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Regulation of cardiac muscle contraction: effect of tropomyosin isoform expression and cardiomyopathy mutations in tropomyosin and troponin

Boussouf, Sabrina Eida (2004) Regulation of cardiac muscle contraction: effect of tropomyosin isoform expression and cardiomyopathy mutations in tropomyosin and troponin. Doctor of Philosophy (PhD) thesis, University of Kent. (doi:10.22024/UniKent/01.02.86304) (KAR id:86304)

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Regulation of the acto-myosin interaction is mediated by the Ca2+ -induced changes in the properties of the thin filament proteins tropomyosin and troponin. Two major tropomyosin isoforms, a and 13, are expressed in striated muscle with larger amounts of 13 expressed in slow-contracting skeletal muscle and slower beating hearts of big mammals. The regulatory properties of a and 13 tropomyosin were defined in terms of the three-state model of regulation. The Ca2+ - dependent regulation of the thin filament was identical for a and 13 in the presence of skeletal troponin proteins. However, 13 tropomyosin-containing thin filaments were more Ca2+ sensitive in the presence of cardiac troponin. The thermal stability of the two isoforms was also examined using Differential Scanning Calorimetry. 13 tropomyosin was significantly less thermostable than a tropomyosin as it is partially unfolded at 37°C when free in solution. In the presence of actin, both u and 13 tropomyosin stability is increased. However, 13 tropomyosin unfolding starts at 40°C, a temperature the body can reach. These findings provide an explanation for the low level of 13 tropomyosin expression in the heart and the fact that it is predominantly found associated with a tropomyosin as a heterodimer. Familial Hypertrophy Cardiomyopathy (FHC) is an autosomal dominant disease, which causes sudden death of young and healthy individuals. The effect of FHC mutations expressed in tropomyosin and troponin proteins on the regulatory process was investigated. Two mutations in u tropomyosin (D175N and EI80G), and three mutations in trponin (G203S and K206Q in TnI, L29E in TnC) were examined. Both D175N and E180G increased the Ca2+ sensitivity of the system when associated with cardiac troponin Also, both mutations decreased the local stability of tropomyosin when free in solution In the presence of actin, D 17 5N tropomyosin thermal stability was indistinguishable from wild type. No detectable changes in the regulatory function of the thin filament were observed with troponin mutations G203S in troponin I and L29E in troponin C. However, K206Q mutation in troponin I caused an increase in the Ca2+ sensitivity interestingly only when troponin I was phosphorylated.

Item Type: Thesis (Doctor of Philosophy (PhD))
Thesis advisor: Geeves, Michael A.
DOI/Identification number: 10.22024/UniKent/01.02.86304
Additional information: This thesis has been digitised by EThOS, the British Library digitisation service, for purposes of preservation and dissemination. It was uploaded to KAR on 09 February 2021 in order to hold its content and record within University of Kent systems. It is available Open Access using a Creative Commons Attribution, Non-commercial, No Derivatives ( licence so that the thesis and its author, can benefit from opportunities for increased readership and citation. This was done in line with University of Kent policies ( If you feel that your rights are compromised by open access to this thesis, or if you would like more information about its availability, please contact us at and we will seriously consider your claim under the terms of our Take-Down Policy (
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
SWORD Depositor: SWORD Copy
Depositing User: SWORD Copy
Date Deposited: 29 Oct 2019 16:49 UTC
Last Modified: 20 Dec 2022 09:31 UTC
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