Abstract
Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, leading to instability of the sarcolemma and skeletal muscle necrosis and atrophy. Resulting changes in muscle-specific gene expression that take place in dystrophin’s 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 disease progression independently of inflammation and regeneration. In effort to better understand these dynamics, we have isolated and sequenced body muscle-specific transcriptomes from C. elegans lacking functional dystrophin at distinct stages of disease progression. We have identified an upregulation of genes involved in mitochondrial function early in disease progression, and an upregulation of genes related to muscle repair in later stages. Our results suggest 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. We have also developed a temperature-based screening method for synthetic paralysis that can be used to rapidly identify genetic partners of dystrophin. Our results allow for the comprehensive identification of transcriptome changes that potentially serve as independent drivers of disease progression and may in turn allow for the identification of new therapeutic targets for the treatment of DMD.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked, recessive disease caused by out of frame mutations in the dystrophin gene [1]
Our results allow for the comprehensive identification of transcriptome changes that potentially serve as independent drivers of disease progression and may in turn allow for the identification of new therapeutic targets for the treatment of DMD
The original wt PAP strain expresses the gene pab-1 fused to GFP (N-terminus) and a 3xFLAG tag (Cterminus) restricted to the muscle by the tissue-specific promoter Pmyo-3 [31, 32]. pab-1 is the C. elegans ortholog of the human cytoplasmic PABPC1, which typically binds the polyA track of mature mRNAs in the cytoplasm and is required for translation [35]
Summary
Duchenne muscular dystrophy (DMD) is an X-linked, recessive disease caused by out of frame mutations in the dystrophin gene [1]. Outside of dystrophin’s structural role, decades of research have led to the proposal that dystrophin has an essential signaling role in the muscle as well, and its absence may induce a myriad of changes in gene expression that in turn influence the progression of DMD symptoms. Despite all the progress made in elucidating the signaling role of dystrophin, we still do not have an all-encompassing definition of the signaling consequences of dystrophin deficiencies. This issue is due in part to the fact that chronic inflammation of mammalian muscle has the ability to obscure more subtle changes in gene expression outside of the inflammatory pathway
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