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

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

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


Jennifer E. Hewitt

Amelia K. Pollard

Leila Lesanpezeshki

Colleen S. Deane

Christopher J. Gaffney

Timothy Etheridge

Nathaniel J. Szewczyk

Siva A. Vanapalli


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 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, and display mitochondrial network fragmentation in the body wall muscles as well as 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.

Journal Article Type Article
Acceptance Date Oct 31, 2018
Online Publication Date Nov 5, 2018
Publication Date Dec 4, 2018
Deposit Date Nov 7, 2018
Publicly Available Date Feb 25, 2019
Journal Disease Models & Mechanisms
Print ISSN 1754-8403
Electronic ISSN 1754-8411
Publisher Company of Biologists
Peer Reviewed Peer Reviewed
Volume 11
Issue 12
Keywords Muscular dystrophy; C. elegans; Muscle strength; Prednisone; Melatonin
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