcium regulation, mitochondrial structure, and slowing down muscle cell death [ 147 ].…”