Review Paper

Journal of Muscle Research and Cell Motility

, Volume 29, Issue 6, pp 189-201

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Myofilament dysfunction in cardiac disease from mice to men

  • Nazha HamdaniAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center
  • , Monique de WaardAffiliated withExperimental Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam
  • , Andrew E. MesserAffiliated withCardiac Medicine, National Heart and Lung Institute, Imperial College London
  • , Nicky M. BoontjeAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center
  • , Viola KooijAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center
  • , Sabine van DijkAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center
  • , Amanda VersteilenAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center
  • , Regis LambertsAffiliated withLaboratory for Physiology, Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center
  • , Daphne MerkusAffiliated withExperimental Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam
    • , Cris dos RemediosAffiliated withMuscle Research Unit, Institute for Biomedical Research, The University of Sydney
    • , Dirk J. DunckerAffiliated withExperimental Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam
    • , Attila BorbelyAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical CenterInstitute of Cardiology, UDMHSC
    • , Zoltan PappAffiliated withInstitute of Cardiology, UDMHSC
    • , Walter PaulusAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center
    • , Ger J. M. StienenAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center
    • , Steven B. MarstonAffiliated withCardiac Medicine, National Heart and Lung Institute, Imperial College London
    • , Jolanda van der VeldenAffiliated withLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center Email author 

Abstract

In healthy human myocardium a tight balance exists between receptor-mediated kinases and phosphatases coordinating phosphorylation of regulatory proteins involved in cardiomyocyte contractility. During heart failure, when neurohumoral stimulation increases to compensate for reduced cardiac pump function, this balance is perturbed. The imbalance between kinases and phosphatases upon chronic neurohumoral stimulation is detrimental and initiates cardiac remodelling, and phosphorylation changes of regulatory proteins, which impair cardiomyocyte function. The main signalling pathway involved in enhanced cardiomyocyte contractility during increased cardiac load is the β-adrenergic signalling route, which becomes desensitized upon chronic stimulation. At the myofilament level, activation of protein kinase A (PKA), the down-stream kinase of the β-adrenergic receptors (β-AR), phosphorylates troponin I, myosin binding protein C and titin, which all exert differential effects on myofilament function. As a consequence of β-AR down-regulation and desensitization, phosphorylation of the PKA-target proteins within the cardiomyocyte may be decreased and alter myofilament function. Here we discuss involvement of altered PKA-mediated myofilament protein phosphorylation in different animal and human studies, and discuss the roles of troponin I, myosin binding protein C and titin in regulating myofilament dysfunction in cardiac disease. Data from the different animal and human studies emphasize the importance of careful biopsy procurement, and the need to investigate localization of kinases and phosphatases within the cardiomyocyte, in particular their co-localization with cardiac myofilaments upon receptor stimulation.

Keywords

Myofilament function Phosphorylation Kinase Phosphatase, adrenergic signalling Protein kinase A Heart failure