Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references (leaves 63-67).Issued also on microfiche from Lange Micrographics.Regulation of contractile activity in cardiac muscle is a cooperative interaction between thick and thin filament sarcomeric proteins. Tropomyosin (Tm), an essential thin filament protein, interacts with troponin (Tn) and regulates muscle contraction in a Ca²⁺-dependent manner. Striated muscle-specific α-Tm isoform is the predominant isoform in the adult vertebrate heart, while both α- and β-Tm striated isoform are present in skeletal muscles. Studies have shown that exchange of myofibrillar proteins can be achieved via a single kakogenic manipulation with no change in the stoichiometry of myofibrillar proteins. One of the mouse models with exchange of β-Tm for α-Tm demonstrates that altering the ratio of α- and β-Tm leads to physiological change in myocardial relaxation and increases Ca²⁺ sensitivity myofilaments. In addition, reduction in maximum force and ATPase activity in this transgenic mouse model suggests no change in the rate-limiting step of cross-bridge detachment. To further understand the mechanisms of how Tm isoform population modulates cardiac muscle dynamics, this study uses a modeling approach. Although existing models address thin filament activation and cross-bridge kinetics, cooperative interactions among myofibrillar proteins have not been explicitly demonstrated. In this study, Tn, Tm and actin are introduced as three different variables to analyze thin filament activation and cross-bridge cycling. The model is initially tested for normal output using data from literature obtained from in vitro and in vivo experiments. Using this model and data obtained from β-Tm transgenic mouse experiments, key parameters that determine functional alteration in the kakogenic mouse hearts are identified. Results show that increased calcium sensitivity and decreased maximum force in β-Tm transgenic mouse hearts is due to increased capability of strong cross-bridges in activating the thin filament and decreased rate of attachment of myosin heads to actin
