Mutations in Troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function?

Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 4.66). 11/2009; 48(5):882-92. DOI: 10.1016/j.yjmcc.2009.10.031
Source: PubMed

ABSTRACT Troponin (Tn) is a critical regulator of muscle contraction in cardiac muscle. Mutations in Tn subunits are associated with hypertrophic, dilated and restrictive cardiomyopathies. Improved diagnosis of cardiomyopathies as well as intensive investigation of new mouse cardiomyopathy models has significantly enhanced this field of research. Recent investigations have showed that the physiological effects of Tn mutations associated with hypertrophic, dilated and restrictive cardiomyopathies are different. Impaired relaxation is a universal finding of most transgenic models of HCM, predicted directly from the significant changes in Ca(2+) sensitivity of force production. Mutations associated with HCM and RCM show increased Ca(2+) sensitivity of force production while mutations associated with DCM demonstrate decreased Ca(2+) sensitivity of force production. This review spotlights recent advances in our understanding on the role of Tn mutations on ATPase activity, maximal force development and heart function as well as the correlation between the locations of these Tn mutations within the thin filament and myofilament function.

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    • "Strong evidence links the disease phenotypes with the increased Ca 2? -sensitivity (Jagatheesan et al. 2007; Pinto et al. 2008) thereby strengthening the rationale of using reconstituted mutated systems to model the phenotype. There have been several recent studies and reviews of sarcomeric proteins whose mutations are linked to HCM and RCM (Robinson et al. 2007; Parvatiyar et al. 2010; Gomes et al. 2004; Tardiff 2005; Marston 2011; Ohtsuki and Morimoto 2008; Willott et al. 2009; Tardiff 2011; Redwood and Robinson 2013; Spudich 2014). In this review, we will mainly focus on some mutations in cardiac troponin I (cTnI) and briefly discuss some of the studies with the other thin filament proteins Tm, cTnC and cardiac troponin T (cTnT) that provide evidence of increased contribution of the M 2 state. "
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    ABSTRACT: This review proposes a link between the hypertrophic (HCM) and restrictive cardiomyopathies caused by mutations in several sarcomeric thin filament proteins, and the open state of the three-state muscle regulation theory. The three characteristics of various muscle systems reconstituted from HCM mutated proteins (increased Ca(2+)-sensitivity, increased basal activity in the absence of Ca(2+), and decreased cooperativity) can be explained by the contribution of a myosin-induced open state (M (-) ), which elevates the basal activity and competes with the normal Ca(2+)-activated pathway. A model based on the three-state theory of regulation, shows how a change in the closed/blocked equilibrium caused by a mutation that weakens the binding of troponin I to tropomyosin-actin can produce the characteristics of HCM. This review also shows that in the M (-) state, Ca(2+) can shift the closed-open equilibrium of the N-terminal hydrophobic region of troponin C without affecting activity.
    Journal of Muscle Research and Cell Motility 04/2014; 35(2). DOI:10.1007/s10974-014-9383-z · 2.09 Impact Factor
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    • "Other groups also reported similar results.[66]–[68] Almost all DCM-causing mutations reported in cTnT to date, e.g., R131W, R141W, R205, ΔK210, R205L, and D270N, etc., have demonstrated a Ca2+-desensitizing effect on skinned fiber force generation and myofibrillar or actomyosin ATPase activity.[65],[68]–[70] These results strongly suggest that Ca2+ desensitization of cardiac muscle contraction is a primary mechanism for the pathogenesis of DCM caused by cTnT mutation, in contrast to HCM where Ca2+ sensitization is a primary mechanism for the pathogenesis. "
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    ABSTRACT: Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca(2+)-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca(2+) sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca(2+) sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.
    Journal of Geriatric Cardiology 03/2013; 10(1):91-101. DOI:10.3969/j.issn.1671-5411.2013.01.014 · 1.40 Impact Factor
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    • "Because the extended N-terminus of cTnT is located around the head-to-tail overlapping region of two contiguous Tms, the presence of this highly acidic region in cTnT is strongly suggestive of a cardiac-specific functional role (Perry, 1998). The functional significance of the N-terminus of cTnT is further highlighted by the fact that numerous mutations, which are associated with familial hypertrophic cardiomyopathy, have been identified in the N-terminus of human cTnT (Willott et al. 2010). Moreover, some forms of human heart failure are associated with reexpression of embryonic isoforms that differ in the N-terminus of cTnT (Anderson et al. 1995). "
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    ABSTRACT: Cardiac troponin T (cTnT) has a highly acidic extended N-terminus, the physiological role of which remains poorly understood. To decipher the physiological role of this unique region, we deleted specific regions within the N-terminus of mouse cTnT (McTnT) to create McTnT(1-44Δ) and McTnT(45-74Δ) proteins. Contractile function and dynamic force-length measurements were made after reconstituting the McTnT deletion proteins into detergent-skinned cardiac papillary fibres harvested from nontransgenic mice that expressed α-tropomyosin (Tm). To further understand how the functional effects of N-terminus of cTnT are modulated by Tm isoforms, McTnT deletion proteins were reconstituted into detergent-skinned cardiac papillary fibres harvested from transgenic mice that expressed both α- and β-Tm. McTnT(1-44Δ), but not McTnT(45-74Δ), attenuated maximal activation of the thin filament. Myofilament Ca(2+) sensitivity, as measured by pCa(50) (-log of [Ca(2+)](free) required for half maximal activation), decreased in McTnT(1-44Δ) (α-Tm) fibres. The desensitizing effect of McTnT(1-44Δ) on pCa(50) was ablated in β-Tm fibres. McTnT(45-74Δ) enhanced pCa(50) in both α- and β-Tm fibres, with β-Tm having a bigger effect. The Hill coefficient of tension development was significantly attenuated by McTnT(45-74Δ), suggesting an effect on thin filament cooperativity. The rate of crossbridge (XB) detachment and the strained XB-mediated impact on other XBs were augmented by McTnT(1-44Δ) in β-Tm fibres. The magnitude of the length-mediated recruitment of XBs was attenuated by McTnT(1-44Δ) in β-Tm fibres. Our data demonstrates that the 1-44 region of McTnT is essential for maximal activation, whereas the cardiac-specific 45-74 region of McTnT is essential for augmenting cooperativity. Moreover, our data shows that α- and β-Tm isoforms have divergent effects on McTnT deletion mutant's ability to modulate cardiac thin filament activation and Ca(2+) sensitivity. Our results not only provide the first explicit evidence for the existence of two distinct functional regions within the N-terminus of cTnT, but also offer mechanistic insights into the divergent physiological roles of these regions in mediating cardiac contractile activation.
    The Journal of Physiology 12/2012; 591(5). DOI:10.1113/jphysiol.2012.243394 · 5.04 Impact Factor
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