Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts

Research output: Contribution to journalArticle

Abstract

Phospholamban ablation is associated with significant increases in the sarcoplasmic reticulum Ca2+-ATPase activity and the basal cardiac contractile parameters. To determine whether the observed phenotype is due to loss of phospholamban alone or to accompanying compensatory mechanisms, hearts from phospholamban-deficient and age-matched wild-type mice were characterized in parallel. There were no morphological alterations detected at the light microscope level. Assessment of the protein levels of the cardiac sarcoplasmic reticulum Ca2+-ATPase, calsequestrin, myosin, actin, troponin I, and troponin T revealed no significant differences between phospholamban-deficient and wild-type hearts. However, the ryanodine receptor protein levels were significantly decreased (25%) upon ablation of phospholamban, probably in an attempt to regulate the release of Ca2+ from the sarcoplasmic reticulum, which had a significantly higher diastolic Ca2+ content in phospholamban-deficient compared with wild-type hearts (16.0±2.2 versus 8.6±1.0 mmol Ca2+/kg dry wt, respectively). The increases in Ca2+ content were specific to junctional sarcoplasmic reticulum stores, as there were no alterations in the Ca2+ content of the mitochondria or A band. Assessment of ATP levels revealed no alterations, although oxygen consumption increased (1.6-fold) to meet the increased ATP utilization in the hyperdynamic phospholamban-deficient hearts. The increases in oxygen consumption were associated with increases (2.2-fold) in the active fraction of the mitochondrial pyruvate dehydrogenase, suggesting increased tricarboxylic acid cycle turnover and ATP synthesis. 31P nuclear magnetic resonance studies demonstrated decreases in phosphocreatine levels and increases in ADP and AMP levels in phospholamban-deficient compared with wild-type hearts. However, the creatine kinase activity and the creatine kinase reaction velocity were not different between phospholamban-deficient and wild-type hearts. These findings indicate that ablation of phospholamban is associated with downregulation of the ryanodine receptor to compensate for the increased Ca2+ content in the sarcoplasmic reticulum store and metabolic adaptations to establish a new energetic steady state to meet the increased ATP demand in the hyperdynamic phospholamban-deficient hearts.

Details

Authors
  • Guoxiang Chu
  • Wusheng Luo
  • Jay P. Slack
  • Carola Tilgmann
  • Wendy E. Sweet
  • Matthias Spindler
  • Kurt W. Saupe
  • Gregory P. Boivin
  • Christine S. Moravec
  • Mohammed A. Matlib
  • Ingrid L. Grupp
  • Joanne S. Ingwall
  • Evangelia G. Kranias
External organisations
  • University of Cincinnati
  • Clinic Foundation
  • Harvard University
Research areas and keywords

Keywords

  • Ca stores, mitochondrial enzymes, nuclear magnetic resonance, phospholamban, sarcoplasmic reticulum
Original languageEnglish
Pages (from-to)1064-1076
Number of pages13
JournalCirculation Research
Volume79
Issue number6
StatePublished - 1996
Peer-reviewedYes
Externally publishedYes