Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy. Academic Article uri icon


  • 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.

published proceedings

  • J Clin Invest

altmetric score

  • 30.15

author list (cited authors)

  • Russell, A. J., DuVall, M., Barthel, B., Qian, Y., Peter, A. K., Newell-Stamper, B. L., ... Koch, K.

citation count

  • 0

complete list of authors

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

publication date

  • May 2023