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Myofibrillar Ca2+ sensitivity of cardiomyopathic hamster hearts
S Heyder1, A Malhotra, J C Rüegg
1II. Physiologisches Institut, University of Heidelberg, Germany.
Insights
Cardiomyopathy in hamsters increases heart muscle calcium sensitivity. This heightened sensitivity may be linked to altered regulatory proteins, potentially impacting heart function.
Area of Science:
- Cardiovascular Physiology
- Muscle Biology
- Biochemistry
Background:
- Genetic cardiomyopathies, such as in Bio-To-2 Syrian hamsters, alter cardiac muscle function.
- Understanding calcium (Ca2+) responsiveness is crucial for diagnosing and treating heart conditions.
Purpose of the Study:
- To investigate the Ca2+ responsiveness of cardiac muscle fibers in normal and cardiomyopathic hamsters.
- To explore the role of regulatory proteins in altered Ca2+ sensitivity.
Main Methods:
- Studied skinned muscle fiber preparations from Syrian hamster ventricles (normal FIB vs. cardiomyopathic Bio-To-2).
- Compared Ca2+/force relationships and Ca2+ sensitivity (pCa50) between groups.
- Utilized protein manipulation (troponin I replacement) and pharmacological agents (EMD 53998, protein kinase).
Main Results:
- Myopathic hamsters exhibited significantly higher Ca2+ sensitivity (pCa50) compared to controls.
- Replacing troponin I normalized Ca2+ sensitivity in myopathic fibers.
- A Ca2+ sensitizer (EMD 53998) affected both groups equally.
- Cyclic-AMP-dependent protein kinase reduced Ca2+ sensitivity, normalizing the myopathic response.
Conclusions:
- Genetic cardiomyopathy enhances cardiac muscle Ca2+ sensitivity, likely due to alterations in regulatory proteins like troponin I.
- Pharmacological and biochemical interventions can modulate this altered Ca2+ sensitivity.
- The pathological increase in Ca2+ sensitivity may represent either a maladaptation or a compensatory mechanism in heart failure.
Abstract:
We studied the Ca2+ responsiveness of skinned muscle fibre preparations from the right and left ventricles of normal (FIB) and genetically cardiomyopathic (Bio-To-2) Syrian hamsters. Thus, we compared the Ca2+/force relationships of preparations from myopathic hamsters to those of age-matched (11-16 months old) normal animals. The pCa (i.e. -log10 [Ca2+]) required for 50% force activation (Ca2+ sensitivity) was higher in the myopathic hamsters than in controls (pCa50 values of 5.3 +/- 0.03 and 5.17 +/- 0.04, respectively); this difference might be due to an alteration in regulatory proteins. Indeed, after extraction (with vanadate) and replacement of troponin I with bovine cardiac troponin the pCa50 values were similar (pCa 5.35) to those of bovine ventricular fibres. The Ca2+ sensitizer EMD 53998 (10 microM) increased Ca2+ sensitivity in preparations from normal and cardiomyopathic hamsters equally, by 0.4 pCa units. Incubation of fibre bundles with the catalytic subunit of cyclic-adenosine-monophosphate-dependent protein kinase decreased Ca2+ sensitivity, thereby "normalizing" the enhanced Ca2+ responsiveness of fibres from cardiomyopathic hamsters. It is not clear, however, whether the pathologically increased Ca2+ sensitivity of the hearts of aged myopathic hamsters reflects a maladaptation, or a compensatory mechanism of the failing heart.