Expression of tropomyosin-κ induces dilated cardiomyopathy and depresses cardiac myofilament tension by mechanisms involving cross-bridge dependent activation and altered tropomyosin phosphorylation

  • Chehade N. Karam
  • Chad M. Warren
  • Sudarsan Rajan
  • Pieter P. de Tombe
  • David F. Wieczorek
  • R. John Solaro
Original Paper


Tropomyosin-kappa (TPM1-κ) is a newly discovered tropomyosin (TM) isoform that is exclusively expressed in the human heart and generated by an alternative splicing of the α-TM gene. We reported that TPM1-κ expression was increased in the hearts of patients with chronic dilated cardiomyopathy (DCM). To increase our understanding of the significance of this shift in isoform population, we generated transgenic (TG) mice expressing TPM1-κ in the cardiac compartment where TPM1-κ replaces 90% of the native TM. We previously showed that there was a significant inhibition of the ability of strongly bound cross-bridges to induce activation of TG myofilaments (Rajan et al., Circulation 121:410–418, 2010). Here, we compared the force–Ca2+ relations in detergent extracted (skinned) fiber bundles isolated from non-transgenic (NTG) and TG-TPM1-κ hearts at two sarcomere lengths (SLs). Our data demonstrated a significant decrease in the Ca2+ sensitivity of the myofilaments from TG-TPM1-κ hearts with no change in the maximum developed tension, length-dependent activation, and the ratio of ATPase rate to tension. There was also no difference in the affinity and cooperativity of Ca2+-binding to troponin in thin filaments reconstituted with either TPM1-κ or α-TM. We also compared protein phosphorylation in NTG and TG-TPM1-κ myofilaments. There was a decrease in the total phosphorylation of TPM1-κ compared to α-TM, but no significant change in other major sarcomeric proteins. Our results identify a novel mode of myofilament desensitization to Ca2+ associated with a DCM linked switch in TM isoform population.


Calcium sensitivity Tension cost Thin filament regulation ATPase Sarcomeric proteins 



The authors would like to thank both Dr. Tomoyoshi Kobayashi for his help with the TnC binding measurements and Bindiya G. Patel for her assistance with the 2D-DIGE experiments. This work was supported by American Heart Association-Midwest Pre-Doctoral Fellowship (CNK) and by NIH Grants PO1 HL062426 (RJS, PdeT), RO1 HL022231 (RJS), RO1 HL081680, and RO1 HL071952 (DFW).


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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Chehade N. Karam
    • 1
  • Chad M. Warren
    • 1
  • Sudarsan Rajan
    • 2
  • Pieter P. de Tombe
    • 3
  • David F. Wieczorek
    • 2
  • R. John Solaro
    • 1
  1. 1.Department of Physiology and Biophysics, Center for Cardiovascular Research, College of MedicineUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of Molecular Genetics, Biochemistry and Microbiology, College of MedicineUniversity of CincinnatiCincinnatiUSA
  3. 3.Department of Cell and Molecular Physiology, Stritch School of MedicineLoyola University ChicagoChicagoUSA

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