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

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

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 6

Selective inhibition of active contraction in fast skeletal muscle decreases CK and increases habitual activity in DMD dogs.

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Selective inhibition of active contraction in fast skeletal muscle decre...
(A) Plasma CK activity in 7-month-old DMD dogs (n = 4) before, during, and after 14 days oral gavage with EDG-5506. Each data point represents CK activity from an individual blood draw (2–3 draws during the vehicle baseline, 5–8 draws during the dosing period, and 2 draws during the vehicle washout). In a separate study, the same 4 dogs were dosed daily with vehicle, and blood CK was at regular intervals for 14 days (indicated as vehicle repeat, 6–9 blood draws per dog). Data are shown as the mean ± SEM. (B) Average daily activity measures from an electronic activity monitor (FitBark) in the same DMD dogs (n = 3, 15 months old) before, during, and after an 11-day oral gavage with EDG-5506 (2 mg/kg daily for 4 days, then every other day). Each data point represents the daily average activity for the 3 dogs. (C) Timed function data from the same activity monitors. Average daily active time, average daily play time, and average daily rest time. Each point represents average activity for 1 day (2 mg/kg represents approximately 68.2 μmol EDG-5506/dog). Significance was calculated by 1-way ANOVA with Tukey’s multiple-comparison correction. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.