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-myosin mutations cause highly variable calcium-sensitivity with functional imbalances among individual muscle cells
1 Molecular and Cell Physiology, Medical School Hannover, Hannover, Germany
2 Vegetative Physiology, Medical School Hannover, Hannover, Germany
3 Molecular Cardiology Laboratory, Hospital Clinic, University of Barcelona, Barcelona, Spain; National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyzstan
4 National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyzstan
5 Molecular Cardiology Laboratory, Hospital Clinic, University of Barcelona, Barcelona, Spain
6 Kardiologie am Campus Buch und Virchow-Klinikum, Charite - Universitaetsmedizin Berlin, Berlin, Germany
* To whom correspondence should be addressed. E-mail: Kraft.Theresia{at}mh-hannover.de.
Disease causing mutations in the cardiac myosin heavy chain (
-MHC) are identified in about one third of families with Hypertrophic Cardiomyopathy (HCM). The effect of myosin mutations on calcium-sensitivity of the myofilaments, however, is largely unknown. As normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium-sensitivity (pCa50) and the steepness of the force-pCa-relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations. Fibers with the mutation Arg723Gly and Arg719Trp showed a decrease in mean pCa50, while mutation Ile736Thr slightly increased mean pCa50 with higher active forces at low calcium-concentrations and residual active force even under relaxing conditions. In addition, there was a marked variability in pCa50 between individual fibers carrying the same mutation ranging from an almost normal response to highly significant differences which were not observed in controls. While changes in mean pCa50 may suggest specific pharmacological treatment (e.g., calcium antagonists), the observed large functional variability among individual muscle cells might negate such selective treatment. More importantly, the variability in pCa50 from fiber to fiber is likely to cause imbalances in force generation and be the primary cause for contractile dysfunction and development of disarray in the myocardium.
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