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 Therapeutics

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 5

Longer-term exposure of protective levels of myosin inhibition are sufficient to decrease muscle degeneration and fibrosis in mdx mice.

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Longer-term exposure of protective levels of myosin inhibition are suffi...
(A) Average grip strength (experimenter blinded) measured after 5 weeks of dosing in mdx mice (n = 5–10). (B) Left: Representative images. Right: Quantification of collagen (stained with picrosirius red) in mdx mouse diaphragm after 8 weeks of treatment (n = 9–10). Scale bar: 200 μm. (C) RNA-Seq meta-analysis. Colors are graded by log2 fold change (WT, n = 2; mdx vehicle, EDG-5506, n = 3). (D) Histological quantification of central nuclei and eMHC-positive fibers in soleus muscle sections from post-weaning mdx mice after 3 weeks EDG-5506 administration. (E) Specific force in the soleus muscle ex vivo in postweaning mdx and WT mice after 3 weeks of treatment with EDG-5506 or vehicle. (F) Representative histology sections examining muscle fibrosis in DBA/2 mdx mice after 12 weeks of treatment with control or EDG-5506 chow (50 ppm or 0.13 mmol/Kg chow). Scale bar: 900 μm (heart); 700 μm (anterior tibialis [TA] muscle); 300 μm (diaphragm). (G) Quantification of collagen (picrosirius red area). Left: Collagen quantification in select muscles (GC, gastrocnemius). Right: Collagen quantification in the left ventricle (LV; n = 9–10). Data are shown as the mean ± SEM. Significance was calculated by 1-way ANOVA with Dunnett’s multiple-comparison test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.