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Am J Physiol Heart Circ Physiol (June 13, 2002). doi:10.1152/ajpheart.00351.2002
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Articles in PresS, published online ahead of print June 13, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00351.2002
Submitted on May 8, 2002
Accepted on June 13, 2002

Expression of Tropomyosin 3 in Murine Hearts Leads to Hypercontractility and Attentuates Myofilament Length Dependent Ca2+ Activation

Kathy Pieples1, Grace Arteaga2, R. John Solaro2, Ingrid Grupp3, John N. Lorenz4, Greg P. Boivin5, Ganapathy Jagatheesan1, Erin Labitzke1, Pieter P. deTombe2, John P. Konhilas2, Thomas C. Irving6, and David F. Wieczorek1*

1 Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
2 Physiology and Biophysics, University of Illinois Chicago: College of Medicine, Chicago, IL, USA
3 Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
4 Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
5 Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
6 CSRRI and BCPC, Illinois Institute of Technology, Chicago, IL, USA

* To whom correspondence should be addressed. E-mail: david.wieczorek{at}uc.edu.

Tropomyosin (TM), an integral component of the sarcomere, is encoded by three isoforms: {alpha}-TM, ß-TM, and TPM 3. Although {alpha}-TM and ß-TM isoforms are well characterized, less is known about the function of TPM 3. To determine its functional significance, we ectopically expressed TPM 3 in the hearts of transgenic mice. We generated six transgenic 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 using closed-chest analyses and a work-performing model reveals a hyperdynamic effect on systolic and diastolic function. Fiber bundles demonstrate 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 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.




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