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Hypertrophic and Dilated Cardiomyopathy-Associated Troponin T Mutations R130C and ΔK210 Oppositely Affect

Marcel Groen1, Alfredo Jesus López-Dávila2, Stefan Zittrich3

  • 1Department of Neurology and Neurogeriatry, Johannes Wesling Medical Center, Ruhr-University Bochum, Bochum, Germany.

Frontiers in Physiology
|June 26, 2020
PubMed

Insights

Mutations in human cardiac troponin T (hcTnT) influence myocardial force generation and calcium sensitivity. These findings suggest that altered length-dependent activation in hcTnT may contribute to hypertrophic and dilated cardiomyopathy phenotypes.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Biophysics

Background:

  • The Frank-Starling mechanism relies on length-dependent activation of myocardial force.
  • Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are distinct heart muscle diseases.
  • Troponin T (TnT) mutations are associated with HCM and DCM, but their direct effects on contractility are not fully understood.

Purpose of the Study:

  • To investigate the functional impact of HCM- and DCM-associated human cardiac troponin T (hcTnT) mutations on calcium-dependent force generation and length-dependent activation in cardiac muscle.
  • To compare the effects of specific hcTnT mutations (R130C for HCM, ΔK210 for DCM) against a wild-type control.

Main Methods:

  • Recombinant human cardiac troponin complexes with wild-type (hcTnTWT), HCM-associated (hcTnTR130C), or DCM-associated (hcTnTΔK210) troponin T subunits were used to exchange the native troponin complex in skinned guinea pig trabecular fibers.
  • Force-calcium relationships were measured at two fiber lengths: 110% (short) and 125% (long) of slack length (L0).
  • Calcium sensitivity was quantified by pCa50 (negative logarithm of calcium concentration at half-maximal force).

Main Results:

  • At short fiber length (1.1 L0), calcium sensitivity (pCa50) was highest for hcTnTR130C, intermediate for hcTnTWT, and lowest for hcTnTΔK210.
  • Fiber lengthening from 1.1 L0 to 1.25 L0 increased calcium sensitivity for hcTnTR130C, had no effect on hcTnTWT, and decreased sensitivity for hcTnTΔK210.
  • The changes in calcium sensitivity with length (delta-pCa50) differed significantly between the HCM and DCM mutations (P < 0.001).

Conclusions:

  • Primary effects of hcTnT mutations on length-dependent activation significantly influence myocardial force generation.
  • Altered length-dependent activation by HCM- and DCM-associated hcTnT mutations may be a key factor contributing to the distinct clinical phenotypes of these cardiomyopathies.
  • These findings highlight the critical role of troponin T in integrating mechanical load and calcium signaling to regulate cardiac contractility.

Keywords:
calcium sensitivitycardiomyopathycontractilityforce generationlength dependent activationsarcomere lengththin filament regulationtroponin

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