Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium

J Physiol. 2007 Jul 15;582(Pt 2):695-709. doi: 10.1113/jphysiol.2007.134486. Epub 2007 May 3.


The positive force-frequency relation, one of the key factors modulating performance of healthy myocardium, has been attributed to an increased Ca(2+) influx per unit of time. In failing hearts, a blunted, flat or negative force-frequency relation has been found. In healthy and failing hearts frequency-dependent alterations in Ca(2+) sensitivity of the myofilaments, related to different phosphorylation levels of contractile proteins, could contribute to this process. Therefore, the frequency dependency of force, intracellular free Ca(2+) ([Ca(2+)](i)), Ca(2+) sensitivity and contractile protein phosphorylation were determined in control and monocrotaline-treated, failing rat hearts. An increase in frequency from 0.5 to 6 Hz resulted in an increase in force in control (14.3 +/- 3.0 mN mm(-2)) and a decrease in force in failing trabeculae (9.4 +/- 3.2 mN mm(-2)), whereas in both groups the amplitude of [Ca(2+)](i) transient increased. In permeabilized cardiomyocytes, isolated from control hearts paced at 0 and 9 Hz, Ca(2+) sensitivity remained constant with frequency (pCa(50): 5.55 +/- 0.02 and 5.58 +/- 0.01, respectively, P>0.05), whereas in cardiomyocytes from failing hearts Ca(2+) sensitivity decreased with frequency (pCa(50): 5.62 +/- 0.01 and 5.57 +/- 0.01, respectively, P<0.05). After incubation of the cardiomyocytes with protein kinase A (PKA) this frequency dependency of Ca(2+) sensitivity was abolished. Troponin I (TnI) and myosin light chain 2 (MLC2) phosphorylation remained constant in control hearts but both increased with frequency in failing hearts. In conclusion, in heart failure frequency-dependent myofilament Ca(2+) desensitization, through increased TnI phosphorylation, contributes to the negative force-frequency relation and is counteracted by a frequency-dependent MLC2 phosphorylation. We propose a novel role for PKC-mediated TnI phosphorylation in modulating the force-frequency relation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Animals
  • Calcium / metabolism*
  • Cardiac Output, Low / chemically induced
  • Cardiac Output, Low / metabolism
  • Cardiac Output, Low / physiopathology*
  • Contractile Proteins / metabolism
  • Heart / physiopathology*
  • Heart Ventricles
  • Intracellular Membranes / metabolism
  • Male
  • Monocrotaline
  • Myocardial Contraction*
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism
  • Myosin Light Chains / metabolism
  • Phosphorylation
  • Pressure
  • Protein Kinase C-alpha / metabolism
  • Rats
  • Rats, Wistar
  • Troponin I / metabolism


  • Contractile Proteins
  • Myosin Light Chains
  • Troponin I
  • Monocrotaline
  • Protein Kinase C-alpha
  • Calcium