Copyright © 2005, European Society of Cardiology
Length and protein kinase A modulations of myocytes in cardiac myosin binding protein C-deficient mice
aINSERM, U 637, Montpellier, F-34295, France
bUniversité MONTPELLIER1, UFR de Médecine, Montpellier, F-34295, France
cINSERM, U 582, Paris, F-75013, France
dUniversité Pierre et Marie Curie, UFR de Médecine, Paris, F-75013, France
eInstitute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
* Corresponding author. INSERM U-637, CHU Arnaud de Villeneuve, 34295 Montpellier, France. Tel.: +33 467 41 52 44; fax: +33 467 41 52 42. Email address: cazorla{at}montp.inserm.fr
Objective: β-Adrenergic stimulation modulates cardiac contractility through protein kinase A (PKA), which phosphorylates proteins such as troponin I (cTnI) and C-protein (cMyBP-C). The relative contributions of cTnI and cMyBP-C to the regulation of myofilament Ca2+ sensitivity are still controversial because of difficulty in targeting specific protein phosphorylation. Recently, impaired relaxation was found in cMyBP-C-deficient mice (KO) in vivo under basal conditions and after β-adrenergic stimulation. The goal of this study was to analyse the length-dependent and PKA-dependent modulations of the cardiac contractile machinery in a mouse model lacking cMyBP-C.
Methods: In the present work, we studied the PKA effect on myofilament Ca2+ sensitivity of left ventricular skinned myocytes isolated from 5-week- and 55-week-old wild-type (WT) and cMyBP-C knockout (KO) mice at 1.9 and 2.3 µm sarcomere lengths (SL). The cTnI content and phosphorylation status were examined by Western blot analysis.
Results: Without PKA stimulation and at the shorter SL, Ca2+ sensitivity was higher in KO compared to WT. The difference disappeared at the longer SL. No difference in passive tension or maximal active tension was observed. PKA stimulation induced a desensitization of WT myofilaments at both SL but had almost no effect in KO myofilaments despite similar levels of cTnI phosphorylation. We also observed expression of slow skeletal TnI in KO animals that was not correlated with the PKA effects.
Conclusion: The results suggest that cMyBP-C contributes to the regulation of cardiac contraction at short sarcomere length and that myofilament desensitization induced by PKA requires the presence of cMyBP-C and does not depend only upon TnI phosphorylation.
KEYWORDS Ca2+ sensitivity; β-Adrenergic; Frank–Starling law; TnI
1 These authors contributed equally to this work.
Time for primary review 26 days
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