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ResearchIn-Press PreviewMuscle biologyTherapeutics Open Access |
10.1172/JCI153837
MODULATING FAST SKELETAL MUSCLE CONTRACTION PROTECTS SKELETAL MUSCLE IN ANIMAL
MODELS OF DUCHENNE MUSCULAR DYSTROPHY
ALAN J. RUSSELL,1 MIKE DUVALL,1 BENJAMIN BARTHEL,1 YING QIAN,1 ANGELA K. PETER,1
BREANNE L. NEWELL-STAMPER,1 KEVIN HUNT,1 SARAH J. LEHMAN,1 MOLLY R. MADDEN,1
STEPHEN T. SCHLACHTER,1 BENJAMIN D. ROBERTSON,1 ASHLEIGH VAN DEUSEN,1 HECTOR M.
RODRIGUEZ,2 CARLOS D. VERA,3 YU SU,4 DENNIS R. CLAFLIN,5 SUSAN V. BROOKS,4 PETER
P. 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 AND KEVIN KOCH1
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Russell, A. in: JCI | PubMed | Google Scholar |
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by DuVall, M. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Barthel, B. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Qian, Y. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Peter, A. in: JCI | PubMed | Google Scholar |
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Newell-Stamper, B. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Hunt, K. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Lehman, S. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Madden, M. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Schlachter, S. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Robertson, B. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Van Deusen, A. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Rodriguez, H. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Vera, C. in: JCI | PubMed | Google Scholar |
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Su, Y. in: JCI | PubMed | Google Scholar |
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Claflin, D. in: JCI | PubMed | Google Scholar |
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Brooks, S. in: JCI | PubMed | Google Scholar |
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Nghiem, P. in: JCI | PubMed | Google Scholar |
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Rutledge, A. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Juehne, T. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
Find articles by Yu, J. in: JCI | PubMed | Google Scholar
1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
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1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
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1BioFrontiers Institute, Edgewise Therapeutics, Boulder, United States of
America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
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America
2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
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3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
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2Biochemistry, BridgeBio Inc., Palo Alto, United States of America
3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
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America
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3Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, United States of America
4Molecular and Integrative Physiology, The University of Michigan, Ann Arbor,
United States of America
5Department of Surgery, Section of Plastic Surgery, The University of Michigan,
Ann Arbor, United States of America
6College of Veterinary Medicine and Biomedical Sciences, Texas A&M University,
College Station, United States of America
7Genome Technology Access Center, Department of Genetics, Washington University
in Saint Louis, School of Medicine, St. Louis, United States of America
8Department of Applied Physiology and Kinesiology and Myology Institute,
University of Florida College of Health and Human Performance, Gainesville,
United States of America
9Departments of Medicine and Biological Chemistry, IFBR, John Hopkins University
Medical School, St. Petersburg, United States of America
10Department of Pharmacology & Therapeutics and Myology Institute, University of
Florida College of Medicine, Gainesville, United States of America
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Published March 30, 2023 - More info
J Clin Invest. https://doi.org/10.1172/JCI153837.
Copyright © 2023, Russell et al. This work is licensed under the Creative
Commons Attribution 4.0 International License. To view a copy of this license,
visit http://creativecommons.org/licenses/by/4.0/.
Published March 30, 2023 - Version history
View PDF
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 from 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, the relationship between 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 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.
Graphical Abstract
Supplemental material
View SUPPLEMENTARY DATA 1: Excel file of profiling data for off-target
activities of EDG-5506 via KINOMEscan and SAFETYscan assays
View SUPPLEMENTARY DATA 2: Excel file of profiling data for phosphoprotein
changes with EDG-5506 in EDL muscles ex vivo
View SUPPLEMENTARY DATA 3: Excel file showing RNAseq data from mdx mouse muscle
after treatment with vehicle or EDG-5506
View SUPPLEMENTARY DATA 4: Somascan proteomics analysis of differences between
GRMD and healthy dog plasma
View SUPPLEMENTARY DATA 5: Somascan proteomics analysis of differences between
GRMD pretreatment, GRMD with 2 weeks EDG-5506 treatment and GRMD after EDG-5506
washout
View SUPPLEMENTARY DATA 6: Somascan proteomics analysis of similarities between
GRMD and DMD protein signatures and effect of EDG-5506 on these signatures
View SUPPLEMENTARY MOVIE 1: mdx mouse lumbrical muscle preincubated with vehicle
before repeated isometric contractions.
View SUPPLEMENTARY MOVIE 2: mdx mouse lumbrical muscle preincubated with 0.3 uM
EDG-5506 before repeated isometric contractions.
View SUPPLEMENTARY MOVIE 3: mdx mouse lumbrical muscle preincubated with 1 uM
EDG-5506 before repeated isometric contractions.
View
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