Prof. Pieter P. de Tombe
Department of Cell and Molecular Physiology, Loyola University, Chicago, IL, USA
Room 281, Physics and Astronomy Dept., University of Florence
Published on-line at 05:45:37 PM on Tuesday, March 12th, 2013
Myofilament length dependent activation and the Frank-Starling law of the heart
Troponin-I, and in particular cTnI-Thr144, plays a pivotal role in Myofilament Length Dependent Activation.
Myofilament Length Dependent Activation (LDA) underlies the Frank-Starling Law of the heart. The molecular mechanisms that regulate LDA are incompletely understood. We have recently identified troponin-I, and in particular cTnI-Thr144, playing a pivotal role in LDA. Moreover, we found that LDA develops within 5 ms, excluding post-translational modifications as mechanism for LDA. Further, our 2D X-ray diffraction studies indicate that stretch is associated with structural changes in both myosin and troponin in relaxed cardiac muscle.
Preliminary studies employing fluorescent probes in skinned isolated myocardium corroborate these data. Finally, expression of a giant isoform of titin in a mutant rat strain is associated with a blunted Frank-Starling response, blunted LDA, and absence of structural rearrangements in troponin and myosin upon stretch in relaxed cardiac muscle. We propose that myofilament length dependent activation is due to the direct transmission prior to activation of titin strain to troponin or weakly-bound cross-bridges inducing structural rearrangements that lead to increase myofilament calcium sensitivity.
For further informations, please contact Dr. Leonardo Sacconi.
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