Abstract
Proteolytic degradation of Troponin I (cTnI) may be the cause for the depressed contractility that is seen in myocardial stunning. Here, we studied the impact of a proteolytic fragment cTnI63-193 (identified by McDonough et al, 1999) on cross-bridge cycling dynamics in isolated myocardium. Murine cTnI63-193 mutant, as well as wild type cTnC and cTnT, were expressed in E.coli. Next, FPLC purified Troponin (cTn) complex containing either wild type cTnI or cTnI63-193 was exchanged for endogenous cTn in skinned rat cardiac trabeculae; Western blot analysis confirmed that >75% cTn was exchanged. Myofilament chemo-mechanical cross-bridge dynamics were determined as function of [Ca2+] at SL=2.2 µm using an enzyme-coupled UV absorbance technique (de Tombe & Stienen, 1995).Compared to wild-type exchange, cTnI63-193 exchanged fibers displayed ∼30% decrease in myofilament Ca2+ sensitivity (EC50). In contrast, neither maximal tension development, nor maximal ATPase activity (and consequently tension-cost), were significant different between the groups, nor was cooperative thin filament activation (Hill coefficient). We conclude that cTnI63-193 found following severe ischemic/reperfusion affects cardiac function predominantly via decreased myofilament Ca2+-sensitivity. Our results may benefit rational drug development aimed to prevent ischemic/reperfusion injury in patients.
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