2. Academic Validation
  3. Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy

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

  • J Clin Invest. 2023 May 15;133(10):e153837. doi: 10.1172/JCI153837.
Alan J Russell 1,  Mike DuVall 1,  Ben Barthel 1,  Ying Qian 1,  Angela K Peter 1,  Breanne L Newell-Stamper 1,  Kevin Hunt 1,  Sarah Lehman 1,  Molly Madden 1,  Stephen Schlachter 1,  Ben Robertson 1,  Ashleigh Van Deusen 1,  Hector M Rodriguez 2,  Carlos Vera 3,  Yu Su 4,  Dennis R Claflin 5,  Susan V Brooks 4,  Peter Nghiem 6,  Alexis Rutledge 6,  Twlya I Juehne 7,  Jinsheng Yu 7,  Elisabeth R Barton 8,  Yangyi E Luo 8,  Andreas Patsalos 9,  Laszlo Nagy 9,  H Lee Sweeney 10,  Leslie A Leinwand 3,  Kevin Koch 1
Affiliations

Affiliations

  • 1 Edgewise Therapeutics, BioFrontiers Institute, University of Colorado, Boulder, Colorado, USA.
  • 2 BridgeBio Inc., Palo Alto, California, USA.
  • 3 Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, Colorado, USA.
  • 4 Molecular and Integrative Physiology and.
  • 5 Department of Surgery, Section of Plastic Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • 6 Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
  • 7 Genome Technology Access Center, Department of Genetics, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA.
  • 8 Department of Applied Physiology and Kinesiology and Myology Institute, University of Florida College of Health and Human Performance, Gainesville, Florida, USA.
  • 9 Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, USA.
  • 10 Department of Pharmacology and Therapeutics and Myology Institute, University of Florida College of Medicine, Gainesville, Florida, USA.
PMID: 36995778 DOI: 10.1172/JCI153837
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.

Keywords

Muscle Biology; Neuromuscular disease; Skeletal muscle; Therapeutics.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148799
    99.46%, Myosin Inhibitor