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Am J Physiol Heart Circ Physiol 283: H1344-H1353, 2002. First published June 13, 2002; doi:10.1152/ajpheart.00351.2002
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Vol. 283, Issue 4, H1344-H1353, October 2002

Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-dependent Ca2+ activation

Kathy Pieples1, Grace Arteaga5, R. John Solaro5, Ingrid Grupp2, John N. Lorenz3, Greg P. Boivin4, Ganapathy Jagatheesan1, Erin Labitzke1, Pieter P. deTombe5, John P. Konhilas5, Thomas C. Irving6, and David F. Wieczorek1

1 Department of Molecular Genetics, Biochemistry, and Microbiology, 2 Department of Pharmacology and Cell Biophysics, 3 Department of Molecular and Cellular Physiology, 4 Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0529; 5 Department of Physiology and Biophysics, College of Medicine, University of Illinois, Chicago, 60612; and 6 Center for Synchrotron Radiation Research and Instrumentation and Department of Biological, Chemical, and Physical Sciences, Illinois Institute of Technology, Chicago, Illinois 60616

Tropomyosin (TM), an integral component of the thin filament, is encoded by three striated muscle isoforms: alpha -TM, beta -TM, and TPM 3. Although the alpha -TM and beta -TM isoforms are well characterized, less is known about the function of the TPM 3 isoform, which is predominantly found in the slow-twitch musculature of mammals. To determine its functional significance, we ectopically expressed this isoform in the hearts of transgenic mice. We generated six transgenic mouse lines that produce varying levels of TPM 3 message with ectopic TPM 3 protein accounting for 40-60% of the total striated muscle tropomyosin. The transgenic mice have normal life spans and exhibit no morphological abnormalities in their sarcomeres or hearts. However, there are significant functional alterations in cardiac performance. Physiological assessment of these mice by using closed-chest analyses and a work-performing model reveals a hyperdynamic effect on systolic and diastolic function. Analysis of detergent-extracted fiber bundles demonstrates a decreased sensitivity to Ca2+ in force generation and a decrease in length-dependent Ca2+ activation with no detectable change in interfilament spacing as determined by using X-ray diffraction. Our data are the first to demonstrate that TM isoforms can affect sarcomeric performance by decreasing sensitivity to Ca2+ and influencing the length-dependent Ca2+ activation.

heart; cardiac muscle; thin filament regulation


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