Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations Journal Article


Authors: Sequeira, V; Wijnker, P. J.; Nijenkamp, L. L.; Kuster, D. W.; Najafi, A.; Witjas-Paalberends, E. R.; Regan, J. A.; Boontje, N.; Ten Cate, F. J.; Germans, T.; Carrier, L.; Sadayappan, S; van Slegtenhorst, M. A.; Zaremba, R.; Foster, D. B.; Murphy, A. M.; Poggesi, C; Dos Remedios, C.; Stienen, G. J.; Ho, C. Y.; Michels, M.; van der Velden, J.
Article Title: Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations
Abstract: 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.
Journal Title: Circulation research
Volume: 112
Issue: 11
ISSN: 1524-4571; 0009-7330
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: 1491
End Page: 1505
Language: eng
DOI/URL:
Notes: GR: N01 HV028180/HV/NHLBI NIH HHS/United States; GR: R01 HL063038/HL/NHLBI NIH HHS/United States; GR: R01 HL63038/HL/NHLBI NIH HHS/United States; JID: 0047103; 0 (Carrier Proteins); 0 (MYH7 protein, human); 0 (Myosin Heavy Chains); 0 (TNNT2 protein, human); 0 (TPM1 protein, human); 0 (Tropomyosin); 0 (Troponin T); 0 (myosin-binding protein C); 7440-70-2 (Calcium); EC 2.7.11.1 (TNNI3K protein, human); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 3.6.1.- (Cardiac Myosins); CIN: Circ Res. 2013 May 24;112(11):1409-11. PMID: 23704214; NIHMS470681; OID: NLM: NIHMS470681 [Available on 05/24/14]; OID: NLM: PMC3675884 [Available on 05/24/14]; OTO: NOTNLM; PMCR: 2014/05/24 00:00; 2013/03/18 [aheadofprint]; 2013/03/19 [aheadofprint]; ppublish