Troponin T isoforms modulate calcium dependence of the kinetics of the cross-bridge cycle: Studies using a transgenic mouse line

Alternative splicing of troponin T (TnT) in striated muscle during development results in expression of different isoforms, with the splicing of a 5′ exon of TnT resulting in the expression of low-molecular-weight basic adult TnT isoforms and high-molecular-weight acidic embryonic TnT isoforms. Although other differences exist, the main differences between cardiac TnT (cTnT) and fast skeletal muscle TnT (fTnT) are in the NH₂ terminus, with fTnT being less acidic than cTnT. A transgenic mouse line expressing chicken fTnT in the heart was used to investigate the functional significance of TnT NH₂-terminal charge differences on cardiac muscle contractility. The rates of force redevelopment (k_tr) at four levels of Ca²⁺ activation were recorded for skinned left ventricular trabeculae from control and transgenic mice. The k_tr vs Ca²⁺ relationship was different in control mice and transgenic mice, suggesting that the structure of TnT, and possibly the NH₂-terminal region, is involved in determining the kinetics of cross-bridge cycle. These results suggest that isoform shifts in TnT may be an important molecular mechanism for determining the Ca²⁺ dependence of cardiac muscle contractility.