%0 Journal Article %1 Schmitt2006 %A Schmitt, J. P. %A Debold, E. P. %A Ahmad, F. %A Armstrong, A. %A Frederico, A. %A Conner, D. A. %A Mende, U. %A Lohse, M. J. %A Warshaw, D. %A Seidman, C. E. %A Seidman, J. G. %D 2006 %J Proc Natl Acad Sci U S A %K Actins/metabolism Animal Animals Biomechanics Cardiac Cardiac/cytology Cardiomyopathy, Dilated/*metabolism/ultrasonography Disease Echocardiography Heterozygote Homozygote Mice Missense/*genetics Models, Molecular Motor Mutant Mutation, Myocardium/cytology/pathology Myocytes, Myosins/chemistry/*genetics Protein Proteins/metabolism Secondary Structure, %N 39 %P 14525-30 %T Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16983074 %V 103 %X Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.

@article{Schmitt2006, abstract = {Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Schmitt, J. P. and Debold, E. P. and Ahmad, F. and Armstrong, A. and Frederico, A. and Conner, D. A. and Mende, U. and Lohse, M. J. and Warshaw, D. and Seidman, C. E. and Seidman, J. G.}, biburl = {https://www.bibsonomy.org/bibtex/2590a7b9159392de1043889fde7ed31e3/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {69e84d8110460cc40e914fe9c7e2d08b}, intrahash = {590a7b9159392de1043889fde7ed31e3}, issn = {0027-8424 (Print) 0027-8424 (Linking)}, journal = {Proc Natl Acad Sci U S A}, keywords = {Actins/metabolism Animal Animals Biomechanics Cardiac Cardiac/cytology Cardiomyopathy, Dilated/*metabolism/ultrasonography Disease Echocardiography Heterozygote Homozygote Mice Missense/*genetics Models, Molecular Motor Mutant Mutation, Myocardium/cytology/pathology Myocytes, Myosins/chemistry/*genetics Protein Proteins/metabolism Secondary Structure,}, month = {Sep 26}, note = {Schmitt, Joachim P Debold, Edward P Ahmad, Ferhaan Armstrong, Amy Frederico, Andrea Conner, David A Mende, Ulrike Lohse, Martin J Warshaw, David Seidman, Christine E Seidman, J G Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14525-30. Epub 2006 Sep 18.}, number = 39, pages = {14525-30}, shorttitle = {Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function}, timestamp = {2010-12-14T18:21:43.000+0100}, title = {Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16983074}, volume = 103, year = 2006 }