Abstract
Delayed stretch activation (SA) is a prominent feature in the function of the cardiac myocyte and plays an important role in regulating cardiac output. A mechanistic understanding of SA is essential for the development of models that quantitatively and causally connect molecular defects to global cardiac function. We propose a novel mechanism that defines how mechanical forces imposed by stretch affect troponin-actin and myosin-actin bonds and thereby modify calcium-modulated thin filament regulation. Tropomyosin molecules are assumed to form two continuous flexible chains (CFC) along each actin filament; tropomyosin movements are restricted by bound troponins and myosin heads bound to actin. Crossbridges transmit sarcomere forces to the thin and the thick filaments. A stretch applied on a sarcomere extends the thin filaments and associated CFCs imposing additional strain (via the CFC) on the TnI-actin and myosin-actin bonds. The spatial positions of these bonds were calculated using the computational platform, MUSICO (MUscle SImulation COde) and, hence, the forces acting on TnI-actin and myosin-actin bonds before and after stretch at different Ca2+ concentrations. These forces were assessed from finite element analysis of CFCs weakly interacting with the actin surface and strongly interacting with actin via Tn attachments to actin. An imposed stretch leading to sarcomere forces of ∼50% of the maximum isometric force increased the forces on the bonds by more than 10 pN, sufficient to strongly tilt the energy landscapes and accelerate the rate of detachment of Tn from actin, even without Ca2+ bound to TnC. The maximum effect of this behavior is observed in muscle fibers at submaximal activation (pCa ∼ 6). This analysis suggests a mechanism for observed modulation of cardiac myocyte contractility by SA based on altered mechanochemistry of thin filaments regulation via CFC. Supported by NIH R01 AR048776 and R01 DC 011528.
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