title: Fast skeletal muscle troponin activator in the dy2J muscular dystrophy model.
abstract: BACKGROUND
  Tirasemtiv is a novel small molecule activator of the fast skeletal muscle troponin complex that produces sensitization of the sarcomere to calcium. Tirasemtiv is currently in Phase II clinical trials for neuromuscular disease.
  
  
  METHODS
  We conducted a blinded, randomized, placebo-controlled preclinical study of the effect of tirasemtiv on forearm grip strength, endurance, respiratory physiology, and muscle pathology in adequate sample sizes of the Lama2(dy-2J) mouse model of congenital muscular dystrophy.
  
  
  RESULTS
  Mice receiving a high dose of tirasemtiv had significantly higher muscle fiber cross-sectional area and respiratory response to CO₂ stimulation at 16 weeks than mice on low dose or placebo. There were no changes in muscle pathology, serum creatine kinase, strength, endurance, or respiration following long-term treatment.
  
  
  CONCLUSIONS
  We conclude that tirasemtiv influences the structure of the skeletal muscle fiber in this model of muscular dystrophy but does not impact muscle function, as evaluated in this study.
authors.affiliation: Center for Genetic Muscle Disorders, The Kennedy Krieger Institute, 707 North Broadway, Baltimore, Maryland 21205, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Miciak
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Warsing
authors.forename: Maria E
authors.initials: ME
authors.lastname: Tibbs
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jasper
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Jampel
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.forename: Clarke
authors.initials: C
authors.lastname: Tankersley
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Wagner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007797:Laminin / Q000235:genetics; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D009136:Muscular Dystrophies / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010807:Physical Endurance / Q000187:drug effects / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D012143:Respiratory Physiological Phenomena / Q000187:drug effects / Q000235:genetics; D014336:Troponin / Q000378:metabolism*
chemical_list: C572767:CK-2017357; D007093:Imidazoles; D007797:Laminin; D011719:Pyrazines; D014336:Troponin; C102645:laminin alpha 2; D003402:Creatine Kinase
keywords: dy2J; muscular dystrophy; preclinical; tirasemtiv; troponin complex