A new article published in Human Molecular Genetics reported that Duchenne muscular dystrophy (DMD) – a lethal X-linked disease characterized by progressive muscle degeneration, is driven by nonsense and missense mutations in the dystrophin gene, leading to instability of the sarcolemma and skeletal muscle necrosis and atrophy. The authors stated that the resulting changes in muscle-specific gene expression that occur in dystrophins absence remain largely uncharacterized as they are potentially obscured by the chronic inflammation, elicited by muscle damage in humans. Caenorhabditis elegans possess a mild inflammatory response that is not active in the muscle and lack a satellite cell equivalent. This allows for the characterization of the transcriptome rearrangements affecting the disease progression, independent of inflammation and regeneration.

The article reported on the identification of an upregulation of genes involved in mitochondrial function early in the disease progression, and an upregulation of genes related to muscle repair in later stages. The findings indicated that in C. elegans, dystrophin may have a signaling role early in development and its absence may activate compensatory mechanisms that counteract muscle degradation caused by loss of dystrophin.

In addition, a temperature-based screening method was devised for synthetic paralysis, that can be used to rapidly identify genetic partners of dystrophin. The results facilitated a comprehensive identification of transcriptome changes that potentially serve as independent drivers of disease progression, which may allow for the identification of new therapeutic targets for the treatment of DMD.

Source: Human Molecular Genetics. 2020 Mar 30. pii: ddaa055. doi: 10.1093/hmg/ddaa055.