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

Circ Res. 2013 May 24;112(11):1491-505. doi: 10.1161/CIRCRESAHA.111.300436. Epub 2013 Mar 18.


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.

Keywords: calcium; cardiomyopathy; contractility; hypertrophy; myocardium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Calcium / metabolism
  • Cardiac Myosins / genetics
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / pathology*
  • Cardiomyopathy, Hypertrophic / physiopathology
  • Carrier Proteins / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Humans
  • Isometric Contraction / physiology
  • MAP Kinase Kinase Kinases / genetics
  • Male
  • Mice
  • Middle Aged
  • Mutation, Missense
  • Myocardial Contraction / physiology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myofibrils / pathology*
  • Myofibrils / physiology*
  • Myosin Heavy Chains / genetics
  • Phosphorylation / physiology
  • Protein Serine-Threonine Kinases
  • Sarcomeres / pathology*
  • Sarcomeres / physiology*
  • Tropomyosin / genetics
  • Troponin T / genetics
  • Young Adult


  • Carrier Proteins
  • MYH7 protein, human
  • TNNT2 protein, human
  • TPM1 protein, human
  • Tropomyosin
  • Troponin T
  • myosin-binding protein C
  • Protein Serine-Threonine Kinases
  • TNNI3K protein, human
  • Cyclic AMP-Dependent Protein Kinases
  • MAP Kinase Kinase Kinases
  • Cardiac Myosins
  • Myosin Heavy Chains
  • Calcium