title: Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments.
abstract: The sarcomere is the functional unit of the heart. Alterations in sarcomere activation lead to disease states such as hypertrophic and restrictive cardiomyopathy (HCM/RCM). Mutations in many of the sarcomeric genes are causal for HCM/RCM. In most cases, these mutations result in increased Ca(2+) sensitivity of the sarcomere, giving rise to altered systolic and diastolic function. There is emerging evidence that small-molecule sarcomere neutralization is a potential therapeutic strategy for HCM/RCM. To pursue proof-of-concept, W7 was used here because of its well-known Ca(2+) desensitizer biochemical effects at the level of cardiac troponin C. Acute treatment of adult cardiac myocytes with W7 caused a dose-dependent (1-10 μM) decrease in contractility in a Ca(2+)-independent manner. Alkalosis was used as an in vitro experimental model of acquired heightened Ca(2+) sensitivity, resulting in increased live cell contractility and decreased baseline sarcomere length, which were rapidly corrected with W7. As an inherited cardiomyopathy model, R193H cardiac troponin I (cTnI) transgenic myocytes showed significant decreased baseline sarcomere length and slowed relaxation that were rapidly and dose-dependently corrected by W7. Langendorff whole heart pacing stress showed that R193H cTnI transgenic hearts had elevated end-diastolic pressures at all pacing frequencies compared with hearts from nontransgenic mice. Acute treatment with W7 rapidly restored end-diastolic pressures to normal values in R193H cTnI hearts, supporting a sarcomere intrinsic mechanism of dysfunction. The known off-target effects of W7 notwithstanding, these results provide further proof-of-concept that small-molecule-based sarcomere neutralization is a potential approach to remediate hyper-Ca(2+)-sensitive sarcomere function.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Thompson
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.
authors.forename: Joshua
authors.initials: J
authors.lastname: Martindale
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota metzgerj@umn.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
mesh_terms: D000471:Alkalosis / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D012518:Sarcomeres / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D019210:Troponin I / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D019210:Troponin I; C017967:W 7; D017871:Calcium-Calmodulin-Dependent Protein Kinases
keywords: calcium sensitivity; hypertrophic cardiomyopathy; troponin