Cardiomyopathy-Related Mutations in Cardiac Troponin C, L29Q and G159D, Have Divergent Effects on Rat Cardiac Myofiber Contractile Dynamics

Previous studies of cardiomyopathy-related mutations in cardiac troponin C (cTnC)—L29Q and G159D—have shown diverse findings. The link between such mutant effects and their divergent impact on cardiac phenotypes has remained elusive due to lack of studies on contractile dynamics. We hypothesized that a cTnC mutant-induced change in the thin filament will affect global myofilament mechanodynamics because of the interactions of thin filament kinetics with both Ca(2+) binding and crossbridge (XB) cycling kinetics. We measured pCa-tension relationship and contractile dynamics in detergent-skinned rat cardiac papillary muscle fibers reconstituted with the recombinant wild-type rat cTnC (cTnC(WT)), cTnC(L29Q), and cTnC(G159D) mutants. cTnC(L29Q) fibers demonstrated a significant decrease in Ca(2+) sensitivity, but cTnC(G159D) fibers did not. Both mutants had no effect on Ca(2+)-activated maximal tension. The rate of XB recruitment dynamics increased in cTnC(L29Q) (26%) and cTnC(G159D) (25%) fibers. The rate of XB distortion dynamics increased in cTnC(G159D) fibers (15%). Thus, the cTnC(L29Q) mutant modulates the equilibrium between the non-cycling and cycling pool of XB by affecting the on/off kinetics of the regulatory units (Tropomyosin-Troponin); whereas, the cTnC(G159D) mutant increases XB cycling rate. Different effects on contractile dynamics may offer clue regarding how cTnC(L29Q) and cTnC(G159D) cause divergent effects on cardiac phenotypes.