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Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy
Alan J. Russell, … , Leslie A. Leinwand, Kevin Koch
Alan J. Russell, … , Leslie A. Leinwand, Kevin Koch
Published March 30, 2023
Citation Information: J Clin Invest. 2023;133(10):e153837. https://doi.org/10.1172/JCI153837.
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Research Article Muscle biology Article has an altmetric score of 27

Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy

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Abstract

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.

Authors

Alan J. Russell, Mike DuVall, Ben Barthel, Ying Qian, Angela K. Peter, Breanne L. Newell-Stamper, Kevin Hunt, Sarah Lehman, Molly Madden, Stephen Schlachter, Ben Robertson, Ashleigh Van Deusen, Hector M. Rodriguez, Carlos Vera, Yu Su, Dennis R. Claflin, Susan V. Brooks, Peter Nghiem, Alexis Rutledge, Twlya I. Juehne, Jinsheng Yu, Elisabeth R. Barton, Yangyi E. Luo, Andreas Patsalos, Laszlo Nagy, H. Lee Sweeney, Leslie A. Leinwand, Kevin Koch

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Figure 1

EDG-5506 is a selective inhibitor of fast skeletal myosin ATPase and force generation in fast skeletal muscle.

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EDG-5506 is a selective inhibitor of fast skeletal myosin ATPase and for...
(A) Chemical structure of EDG-5506. (B) Myofibril ATPase activity curves for EDG-5506, with myofibrils isolated from rabbit fast skeletal muscle, bovine cardiac ventricle, and slow bovine masseter muscle. (C) Purified myosin S1 ATPase activity curves for EDG-5506, with rabbit fast skeletal muscle (psoas muscle), pig cardiac muscle, and smooth muscle myosin S1 isolated from chicken gizzard. ATPase activity in the myofibrils is measured at the pCa50 (calcium concentration where ATPase activity is 50% of maximum) value for free calcium for each muscle type (n = 2). (D) Representative force-calcium curve in single permeabilized fast skeletal muscle fibers (rabbit psoas) with EDG-5506. (E) Percentage of initial force with time after addition of EDG-5506 in WT mouse EDL muscle ex vivo. Force was recorded at 250 Hz. Each point represents mean peak force ± 1 SEM (n = 4). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Significance was calculated by 1-way ANOVA with Dunnett’s multiple-comparison test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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