DCM mutations in thin filament regulatory proteins consistently depressed myofibrillar function by reducing Ca(2+) sensitivity of activation compared to wild-type proteins.
Do DCM-causing mutations in thin filament regulatory proteins alter contractile function compared to wild-type proteins?
DCM-causing mutations in thin filament regulatory proteins consistently depress myofibrillar function, suggesting that decreased contractility may trigger pathways leading to the clinical phenotype.
Dilated cardiomyopathy (DCM), characterized by cardiac dilatation and contractile dysfunction, is a major cause of heart failure. Inherited DCM can result from mutations in the genes encoding cardiac troponin T, troponin C, and alpha-tropomyosin; different mutations in the same genes cause hypertrophic cardiomyopathy. To understand how certain mutations lead specifically to DCM, we have investigated their effect on contractile function by comparing wild-type and mutant recombinant proteins. Because initial studies on two troponin T mutations have generated conflicting findings, we analyzed all eight published DCM mutations in troponin T, troponin C, and alpha-tropomyosin in a range of in vitro assays. Thin filaments, reconstituted with a 1:1 ratio of mutant/wild-type proteins (the likely in vivo ratio), all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and except for one alpha-tropomyosin mutant showed lower maximum Ca(2+) activation. Incorporation of either of two troponin T mutants in skinned cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Structure/function considerations imply that the diverse thin filament DCM mutations affect different aspects of regulatory function yet change contractility in a consistent manner. The DCM mutations depress myofibrillar function, an effect fundamentally opposite to that of hypertrophic cardiomyopathy-causing thin filament mutations, suggesting that decreased contractility may trigger pathways that ultimately lead to the clinical phenotype.
Mirza et al. (Sat,) conducted a other in Dilated cardiomyopathy. DCM mutations in troponin T, troponin C, and alpha-tropomyosin vs. Wild-type recombinant proteins was evaluated on Ca(2+) sensitivity of activation and maximum Ca(2+) activation. DCM mutations in thin filament regulatory proteins consistently depressed myofibrillar function by reducing Ca(2+) sensitivity of activation compared to wild-type proteins.