Inherited cardiomyopathies as a troponin disease

Abstract

Troponin, one of the sarcomeric proteins, plays a central role in the Ca²⁺ regulation of contraction in vertebrate skeletal and cardiac muscles. More than two hundred of mutations in the cardiac sarcomeric proteins, including myosin heavy/light chains, actin, troponin, tropomyosin, myosin-binding protein-C, and titin/connectin, have been found to cause various types of cardiomyopathy in human since 1990, and over sixty mutations in cardiac troponin subunits have been identified in the hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathies. To explore molecular mechanisms for the pathogenesis of these cardiomyopathies, recombinant mutants of human cardiac troponin subunits were exchanged into permeabilized rabbit cardiac muscle fibers and their effects on the Ca²⁺-dependent force generation in cardiac muscle were examined. Most mutations in cardiac troponin subunits associated with HCM had Ca²⁺-sensitizing effects. In contrast, DCM-linked mutations in cardiac troponin T decreased the Ca²⁺ concentrations required for force generation, strongly suggesting that changes in the Ca²⁺ sensitivity of force generation in cardiac muscle in opposite directions, i.e. Ca²⁺-sensitization and desensitization, play important roles in the pathogenesis of these two distinct forms of cardiomyopathy. RCM-linked mutations in cardiac troponin I had much greater Ca²⁺-sensitizing effects on force generation than HCM-linked mutations, suggesting that HCM and RCM-linked mutations in troponin subunits share a common feature of increased Ca²⁺ sensitivity of cardiac myofilament, but more severe change in Ca²⁺ sensitivity is associated with the clinical phenotype of RCM. [J Physiol Sci. 2006;56 Suppl:S37]