Genetic Modification of the Heart
Transgenesis and cardiac energetics: new insights into cardiac metabolism

https://doi.org/10.1016/j.yjmcc.2004.05.020Get rights and content

Abstract

Transgenesis in the mouse heart has provided new and important insights into many aspects of ATP synthesis, supply and utilization. Cardiac energetics has also been useful in assessing the consequences of manipulating proteins in the mouse heart. Here, four topics are reviewed. Part 1 presents a description of the role of “energy circuits” in addressing these questions: how is ATP made in the mitochondria supplied to spatially separated ATPases rapidly enough to support variable and abrupt increases in work? Given the barriers to rapid diffusion of ADP, how is a high chemical driving force maintained at the various sites of ATP hydrolysis; i.e. how is [ADP] maintained low throughout the cell? What are the metabolic sensors matching ATP synthesis and utilization? How are they monitored, delivered to the appropriate sensors and translated to accomplish a constant ATP supply? In Part 2, the consequences of manipulating glucose supply to the heart and regulation of the synthesis of enzymes in glycolysis and fatty acid oxidation are discussed. The questions are: what are the signals that lead to long-term molecular reprogramming of metabolic pathways for ATP synthesis and utilization? How is this accomplished? In Part 3, the focus is on sarcomeric proteins addressing the question: what changes in sarcomeric proteins determine the cost of contraction? Finally, in Part 4, examples are given of how energetics has been used to define the consequences of transgenic manipulations.

Section snippets

On energy circuits or “ how is ATP supplied?”

The concept that ATP supply to sites of utilization is analogous to electric wires providing energy to a machine has been substantially expanded over the past 60 years. The idea that certain enzymes create a shuttle linking sites of ATP synthesis with sites of utilization in the heart should be credited to Samuel Bessman. Based on (then new) information that mitochondrial CK is localized in the inter-membrane space of mitochondria [4] and that MM-CK isozyme was associated with myofibrils as

A mix of substrates is used for ATP synthesis

The metabolic machinery of the heart is designed to allow many different substrate mixes to be used for ATP synthesis.4

On ATP utilization

Mouse heart transgenesis is being used to study the energy cost of contraction and the consequences of altering the myosin isoform composition (both heavy and light chains) in the mouse heart. Transgenesis is also being used to define the consequences of modifying specific ATP-utilizing proteins with the goals of increasing our knowledge about the biology of these proteins and identifying causes of cardiac disease. Instructive examples discussed below are mouse hearts bearing missense mutations

Using energetics as a marker of abnormal cell function

31P NMR spectroscopy of isolated mouse hearts is being used to define the consequences of overexpressing or ablating all sorts of proteins on ATP and PCr levels, the primary end point of energetics. In 1996, there were only two such reports, one studying a heat shock protein [93] in an ejecting mouse heart and the other using the first reported isovolumic mouse heart preparation to study the consequences of deleting phospholamban [94]. A literature search today (March 2004) shows that this

Acknowledgements

This work is supported by NIH grants HL53230 and HL63985. I thank James Balschi, Kirstin Hoyer and Rong Tian for helpful discussions.

References (106)

  • V.I. Veksler et al.

    Muscle creatine kinase-deficient mice. II. Cardiac and skeletal muscles exhibit tissue-specific adaptation of the mitochondrial function

    J Biol Chem

    (1995)
  • R. Ventura-Clapier et al.

    Muscle creatine kinase-deficient mice. I. Alterations in myofibrillar function

    J Biol Chem

    (1995)
  • G.D. Lopaschuk et al.

    Regulation of fatty acid oxidation in the mammalian heart in health and disease

    Biochim Biophys Acta

    (1994)
  • N. Tsunoda et al.

    Regulated expression of 5′-deleted mouse GLUT4 minigenes in transgenic mice: effects of exercise training and high-fat diet

    Biochem Biophys Res Commun

    (1997)
  • P.M. Barger et al.

    PPAR signaling in the control of cardiac energy metabolism

    Trend Cardiovas Med

    (2000)
  • K. Watanabe et al.

    Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity

    J Biol Chem

    (2000)
  • M.E. Young et al.

    Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart

    J Biol Chem

    (2001)
  • F.M. Campbell et al.

    A role for peroxisome proliferator-activated receptor alpha (PPARalpha) in the control of cardiac malonyl-CoA levels: reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase

    J Biol Chem

    (2002)
  • J. St-Pierre et al.

    Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1 alpha and 1 beta (PGC-1 alpha and PGC-1 beta) in muscle cells

    J Biol Chem

    (2003)
  • Z. Wu et al.

    Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1

    Cell

    (1999)
  • P. Puigserver et al.

    A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis

    Cell

    (1998)
  • G.D. Lopaschuk

    Alterations in fatty acid oxidation during reperfusion of the heart after myocardial ischemia

    Am J Cardiol

    (1997)
  • A.S. Marsin et al.

    Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia

    Curr Biol

    (2000)
  • J.S. Ingwall

    Is creatine kinase a target for AMP-activated protein kinase in the heart?

    J Mol Cell Cardiol

    (2002)
  • Y. Xing et al.

    Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase

    J Biol Chem

    (2003)
  • M. Krenz et al.

    Analysis of myosin heavy chain functionality in the heart

    J Biol Chem

    (2003)
  • A. Sanbe et al.

    Abnormal cardiac structure and function in mice expressing nonphosphorylatable cardiac regulatory myosin light chain 2

    J Biol Chem

    (1999)
  • A.A. Geisterfer-Lowrance et al.

    A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation

    Cell

    (1990)
  • J.G. Crilley et al.

    Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy

    J Am Coll Cardiol

    (2003)
  • H. Ashrafian et al.

    Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion

    Trend Genet

    (2003)
  • F. Lipmann

    Metabolic generation and utilization of phosphate bond energy

    Adv Enzymol

    (1941)
  • H. Krebs et al.

    Energy transformations in living matter

    (1957)
  • J.S. Ingwall

    ATP and the heart

    (2002)
  • D.C. Turner et al.

    A protein that binds specifically to the M-line of skeletal muscle is identified as the muscle form of creatine kinase

    Proc Natl Acad Sci USA

    (1973)
  • F. Savabi et al.

    Myofibrillar end of the creatine phosphate energy shuttle

    Am J Physiol

    (1984)
  • S.P. Bessman et al.

    The creatine–creatine phosphate energy shuttle

    Annu Rev Biochem

    (1985)
  • M. Vendelin et al.

    Intracellular diffusion of adenosine phosphates is locally restricted in cardiac muscle

    Mol Cell Biochem

    (2004)
  • V.A. Saks

    Creatine kinase isoenzymes and the control of cardiac contraction

  • D. Neumann et al.

    A molecular approach to the concerted action of kinases involved in energy homoeostasis

    Biochem Soc Trans

    (2003)
  • T. Wallimann et al.

    Some new aspects of creatine kinase (CK): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology

    Biofactors

    (1998)
  • A. Kaasik et al.

    Energetic crosstalk between organelles: architectural integration of energy production and utilization

    Circ Res

    (2001)
  • R. Ventura-Clapier et al.

    Structural and functional adaptations of striated muscles to CK deficiency

    Mol Cell Biochem

    (2004)
  • P.P. Dzeja et al.

    Phosphotransfer networks and cellular energetics

    J Exp Biol

    (2003)
  • M. Spindler et al.

    Mitochondrial creatine kinase is critically necessary for normal myocardial high-energy phosphate metabolism

    Am J Physiol Heart Circ Physiol

    (2002)
  • B. Crozatier et al.

    Role of creatine kinase in cardiac excitation–contraction coupling: studies in creatine kinase-deficient mice

    FASEB J

    (2002)
  • K.W. Saupe et al.

    Impaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase

    Circ Res

    (1998)
  • M.K. Aliev et al.

    Mathematical model of compartmentalized energy transfer: its use for analysis and interpretation of 31P-NMR studies of isolated heart of creatine kinase deficient mice

    Mol Cell Biochem

    (1998)
  • A.J. Carrasco et al.

    Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels

    Proc Natl Acad Sci USA

    (2001)
  • D. Pucar et al.

    Adenylate kinase AK1 knockout heart: energetics and functional performance under ischemia–reperfusion

    Am J Physiol Heart Circ Physiol

    (2002)
  • F.A. Van Dorsten et al.

    31P NMR studies of creatine kinase flux in M-creatine kinase-deficient mouse heart

    Am J Physiol

    (1998)

    • Cited by (0)

    View full text
    Copyright © 2004 Elsevier Ltd. All rights reserved.