Cooperative cross-bridge activation of thin filaments contributes to the Frank-Starling mechanism in cardiac muscle.
Myosin cross-bridges play an important role in the regulation of thin-filament activation in cardiac muscle. To test the hypothesis that sarcomere length (SL) modulation of thin-filament activation by strong-binding cross-bridges underlies the Frank-Starling mechanism, we inhibited force and strong cross-bridge binding to intermediate levels with sodium vanadate (Vi). Force and stiffness varied proportionately with [Ca(2+)] and [Vi]. Increasing [Vi] (decreased force) reduced the pCa(50) of force-[Ca(2+)] relations at 2.3 and 2.0 microm SL, with little effect on slope (n(H)). When maximum force was inhibited to approximately 40%, the effects of SL on force were diminished at lower [Ca(2+)], whereas at higher [Ca(2+)] (pCa < 5.6) the relative influence of SL on force increased. In contrast, force inhibition to approximately 20% significantly reduced the sensitivity of force-[Ca(2+)] relations to changes in both SL and myofilament lattice spacing. Strong cross-bridge binding cooperatively induced changes in cardiac troponin C structure, as measured by dichroism of 5' iodoacetamido-tetramethylrhodamine-labeled cardiac troponin C. This apparent cooperativity was reduced at shorter SL. These data emphasize that SL and/or myofilament lattice spacing modulation of the cross-bridge component of cardiac thin-filament activation contributes to the Frank-Starling mechanism.
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
L
L
Smith
C
C
Tainter
M
M
Regnier
D A
DA
Martyn
D008841:Actin Cytoskeleton / Q000473:pathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004548:Elasticity; D005454:Fluorescence Polarization; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D008297:Male; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D009218:Myosins / Q000378:metabolism*; D009465:Neuromuscular Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012235:Rhodamines; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology*; D019209:Troponin C / Q000235:genetics / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D009465:Neuromuscular Agents; D012235:Rhodamines; D019209:Troponin C; D014638:Vanadates; C034996:tetramethylrhodamine iodoacetamide; D009218:Myosins; D002118:Calcium