EFFECTS OF CARDIOMYOPATHY-RELATED MUTATIONS IN THE N-TERMINUS OF CARDIAC TROPONIN T AND IMPLICATIONS FOR CARDIAC DYSFUNCTION
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Hypertrophic cardiomyopathy (HCM)-related mutations in the N-terminus of cardiac troponin T (TnT) are associated with cardiac dysfunction and a high incidence of sudden cardiac death, however, the primary myofilament dysfunction that underlies such effects are generally unknown. Mutations within the N-terminus of TnT (residues 1-180) are of particular interest because a portion of this region directly interacts with tropomyosin (Tm) to modulate myofilament cooperativity, Ca2+ sensitivity, and crossbridge (XB) recruitment dynamics. Because the modulatory role of the TnT-Tm interaction is differently altered by expression of α- and β-myosin heavy chain (MHC) isoforms, the effects of HCM mutations in the N-terminus of TnT may be differently altered by MHC isoforms. Furthermore, thin filament cooperativity and XB recruitment dynamics, mediated by TnT, are important for length-dependent activation (LDA) in cardiac myofilaments, a process whereby an increase in sarcomere length (SL) enhances myofilament Ca2+ sensitivity. Therefore, HCM mutations within the central region (residues 80-180) of TnT, which directly interacts with Tm, may impair mechanisms underlying LDA. The overall objective of this work is to determine how structural alterations in TnT, mediated by HCM-related mutations, affect cardiac contractile function in an MHC isoform- and SL-dependent manner. The central hypothesis is that HCM-related mutations in TnT (A28V, R94H, and D86A) affect XB recruitment dynamics in cardiac myofilaments, and such effects are differently altered by MHC isoforms and changes in SL. Our hypothesis was tested by measuring cardiac contractile dynamics in muscle fibers containing recombinant TnT variants. Specific Aim 1 was designed to determine whether the functional effects of the A28V mutation are differently altered by α- and β-MHC isoforms. Specific Aim 2 was designed to determine whether HCM mutations in the CR of TnT (R94H and D86A) differently affect contractile function at short and long SL. Our findings indicate that the effects of HCM mutations in the N-terminus of TnT on XB recruitment dynamics are differently altered by MHC isoform and changes in SL. By gaining a detailed understanding of the mechanisms underlying myofilament dysfunction caused by mutations, such findings may aid in the development of treatments for cardiac dysfunction due to HCM mutations.