Abnormal Thin Filament Calcium Binding Associated with Cardiac Muscle Diseases Can be Corrected Through TnC Mutagenesis

Abstract

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, TnC's Ca2+ binding properties may be affected by the disease related protein modifications. To test this hypothesis, a fluorescent TnC was utilized to measure the Ca2+ binding sensitivity of TnC in the physiologically relevant biochemical model system of reconstituted thin filaments. Consistent with the pathophysiology, the inherited restrictive cardiomyopathy (RCM) mutation TnI R192H and ischemia induced truncation of TnI (residues 1-192) increased TnC's Ca2+ binding sensitivity ∼3 fold and ∼7 fold, respectively; while the dilated cardiomyopathy (DCM) mutation TnT deltaK210 decreased TnC's Ca2+ binding sensitivity ∼ 3 fold.