Troponin T Isoform Regulation and Structure-Function Relation- ships

Three fiber type-specific genes have evolved in vertebrates to encode cardiac, slow and fast skeletal muscle troponin Ts (TnT). From the transcript of each gene, alternative RNA splicing produces multiple TnT isoforms with structural differences in three variable regions of the polypeptide chain. The expression of TnT isoform is regulated during heart and muscle development and adaptation. Muscles containing different TnT isoforms show differences in their sensitivity to Ca-activation and cooperativity of contraction. The NH2-terminal region of TnT is hypervariable among isoforms and may play a role in modulating the contractility corresponding to the cellular environment and functional state of the muscle. Molecular evolution of the NH2-terminal variable region of TnT indicates its tolerance to structural variation and role in the functional divergence of striated muscle. Physical property of the NH2-terminal domain of TnT modulates conformation and function of other regions of TnT, explaining the functional significance of TnT isoform regulation. Speciesspecific timing of cardiac TnT isoform switching is synchronized in the heart and skeletal muscle, suggesting control by a genetic program. Therefore, the regulation of TnT isoform expression is not only a response to functional demands but may contribute to both physiological adaptation and pathogenesis.