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Familial hypertrophic cardiomyopathy: functional effects of myosin mutation R723G in cardiomyocytes

Theresia Kraft1, E Rosalie Witjas-Paalberends, Nicky M Boontje

  • 1Molecular and Cell Physiology, Hannover Medical School, D-30625 Hannover, Germany. Kraft.Theresia@mh-hannover.de

Journal of Molecular and Cellular Cardiology
|January 16, 2013
PubMed

Insights

Familial Hypertrophic Cardiomyopathy (FHC) mutations impact cardiac myosin function. The R723G mutation reduces cardiomyocyte force but not calcium sensitivity, unlike in soleus fibers, due to altered protein phosphorylation and myofibrillar structure.

Area of Science:

  • Cardiovascular Research
  • Muscle Physiology
  • Molecular Cardiology

Background:

  • Familial Hypertrophic Cardiomyopathy (FHC) is often caused by mutations in the β-cardiac myosin heavy chain (β-MyHC).
  • Understanding mutation-specific effects on sarcomeric function is crucial for distinguishing FHC pathology.
  • Previous work identified the R723G mutation's effect on myosin in soleus muscle fibers.

Purpose of the Study:

  • To investigate the contractile properties of left ventricular cardiomyocytes from FHC patients with the R723G mutation (MyHC723).
  • To compare these cardiomyocyte findings with previously observed effects in MyHC723-soleus muscle fibers.
  • To explore the role of protein phosphorylation in mediating mutation-specific functional alterations.

Main Methods:

  • Mechanically isolated, triton-permeabilized cardiomyocytes and soleus muscle fibers from FHC patients and controls.
  • Measurement of maximum force generation and calcium sensitivity.
  • Analysis of protein phosphorylation patterns in sarcomeric proteins (troponin I and T, myosin-binding protein C, myosin-light-chain 2).
  • Experimental manipulation of protein-kinase-A phosphorylation sites.

Main Results:

  • MyHC723-cardiomyocytes exhibited significantly lower maximum force but unchanged calcium sensitivity compared to donors.
  • MyHC723-soleus fibers showed higher maximum force and reduced calcium sensitivity.
  • MyHC723-myocardium displayed reduced phosphorylation of key sarcomeric proteins.
  • Restoring phosphorylation in MyHC723-cardiomyocytes mimicked the reduced calcium sensitivity seen in soleus fibers, while maximum force remained low.
  • Myofibrillar disarray and reduced density contributed to decreased maximum force in MyHC723-cardiomyocytes.

Conclusions:

  • The R723G mutation reduces Ca(++)-sensitivity in both cardiomyocytes and soleus fibers.
  • In FHC myocardium, hypophosphorylation of sarcomeric proteins partially compensates for reduced calcium sensitivity.
  • Impaired maximum force generation in MyHC723-cardiomyocytes, due to myofibrillar abnormalities, may be a primary driver of FHC pathology, potentially compensated by hypertrophy.

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