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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/H1242    most recent 00686.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Kirschner, S. E. Articles by Kraft, T. Search for Related Content PubMed PubMed Citation Articles by Kirschner, S. E. Articles by Kraft, T.

Hypertrophic cardiomyopathy-related -myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells

¹Molecular and Cell Physiology and ²Vegetative Physiology, Medical School Hannover, Hannover, Germany; ³Molecular Cardiology Laboratory, Hospital Clinic, University of Barcelona, Barcelona, Spain; ⁴National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyzstan; ⁵Charité, Universitätsmedizin Berlin, Kardiologie am Campus Buch und Virchow-Klinikum, Berlin, Germany; and ⁶The Heart Hospital, University College London, London, United Kingdom

Submitted 12 July 2004 ; accepted in final form 9 November 2004

Disease-causing mutations in 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. Because 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 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 Arg723Gly and Arg719Trp mutations showed a decrease in mean pCa₅₀, whereas those with the Ile736Thr mutation showed 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 that 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.

-myosin heavy chain mutations; force-pCa relationships; human soleus muscle fibers

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