The nematode Caenorhabditis elegans has been a powerful
model system for the study of key muscle genes
relevant to human neuromuscular function and disorders. In their natural habitat, C. elegans likely
spends much of the time burrowing through the soil
matrix. We developed a burrowing assay to challenge
motor output by placing worms in agar-filled pipettes
of increasing densities and found that burrowing involves
distinct kinematics and turning strategies from crawling
that vary with the properties of the substrate. Mutants mimicking Duchenne muscular dystrophy
by lacking a functional ortholog of the dystrophin protein,
DYS-1, crawl normally but are severely impaired in
burrowing. Muscular degeneration in the dys-1 mutant is
hastened and exacerbated by burrowing, while wild type
shows no such damage (figure). Our students performed a genetic screen using dys-1 worms and isolated several suppressor mutants with proficient burrowing despite their dys-1 mutant background.
Present work in our lab is focusing on identifying the molecular mechanisms by which muscles become impaired during the progression of DMD, particularly in response to muscular exertion; identifying the mutations responsible for the rescue of the dys-1 phenotype observed in suppressor mutants, and identifying novel and conserved molecular targets that may contribute to the alleviation of the symptoms of this devastating disease.
Further study of burrowing in C. elegans will enhance the study of diseases affecting neuromuscular integrity, and will provide insights into the natural behavior of this and other nematodes.
Anjelica Rodriguez (MS) and Kiley Hughes (PhD) are our graduate team working on the Duchenne muscular dystrophy.
Undergraduate and high school researchers:
This research is funded by The National Institutes of Health. Grant# 1R15AR068583-01A1.