Article thumbnail

Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of Caenorhabditis elegans and its functional response to drugs

By Jennifer E. Hewitt, Amelia K. Pollard, Leila Lesanpezeshki, Colleen S. Deane, Christopher J. Gaffney, Timothy Etheridge, Nathaniel J. Szewczyk and Siva A. Vanapalli

Abstract

Muscle strength is a key clinical parameter used to monitor the progression of human muscular dystrophies, including Duchenne and Becker muscular dystrophies. Although Caenorhabditis elegans is an established genetic model for studying the mechanisms and treatments of muscular dystrophies, analogous strength-based measurements in this disease model are lacking. Here, we describe the first demonstration of the direct measurement of muscular strength in dystrophin-deficient C. elegans mutants using a micropillar-based force measurement system called NemaFlex. We show that dys-1(eg33) mutants, but not dys-1(cx18) mutants, are significantly weaker than their wild-type counterparts in early adulthood, cannot thrash in liquid at wild-type rates, display mitochondrial network fragmentation in the body wall muscles, and have an abnormally high baseline mitochondrial respiration. Furthermore, treatment with prednisone, the standard treatment for muscular dystrophy in humans, and melatonin both improve muscular strength, thrashing rate and mitochondrial network integrity in dys-1(eg33), and prednisone treatment also returns baseline respiration to normal levels. Thus, our results demonstrate that the dys-1(eg33) strain is more clinically relevant than dys-1(cx18) for muscular dystrophy studies in C. elegans. This finding, in combination with the novel NemaFlex platform, can be used as an efficient workflow for identifying candidate compounds that can improve strength in the C. elegans muscular dystrophy model. Our study also lays the foundation for further probing of the mechanism of muscle function loss in dystrophin-deficient C. elegans, leading to knowledge translatable to human muscular dystrophy. This article has an associated First Person interview with the first author of the paper

Topics: Muscular dystrophy, C. elegans, Muscle strength, Prednisone, Melatonin, Medicine, R, Pathology, RB1-214
Publisher: The Company of Biologists
Year: 2018
DOI identifier: 10.1242/dmm.036137
OAI identifier: oai:doaj.org/article:61baf423958a4552b9c20b2a837bd5da
Journal:
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • https://doaj.org/article/61baf... (external link)
  • https://doaj.org/toc/1754-8411 (external link)
  • http://dmm.biologists.org/cont... (external link)
  • https://doaj.org/toc/1754-8403 (external link)
  • Suggested articles


    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.