Abstract
Striated muscle contraction is a highly cooperative process initiated by Ca2+ binding to the troponin complex, which leads to tropomyosin movement and myosin cross-bridge (XB) formation along thin filaments. Experimental and computational studies suggest skeletal muscle fiber activation is greatly augmented by cooperative interactions between neighboring thin filament regulatory units (RU-RU cooperativity; 1 RU = 7 actin monomers+1 troponin complex+1 tropomyosin molecule). XB binding can also amplify thin filament activation through interactions with RUs (XB-RU cooperativity). Because these interactions occur with a temporal order, they can be considered kinetic forms of cooperativity. Our previous spatially-explicit models illustrated that mechanical forms of cooperativity also exist, arising from XB-induced XB binding (XB-XB cooperativity). These mechanical and kinetic forms of cooperativity are likely coordinated during muscle contraction, but the relative contribution from each of these mechanisms is difficult to separate experimentally. To investigate these contributions we built a multi-filament model of the half sarcomere, allowing RU activation kinetics to vary with the state of neighboring RUs or XBs. Simulations suggest Ca2+ binding to troponin activates a thin filament distance spanning 9 to 11 actins and coupled RU-RU interactions dominate the cooperative force response in skeletal muscle, consistent with measurements from rabbit psoas fibers. XB binding was critical for stabilizing thin filament activation, particularly at submaximal Ca2+ levels, even though XB-RU cooperativity amplified force less than RU-RU cooperativity. Similar to previous studies, XB-XB cooperativity scaled inversely with lattice stiffness, leading to slower rates of force development as stiffness decreased. Including RU-RU and XB-RU cooperativity in this model resulted in the novel prediction that the force-[Ca2+] relationship can vary due to filament and XB compliance. Simulations also suggest kinetic forms of cooperativity occur rapidly and dominate early to get activation, while mechanical forms of cooperativity act more slowly, augmenting XB binding as force continues to develop.
Highlights
Striated muscle contraction is a Ca2+ dependent process
We [4] and others [28] estimated this thin filament activation span to be 10–12 actins for skeletal muscle by using experimental approaches to titrate the number of functional troponin complexes along the length of thin filaments
Predictions from their continuous flexible chain model suggest Ca2+-binding or XB binding may lead to ‘clusters’ of force bearing XBs along the thin filament, near the onset of contraction at low [Ca2+]. This distance agrees well with our estimates of RUspan and supports the idea that cooperative activation occurs at relatively local regions along the thin filament, consistent with clustered islands of XB binding throughout the half-sarcomere that have been demonstrated by previous spatially-explicit models [23,26]. These simulations show that regulatory units (RU)-RU cooperativity occurs rapidly and dominates filament activation early in the contractile process, while the influence of XB-RU and XB-XB cooperativity occurs more slowly, becoming increasingly important as force continues to develop
Summary
Striated muscle contraction is a Ca2+ dependent process. Ca2+ binding to troponin initiates thin filament activation, defined as exposure of sites along F-actin to which myosin can bind and form a cross-bridge (XB). The increase in force production with increasing [Ca2+] is highly non-linear, suggesting there is coupling between Ca2+-dependent and XB-dependent processes to augment thin filament activation and force production. The highly structured organization of the myofilament lattice (Figure S1) has led many investigators to suspect a role for spatial interactions between neighboring thin filament regulatory units (1 RU = 7 actin monomers+1 troponin complex+1 tropomyosin molecule) and/or neighboring XBs along the myofilaments to cooperatively augment thin filament activation [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. A detailed picture of the Ca2+-dependent and XB-dependent cooperative mechanisms remains unclear because multiple cooperative processes are almost certainly coupled as muscle fibers contract
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