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The Ca2+ sensitivity of cardiac muscle force development can be adversely altered during disease.Since troponin C (TnC) is the Ca2+ sensor for muscle contraction, TnCs Ca2+ binding properties may be altered by the disease related protein modifications.Consistent with the pathophysiology, the inherited restrictive cardiomyopathy (RCM) mutation TnI R192H and ischemia induced truncation of TnI (residues 1-192) increased TnCs Ca2+ binding sensitivity ~3 fold and ~7 fold respectively in reconstituted thin filaments, while the dilated cardiomyopathy (DCM) mutation TnT K210 decreased TnCs Ca2+ binding sensitivity ~3 fold.Since abnormal Ca2+ binding might be the potential cause for the disease symptoms, correcting the disease related abnormal Ca2+ binding might improve cardiac function.To achieve this goal, we have engineered TnC constructs with a wide range of Ca2+ binding sensitivities.Ca2+ desensitizing TnC constructs combined with the RCM TnI or truncated TnI corrected the disease related increased Ca2+ sensitivities; while Ca2+ sensitizing TnC constructs combined with the DCM TnT corrected the disease related decreased Ca2+ sensitivity.We were able to fine tune the Ca2+ sensitivity of the TnC constructs, allowing us to correct the disease induced abnormal Ca2+ binding.This study can potentially lead to a novel therapeutic strategy for treating cardiac muscle diseases: (Supported by NIH K99 HL087462 (to SBT); RO1 HL 073828 (to DRS); RO1 AR020792 (to JAR); and AHA SDG 0735079 (to JPD).