Development of Caenorhabditis elegans as a model organism for Duchenne muscular dystrophy using a novel multi-environment phenotyping framework

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Duchenne muscular dystrophy is a serious muscle wasting disorder resulting from mutations in the dystrophin gene; these mutations cause muscle weakness, loss of ambulation, and other serious complications that lead to a severely impaired quality of life and early death. Current research efforts focus on understanding the progression of the disease and effective interventions to prevent or delay the onset of symptoms associated with the absence of the dystrophin protein. Model organisms are often used to study the disease since human studies are financially prohibitive and have restrictive ethical requirements. One model organism, the nematode C. elegans, has a gene called dys-1 that encodes for a dystrophin-like protein; dys-1 mutants of C. elegans have previously been established as a useful model for studying DMD. However, few clinically relevant phenotypes have been described in this nematode model, so most DMD studies with model organisms have therefore instead utilized a mouse model. In this work, we further establish the dys-1 mutant of C. elegans as a useful model for DMD by demonstrating clinically relevant baseline phenotypes and drug responses. Utilizing our novel microfluidic platform that enables measurement of muscle strength in C. elegans, we show that dys-1 mutants are significantly weaker than their wild-type counterparts. Dys-1 mutants are also deficient in their swim motility, exhibit irregularities in mitochondrial structure and function, and have abnormalities in acetylcholine signaling. Furthermore, most of these phenotypes improve under treatment with prednisone, a glucocorticoid that is the standard treatment for DMD in humans. To robustly assess the efficacy of pharmacological treatments for DMD, we then present a novel multi-environment, multi-dimensional platform (MEP) that assesses C. elegans health via three unique assays extracting descriptive measures of nematode physiology in crawling, swimming, and burrowing environments, each of which provides unique information and elicits unique genetic responses in the nematode. Using this platform, we further establish baseline health deficiencies in dys-1 animals and look at efficacy of treatments. Dissection of nematode health via the MEP platform is also performed for additional applications looking at C. elegans with lifespan-extending mutations as well as C. elegans that have undergone exercise training. Finally, we explore the utility of the burrowing assay as the basis for a genetic screen, which allowed us to obtain 66 genetic suppressors of the dys-1 mutation.

C. elegans, Duchenne muscular dystrophy, Phenotyping, Muscle, Microfluidics, Assay development