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
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.
Available from: Arjun Adhikari
- "Regardless of the source of the mammalian myosin, however, the general paradigm holds true that HCM mutations in tropomyosin or troponin are sensitizers to Ca 2+ (e.g. Fig. 6shows HCM mutations for three TnI mutations), while DCM mutations are desensitizers (Willott et al., 2010).The myosin mesa and a possible role for MyBP-C and titin in regulating the number of functionally available myosin heads in the sarcomere "
Available from: Hak-Joon Sung
- "The increased expression of MLC2 gene and protein under healthy, static conditions can explain a critical symptom of DCM, most notably a diminished systolic function accompanied by an inability to generate the necessary contractile force. Therefore, this result supports the idea that CM structure and function are affected by a pathological status (altering cellular mechanism) related to DCM (Marian and Roberts, 1994; Morita et al., 2005; Willott et al., 2010). A previous study reported reduced beating rates and contractility with altered sarcomere structures in iPSC-CMs derived from DCM patients (Sun et al., 2012). "
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ABSTRACT: Primary dilated cardiomyopathy (DCM) is a non-ischemic heart disease with impaired pumping function of the heart. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a healthy volunteer and a primary DCM patient to investigate the impact of DCM on iPSC-CMs׳ responses to different types of anisotropic strain. A bioreactor system was established that generates cardiac-mimetic forces of 150kPa at 5% anisotropic cyclic strain and 1Hz frequency. After confirming cardiac induction of the iPSCs, it was determined that fibronectin was favorable to other extracellular matrix protein coatings (gelatin, laminin, vitronectin) in terms of viable cell area and density, and was therefore selected as the coating for further study. When iPSC-CMs were exposed to three strain conditions (no strain, 5% static strain, and 5% cyclic strain), the static strain elicited significant induction of sarcomere components in comparison to other strain conditions. However, this induction occurred only in iPSC-CMs from a healthy volunteer ("control iPSC-CMs"), not in iPSC-CMs from the DCM patient ("DCM iPSC-CMs"). The donor type also significantly influenced gene expressions of cell-cell and cell-matrix interaction markers in response to the strain conditions. Gene expression of connexin-43 (cell-cell interaction) had a higher fold change in healthy versus diseased iPSC-CMs under static and cyclic strain, as opposed to integrins α-5 and α-10 (cell-matrix interaction). In summary, our iPSC-CM-based study to model the effects of different strain conditions suggests that intrinsic, genetic-based differences in the cardiomyocyte responses to strain may influence disease manifestation in vivo.
Available from: Yin-Biao Sun
- "While FHC mutations have been identified across a wide range of proteins, more than half of all mutations that cause hypertrophy occur in proteins of the sarcomere . As of 2010, 68 mutations in the troponin complex had been linked to FHC . The first mutation associated with FHC in cTnC was L29Q (cTnC(L29Q)), which was identified in a patient suffering from left ventricular hypertrophy . "
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ABSTRACT: Familial Hypertrophic Cardiomyopathy (FHC) is characterized by severe abnormal cardiac muscle growth. The traditional view of disease progression in FHC is that an increase in the Ca(2+)-sensitivity of cardiac muscle contraction ultimately leads to pathogenic myocardial remodeling, though recent studies suggest this may be an oversimplification. For example, FHC may be developed through altered signaling that prevents downstream regulation of contraction. The mutation L29Q, found in the Ca(2+)-binding regulatory protein in heart muscle, cardiac troponin C (cTnC), has been linked to cardiac hypertrophy. However, reports on the functional effects of this mutation are conflicting, and our goal was to combine in vitro and in situ structural and functional data to elucidate its mechanism of action. We used Nuclear Magnetic Resonance and Circular Dichroism to solve the structure and characterize the backbone dynamics and stability of the regulatory domain of cTnC with the L29Q mutation. The overall structure and dynamics of cTnC were unperturbed, although a slight rearrangement of site 1, an increase in backbone flexibility, and a small decrease in protein stability were observed. The structure and function of cTnC was also assessed in demembranated ventricular trabeculae using Fluorescence for In Situ Structure. L29Q reduced the cooperativity of the Ca(2+)-dependent structural change in cTnC in trabeculae under basal conditions and abolished the effect of force-generating myosin cross-bridges on this structural change. These effects could contribute to the pathogenesis of this mutation.
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