The role of thin filament cooperativity in cardiac length-dependent calcium activation |
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Authors: | Farman Gerrie P Allen Edward J Schoenfelt Kelly Q Backx Peter H de Tombe Pieter P |
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Affiliation: | † Center for Cardiovascular Research, Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois ‡ Department of Physiology, University of Toronto, Toronto, Ontario, Canada § Division of Cardiology, University Health Network, Toronto, Ontario, Canada |
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Abstract: | Length-dependent activation (LDA) is a prominent feature of cardiac muscle characterized by decreases in the Ca2+ levels required to generate force (i.e., increases in Ca2+ sensitivity) when muscle is stretched. Previous studies have concluded that LDA originates from the increased ability of (strong) cross-bridges to attach when muscle is lengthened, which in turn enhances Ca2+ binding to the troponin C (TnC) subunit of the troponin complex. However, our results demonstrate that inhibition of strong cross-bridge attachment with blebbistatin had no effect on the length-dependent modulation of Ca2+ sensitivity (i.e., EC50) or Ca2+ cooperativity, suggesting that LDA originates upstream of cross-bridge attachment. To test whether LDA arises from length dependence of thin-filament activation, we replaced native cTnC with a mutant cTnC (DM-TnC) that is incapable of binding Ca2+. Although progressive replacement of native cTnC with DM-TnC caused an expected monotonic decrease in the maximal force (Fmax), DM-TnC incorporation induced much larger increases in EC50 and decreases in Ca2+ cooperativity at short lengths than at long lengths. These findings support the conclusion that LDA arises primarily from the influence of length on the modulation of the Ca2+ cooperativity arising from interaction between adjacent troponin-tropomyosin complexes on the thin filament. |
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