Fig. 1.

The effect of myofilament Ca²⁺ sensitization on myocyte Ca²⁺ handling. Panel (A) shows the effect of three TnT mutations on myofilament Ca²⁺ sensitivity measured in skinned fibers of transgenic mice [78]. Panel (B) shows the effect myofilament Ca²⁺ sensitization on apparent Ca²⁺ buffering. The change in total Ca²⁺ was measured by the Na/Ca exchanger integral (bottom, shaded area) simultaneously with the change in [Ca²⁺]_free (top panel) in voltage clamped fluo-4 loaded myocytes [90, 92]. Note that the peak [Ca²⁺] is lower in TnT-I79N despite a similar change in total Ca²⁺, consistent with increased Ca²⁺ buffering. (C)+(D) Ca²⁺ transients simulated with LabHEART 5.0 [176] containing a newly integrated force response [177]. Ionic current conductances were adjusted to reproduce a typical mouse action potential. The myofilament Ca²⁺ sensitivity curves in (A) were reproduced by changing the TnC Ca²⁺ on/off rates and Ca²⁺ binding cooperativity. Ca²⁺ transients are simulated at 1 Hz (C) and 5 Hz (D) pacing frequency. Note that peak [Ca²⁺] is lower and Ca²⁺ transients are prolonged in Ca²⁺ sensitized mutants, while the diastolic [Ca²⁺] is additionally increased in TnT-I79N at 5 Hz. Panel (C)+(D) were kindly provided by Dr. J. Puglisi, UC Davis.