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Date of Award
Physics and Astronomy
Contraction of cardiac muscle is the basis of heart function. Heart failure, i.e., weakened contraction of cardiac muscle is the most common cause of morbidity and mortality of heart diseases. Cardiac muscle contraction is regulated by calcium via the function of troponin, a protein complex associated with the myofilaments in muscle cells. The cardiac troponin subunits T (cTnT) and I (cTnI) have unique N-terminal extensions that can be selectively removed by restrictive proteolysis during cardiac adaptation to physiological and pathological stresses, indicating a role of these proteins in modulating cardiac contraction. This study aims to understand the effects of the N-terminal extensions of cTnT and cTnI on the actomyosin ATPase kinetics in response to Ca2+ signal, which is the foundation of cardiac muscle power generation. The ATP binding and ADP dissociation rates of the actomyosin ATPase of cardiac myofibrils containing cTnI lacking the N-terminal extension (cTnI-ND) have been measured using stopped flowmetry with mant-dATP and mant-dADP, respectively. The results showed that the second order mant-dATP binding rate for cTnI-ND myofibrils was three-fold as fast as that of wild type myofibrils. Moreover, the ADP dissociation rate of cTnI-ND myofibrils was positively dependent on calcium concentrations, while the wild type controls were not significantly affected. Further studies will be performed to determine the other steps of the ATPase cycle in cTnI-ND myofibrils, as well as the kinetic properties of cardiac myofibrils of which the N-terminus of cTnT has been genetically removed. The anticipated results will determine the rate-limiting steps of actomyosin ATPase cycle that are regulated by the N-terminal extensions of cTnI and cTnT.
Completion of the proposed study will lead to new understanding of the function of the N-terminal segments of cTnI and cTnT as well as troponin-tropomyosin-mediated regulation of cardiac muscle contraction, which in turn, may provide useful information for the development of new treatment for heart failure.
Gunther, Laura, "The Effects Of The N-Terminal Extensions Of Cardiac Troponins On The Ca2+ Regulation Of Myosin Atpase Kinetics In Cardiac Myofibrils" (2016). Wayne State University Dissertations. 1539.