Unchanged mitochondrial organization and compartmentation of high-energy phosphates in creatine-deficient GAMT-/- mouse hearts

Am J Physiol Heart Circ Physiol. 2013 Aug 15;305(4):H506-20. doi: 10.1152/ajpheart.00919.2012. Epub 2013 Jun 21.


Disruption of the creatine kinase (CK) system in hearts of CK-deficient mice leads to changes in the ultrastructure and regulation of mitochondrial respiration. We expected to see similar changes in creatine-deficient mice, which lack the enzyme guanidinoacetate methyltransferase (GAMT) to produce creatine. The aim of this study was to characterize the changes in cardiomyocyte mitochondrial organization, regulation of respiration, and intracellular compartmentation associated with GAMT deficiency. Three-dimensional mitochondrial organization was assessed by confocal microscopy. On populations of permeabilized cardiomyocytes, we recorded ADP and ATP kinetics of respiration, competition between mitochondria and pyruvate kinase for ADP produced by ATPases, ADP kinetics of endogenous pyruvate kinase, and ATP kinetics of ATPases. These data were analyzed by mathematical models to estimate intracellular compartmentation. Quantitative analysis of morphological and kinetic data as well as derived model fits showed no difference between GAMT-deficient and wild-type mice. We conclude that inactivation of the CK system by GAMT deficiency does not alter mitochondrial organization and intracellular compartmentation in relaxed cardiomyocytes. Thus, our results suggest that the healthy heart is able to preserve cardiac function at a basal level in the absence of CK-facilitated energy transfer without compromising intracellular organization and the regulation of mitochondrial energy homeostasis. This raises questions on the importance of the CK system as a spatial energy buffer in unstressed cardiomyocytes.

Keywords: confocal imaging; creatine kinase shuttle; guanidinoacetate methyltransferase; intracellular diffusion barriers; mitochondrial positioning; respiration and ATPase kinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism*
  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Creatine / deficiency*
  • Creatine Kinase / metabolism
  • Disease Models, Animal
  • Energy Metabolism*
  • Female
  • Genotype
  • Guanidinoacetate N-Methyltransferase / deficiency*
  • Guanidinoacetate N-Methyltransferase / genetics
  • Homeostasis
  • Kinetics
  • Language Development Disorders / enzymology*
  • Language Development Disorders / genetics
  • Language Development Disorders / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Mitochondria, Heart / enzymology*
  • Mitochondria, Heart / pathology
  • Models, Cardiovascular
  • Movement Disorders / congenital*
  • Movement Disorders / enzymology
  • Movement Disorders / genetics
  • Movement Disorders / pathology
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Phenotype
  • Pyruvate Kinase / metabolism


  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Gamt protein, mouse
  • Guanidinoacetate N-Methyltransferase
  • Pyruvate Kinase
  • Creatine Kinase
  • Adenosine Triphosphatases
  • Creatine

Supplementary concepts

  • Guanidinoacetate methyltransferase deficiency