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Functional consequence of mutation in rat cardiac troponin T is affected differently by myosin heavy chain isoforms

Cardiac troponin T (cTnT) is an essential component of the thin filament regulatory unit (RU) that regulates Ca2+ activation of tension in the heart muscle. Because there is coupling between the RU and myosin crossbridges, the functional outcome of cardiomyopathy‐related mutations in cTnT may be modified by the type of myosin heavy chain (MHC) isoform. Ca2+ activation of tension and ATPase activity were measured in muscle fibres from normal rat hearts containing α‐MHC isoform and propylthiouracil (PTU)‐treated rat hearts containing β‐MHC isoform. Muscle fibres from normal and PTU‐treated rat hearts were reconstituted with two different mutations in rat cTnT; the deletion of Glu162 (cTnTE162DEL) and the deletion of Lys211 (cTnTK211DEL). α‐MHC and β‐MHC isoforms had contrasting impact on tension‐dependent ATP consumption (tension cost) in cTnTE162DEL and cTnTK211DEL reconstituted muscle fibres. Significant increases in tension cost in α‐MHC‐containing muscle fibres corresponded to 17% (P < 0.01) and 23% (P < 0.001) when reconstituted with cTnTE162DEL and cTnTK211DEL, respectively. In contrast, tension cost decreased when these two cTnT mutants were reconstituted in muscle fibres containing β‐MHC; by approximately 24% (P < 0.05) when reconstituted with cTnTE162DEL and by approximately 17% (P= 0.09) when reconstituted with cTnTK211DEL. Such differences in tension cost were substantiated by the mechano‐dynamic analysis of cTnT mutant reconstituted muscle fibres from normal and PTU‐treated rat hearts. Our observation demonstrates that qualitative changes in MHC isoform alters the nature of cardiac myofilament dysfunction induced by mutations in cTnT.