RATIONALE: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. OBJECTIVE: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. METHODS AND RESULTS: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. CONCLUSIONS: High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.
RATIONALE: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. OBJECTIVE: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. METHODS AND RESULTS: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. CONCLUSIONS: High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.
Authors: Pingbo Zhang; Jonathan A Kirk; Weihua Ji; Cristobal G dos Remedios; David A Kass; Jennifer E Van Eyk; Anne M Murphy Journal: Circulation Date: 2012-09-12 Impact factor: 29.690
Authors: Björn C Knollmann; Paulus Kirchhof; Syevda G Sirenko; Hubertus Degen; Anne E Greene; Tilmann Schober; Jessica C Mackow; Larissa Fabritz; James D Potter; Martin Morad Journal: Circ Res Date: 2003-02-06 Impact factor: 17.367
Authors: Bo Liang; Franca Chung; Yang Qu; Dmitri Pavlov; Todd E Gillis; Svetlana B Tikunova; Jonathan P Davis; Glen F Tibbits Journal: Physiol Genomics Date: 2008-02-19 Impact factor: 3.107
Authors: Tjeerd Germans; Iris K Rüssel; Marco J W Götte; Marieke D Spreeuwenberg; Pieter A Doevendans; Yigal M Pinto; Rob J van der Geest; Jolanda van der Velden; Arthur A M Wilde; Albert C van Rossum Journal: J Cardiovasc Magn Reson Date: 2010-03-15 Impact factor: 5.364
Authors: Vasco Sequeira; E Rosalie Witjas-Paalberends; Diederik W D Kuster; Jolanda van der Velden Journal: Pflugers Arch Date: 2013-11-17 Impact factor: 3.657
Authors: Paul J M Wijnker; Vasco Sequeira; D Brian Foster; Yuejin Li; Cristobal G Dos Remedios; Anne M Murphy; Ger J M Stienen; Jolanda van der Velden Journal: Am J Physiol Heart Circ Physiol Date: 2014-02-28 Impact factor: 4.733
Authors: Diederik W D Kuster; Thomas L Lynch; David Y Barefield; Mayandi Sivaguru; Gina Kuffel; Michael J Zilliox; Kyoung Hwan Lee; Roger Craig; Rajasekaran Namakkal-Soorappan; Sakthivel Sadayappan Journal: Cardiovasc Res Date: 2019-12-01 Impact factor: 10.787
Authors: Paul J M Wijnker; Vasco Sequeira; E Rosalie Witjas-Paalberends; D Brian Foster; Cristobal G dos Remedios; Anne M Murphy; Ger J M Stienen; Jolanda van der Velden Journal: Arch Biochem Biophys Date: 2014-05-09 Impact factor: 4.013