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Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
Hypertrophic cardiomyopathy-related beta-myosin mutations cause highly variable calcium sensitivity with functional
Sebastian E Kirschner1, Edgar Becker, Massimo Antognozzi
1Molecular and Cell Physiology, Medical School Hannover, Germany.
Insights
Genetic mutations causing hypertrophic cardiomyopathy (HCM) affect cardiac myosin function. This study reveals significant variability in muscle fiber calcium sensitivity, potentially explaining contractile dysfunction in HCM patients.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Skeletal Muscle Physiology
Background:
- Mutations in cardiac myosin heavy chain (beta-MHC) are linked to hypertrophic cardiomyopathy (HCM) in about one-third of affected families.
- The impact of these myosin mutations on myofilament calcium sensitivity remains largely unexplored.
- Slow-twitch skeletal muscle, co-expressing normal and mutant beta-MHC, offers a model to study these effects due to accessibility and fewer adaptive responses compared to myocardium.
Purpose of the Study:
- To investigate the effect of specific myosin mutations on calcium sensitivity and force generation in skeletal muscle fibers.
- To compare the functional properties of single muscle fibers from healthy individuals and HCM patients with known myosin mutations.
Main Methods:
- Single soleus muscle fibers were isolated from healthy controls and HCM patients carrying specific myosin mutations (Arg723Gly, Arg719Trp, Ile736Thr).
- Calcium sensitivity (pCa50) and the steepness of force-calcium relations (cooperativity) were measured.
- Functional variability in pCa50 between individual fibers with the same mutation was assessed.
Main Results:
- Fibers with Arg723Gly and Arg719Trp mutations exhibited decreased mean pCa50.
- Fibers with the Ile736Thr mutation showed a slightly increased mean pCa50, with higher active forces at low calcium and residual force under relaxing conditions.
- A significant, mutation-dependent variability in pCa50 was observed among individual muscle fibers, exceeding that in controls.
Conclusions:
- While average changes in calcium sensitivity might suggest pharmacological targets, the substantial fiber-to-fiber variability in pCa50 could hinder effective treatment strategies.
- This functional heterogeneity among muscle cells is a potential driver of contractile dysfunction, myocardial disarray, and the development of HCM.
- Understanding this variability is crucial for elucidating the mechanisms underlying HCM pathogenesis.
Abstract:
Disease-causing mutations in cardiac myosin heavy chain (beta-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 (pCa(50)) 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 pCa(50), whereas those with the Ile736Thr mutation showed slightly increased mean pCa(50) with higher active forces at low calcium concentrations and residual active force even under relaxing conditions. In addition, there was a marked variability in pCa(50) 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 pCa(50) 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 pCa(50) 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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