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• W3143170377 endingPage "108855" @default.
• W3143170377 startingPage "108855" @default.
• W3143170377 abstract "Striated muscle contraction is initiated by Ca2+ binding to, and activating, thin filament regulatory units (RU) within the sarcomere, which then allows myosin cross-bridges from the opposing thick filament to bind actin and generate force. The amount of overlap between the filaments dictates how many potential cross-bridges are capable of binding, and thus how force is generated by the sarcomere. Myopathies and atrophy can impair muscle function by limiting cross-bridge interactions between the filaments, which can occur when the length of the thin filament is reduced or when RU function is disrupted. To investigate how variations in thin filament length and RU density affect ensemble cross-bridge behavior and force production, we simulated muscle contraction using a spatially explicit computational model of the half-sarcomere. Thin filament RUs were disabled either uniformly from the pointed end of the filament (to model shorter thin filament length) or randomly throughout the length of the half-sarcomere. Both uniform and random RU ‘knockout’ schemes decreased overall force generation during maximal and submaximal activation. The random knockout scheme also led to decreased calcium sensitivity and cooperativity of the force-pCa relationship. We also found that the rate of force development slowed with the random RU knockout, compared to the uniform RU knockout or conditions of normal RU activation. These findings imply that the relationship between RU density and force production within the sarcomere involves more complex coordination than simply the raw number of RUs available for myosin cross-bridge binding, and that the spatial pattern in which activatable RU are distributed throughout the sarcomere influences the dynamics of force production." @default.
• W3143170377 created "2021-04-13" @default.
• W3143170377 creator A5004604138 @default.
• W3143170377 creator A5047435506 @default.
• W3143170377 creator A5068156554 @default.
• W3143170377 date "2021-05-01" @default.
• W3143170377 modified "2023-10-12" @default.
• W3143170377 title "The spatial distribution of thin filament activation influences force development and myosin activity in computational models of muscle contraction" @default.
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• W3143170377 doi "https://doi.org/10.1016/j.abb.2021.108855" @default.
• W3143170377 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33781771" @default.

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