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Analysis of Cardiac Contractile Dysfunction and Ca2+ Transients in Rodent Myocytes
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Coordinate downregulation of CaM kinase II and phospholamban accompanies contractile phenotype transition in the

M Jiang1, A Xu, D L Jones

  • 1Dept. of Physiology and Pharmacology, Health Science Center, The University of Western Ontario, London, Ontario, Canada N6A 5C1.

American Journal of Physiology. Cell Physiology
|April 30, 2004
PubMed

Insights

Thyroid hormone excess in rabbits alters muscle contraction by upregulating the SERCA1 pump and downregulating CaM kinase II and phospholamban in soleus muscle. This leads to faster muscle relaxation and increased force.

Area of Science:

  • Muscle Physiology
  • Endocrinology
  • Molecular Biology

Background:

  • Thyroid hormones significantly influence skeletal muscle function and metabolism.
  • Calcium handling by the sarcoplasmic reticulum (SR) is crucial for muscle contraction and relaxation.
  • Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaM kinase II) plays a role in regulating SR function.

Purpose of the Study:

  • To investigate the impact of l-thyroxine-induced hyperthyroidism on CaM kinase II-mediated SR protein phosphorylation, Ca(2+)-ATPase activity, and contraction duration in rabbit soleus muscle.
  • To elucidate the molecular mechanisms underlying thyroid hormone-induced changes in slow-twitch muscle contractility.

Main Methods:

  • Induction of hyperthyroidism in rabbits using l-thyroxine.
  • Measurement of CaM kinase II activity and protein phosphorylation in SR vesicles.
  • Western blotting to quantify levels of SERCA isoforms (SERCA1, SERCA2) and phospholamban (PLN).
  • Assay of SR Ca(2+) uptake and Ca(2+)-stimulated ATPase activity.
  • Measurement of isometric twitch force, time to peak force, and relaxation time in soleus muscle.

Main Results:

  • Hyperthyroidism significantly reduced CaM kinase II-mediated phosphorylation of Ca(2+)-ATPase and PLN.
  • Soleus muscle from hyperthyroid rabbits showed increased SERCA1 expression, unaltered SERCA2 expression, and decreased PLN and CaM kinase II levels.
  • SR vesicles from hyperthyroid rabbits exhibited enhanced Ca(2+) uptake and Ca(2+)-stimulated ATPase activity, with increased Vmax but unchanged affinity for Ca(2+).
  • CaM kinase II-mediated stimulation of Ca(2+) uptake was significantly lower in hyperthyroid muscle.
  • Isometric twitch force was greater, while time to peak force and relaxation time were shorter in hyperthyroid rabbits.

Conclusions:

  • Thyroid hormone-induced changes in rabbit soleus muscle contractility are linked to coordinated downregulation of PLN and CaM kinase II.
  • Selective upregulation of the SERCA1 isoform, but not SERCA2, contributes to enhanced SR Ca(2+) handling in hyperthyroidism.
  • These molecular adaptations explain the observed alterations in muscle contraction dynamics, including faster relaxation and increased force.

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