The Scientist's Guide to Cardiac Metabolism

222 Pages·2016·10.595 MB·English

by  Doenst, Torsten, Schwarzer, Michael

THE SCIENTIST’S
GUIDE TO CARDIAC
METABOLISM
Edited by
Michael Schwarzer and TorSTen doenST
Department of Cardiothoracic Surgery
Friedrich-Schiller-University of Jena
Jena, Germany
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List of Contributors
Christophe Beauloye Université catholique de Miranda Nabben Department of Genetics and
Louvain, Institut de Recherche Expérimentale Cell Biology, Cardiovascular Research Institute
et Clinique, Pole of Cardiovascular Research, Maastricht (CARIM), Maastricht University,
Brussels, Belgium; Université catholique de Maastricht, The Netherlands
Louvain, Cliniques Universitaires Saint Luc,
Tien Dung Nguyen Department of Cardiothoracic
Division of Cardiology, Cardiovascular Intensive
Surgery, Jena University Hospital, Friedrich
Care, Brussels, Belgium
Schiller University of Jena, Jena, Germany
Jessica M. Berthiaume Department of Physiology
Bernd Niemann Department for Adult and
& Biophysics, School of Medicine, Case Western
Pediatric Cardiac Surgery and Vascular Surgery,
Reserve University, Cleveland, OH, USA
University Hospital Giessen and Marburg, Justus
Luc Bertrand Université catholique de Louvain, Liebig University Giessen, Rudolf Buchheim
Institut de Recherche Expérimentale et Clinique, Strasse, Giessen
Pole of Cardiovascular Research, Brussels, Belgium Moritz Osterholt Department of Internal Medicine,
Helios Spital Überlingen, Überlingen, Germany
David I. Brown McAllister Heart Institute,
University of North Carolina at Chapel Hill, Linda R. Peterson Department of Medicine,
Chapel Hill, NC, USA Cardiovascular Division, Washington University
School of Medicine, St. Louis, Missouri, USA
Torsten Doenst Department of Cardiothoracic
Surgery, Jena University Hospital, Friedrich Susanne Rohrbach Institute for Physiology, Justus
Schiller University of Jena, Jena, Germany Liebig University Giessen, Aulweg, Giessen
Jan F.C. Glatz Department of Genetics and Cell Andrea Schrepper Department of Cardiothoracic
Biology, Cardiovascular Research Institute Maas- Surgery, Jena University Hospital, Friedrich
tricht (CARIM), Maastricht University, Maastricht, Schiller University of Jena, Jena, Germany
The Netherlands Paul Christian Schulze Department of Medicine,
Division of Cardiology, Columbia University
Louis Hue Université catholique de Louvain, de
Medical Center, New York, New York
Duve Institute, Protein Phosphorylation Unit,
Brussels, Belgium Michael Schwarzer Department of Cardiothoracic
Surgery, Jena University Hospital, Friedrich
Peter J. Kennel Department of Medicine, Division
Schiller University of Jena, Jena, Germany
of Cardiology, Columbia University Medical
Center, New York, New York Marc van Bilsen Departments of Physiology and
Cardiology, Cardiovascular Research Institute
Terje S. Larsen Cardiovascular Research Group,
Maastricht, Maastricht University, Maastricht, The
Department of Medical Biology, UiT the Arctic
Netherlands
University of Norway, Tromsø, Norway
Christina Werner Department of Cardiothoracic
Craig A. Lygate Radcliffe Department of Medicine, Surgery, Jena University Hospital, Friedrich
Division of Cardiovascular Medicine, University Schiller University of Jena, Jena, Germany
of Oxford, Oxford, UK
ix
x List of Contributors
Monte S. Willis McAllister Heart Institute, Martin E. Young Division of Cardiovascular
University of North Carolina at Chapel Hill; Diseases, Department of Medicine, University
Department of Pathology & Laboratory Medicine, of Alabama at Birmingham, Birmingham,
University of North Carolina Medicine, Chapel AL, USA
Hill, NC, USA
Foreword
If you consider yourself a scientist already or find out which investigative methods have been
want to become one and you have found interest used in the past and which are currently applied
in investigating cardiac metabolism but are lack- to further develop the field. Having read this
ing the fundamentals, you need The Scientist’s book you will know “what the experts in the
Guide to Cardiac Metabolism. Reading this book field are talking about” and develop a solid base
will provide you with the basic and, therefore, for quick understanding of the sometimes dry
often timeless information required to get a fly- appearing but indeed highly interesting publi-
ing start in any good cardiac metabolism lab. cations in this field. We are certain it is worth
You get the chance to refresh your basics on your while.
biochemistry, cell biology, physiology as well as
the required methodology to investigate new ar- Michael Schwarzer, Torsten Doenst
eas. You will be familiarized with fundamental Department of Cardiothoracic Surgery,
principles relevant to cardiac metabolism, learn Jena University Hospital, Friedrich Schiller
regulatory mechanisms and pathways and also University of Jena, Jena, Germany
xi
C H A P T E R
1
Introduction to Cardiac
Metabolism
Michael Schwarzer, Torsten Doenst
Department of Cardiothoracic Surgery, Jena University Hospital,
Friedrich Schiller University of Jena, Jena, Germany
In order for the heart to sustain its regular is directly influenced by metabolism. Again, if
heartbeat, it needs a constant supply of energy ATP is limited (e.g., during ischemia), it is eas-
for contraction [1]. This energy comes primarily ily envisioned that contractile function seizes.
from the hydrolysis of ATP, which is generated However, the scheme finally encompasses myo-
within the cardiomyocyte by utilizing various cardial metabolism as potential target for treat-
competing substrates and oxygen, which again ing contractile dysfunction [5]. Considering that
are supplied by coronary flow [2,3]. Cardiac metabolic processes also influence biosynthesis,
metabolism therefore comprises all processes it becomes clear that metabolism is a prime tar-
involved in the biochemical conversion of mol- get of investigations for nearly all physiologic
ecules within the cell utilizing energy substrates. and pathologic states of the heart, may it be
In addition, cardiac metabolism comprises all ischemia/ reperfusion, diabetes, hypertrophy,
biochemical processes of the cell aimed at the and acute and chronic heart failure [6].
generation of building blocks for cell mainte- In order to develop an understanding for
nance, biosynthesis, and cellular growth. these interrelations and to obtain basic knowl-
There is an intimate connection between car- edge about the methods and tools used for the
diac metabolism and contractile function, which investigation of (cardiac) metabolism, we have
is illustrated schematically in Fig. 1.1. As simple compiled this book. It reflects a selection of
as this illustration, which stems originally from chapters geared toward the transfer of princi-
Heinrich Taegtmeyer, appears as complex is its ples in cardiometabolic research. The book does
meaning [4]. It is clear that changes in contrac- not claim to be complete, but its content should
tile function require changes in cardiac metab- make the reader quickly understand most of the
olism as more power needs more fuel, that is, specific topics he or she intends to specialize in
ATP, and less power needs less fuel. The sche- and to be better able to put the personal investi-
matic also illustrates that contractile function gations into perspective.
The Scientist’s Guide to Cardiac Metabolism 1
http://dx.doi.org/10.1016/B978-0-12-802394-5.00001-7 Copyright © 2016 Elsevier Inc. All rights reserved.
2 1. IntroduCtIon to CArdIAC MEtABolIsM
reader may find that both fatty acid oxidation
and phospholipid ether biosynthesis may be per-
oxisomal processes and that the endoplasmatic/
sarcoplasmatic reticulum has a major role in cal-
cium homeostasis which influences cardiac con-
tractility as well as metabolic enzyme activities.
While the role of ribosomes seems to be better
FIGURE 1.1 Schematic illustration of the interrelation
known, the importance of transport systems and
of cardiac contractile function and substrate metabolism.
vesicle pools may have been less recognized and
Adapted from Ref. [4].
their role in glucose and fatty acid uptake, fis-
sion and fusion of mitochondria is highlighted.
In Chapter 2, Jan Glatz and Miranda Nabben Finally, the authors elegantly explain the differ-
begin with illustrating basics in metabolically ent modes of cell death known as apoptosis, au-
relevant biochemistry. They show that metabo- tophagy, necrosis, and necroptosis. They describe
lism is tightly coupled to all major types of bio- their causes, regulations, and their differences.
molecules as virtually every biomolecule can In Chapter 4, together with Christina Werner,
be used as a substrate or pathway component we address principle metabolic pathways and
in metabolism. Carbohydrates and fatty acids metabolic cycles as they relate to energy produc-
are the main substrates used to produce ATP. tion and building-block generation in the heart.
Amino acids and nucleotides are mainly used This chapter covers the important biochemical
to build proteins and nucleic acids. However, all parts of substrate use in cardiac metabolism.
biomolecules come with specific characteristics The contents of this chapter represent another
and even when they are “exclusively” used as fundamental component of cardiac metabolism,
substrate for ATP generation, their biochemical as it demonstrates how glucose and fatty acids
influence on other cellular processes needs to as the main substrates are metabolized. Here,
be taken into account as well. Furthermore, the the connection between different pathways is
properties of biomolecules influence their trans- illustrated and the importance of the citric acid
port as well as their import into the cell or into cycle for the generation of reducing equivalents
cellular substructures, such as mitochondria. as well as for building blocks for biosynthetic
Fatty acids as lipophilic compounds are not processes becomes readily visible. The role of
readily soluble in the aqueous blood and cyto- the respiratory chain as acceptor of reducing
plasm. Carbohydrates, nucleic acids, and amino equivalents, as consumer of oxygen and most
acids are more hydrophilic and may not cross importantly as the main site of ATP production
membranes without help. Thus, it is important is made apparent. Furthermore, anaplerosis as
to be aware of the properties of biomolecules mechanism to “refill” exploited moieties within
and their biochemistry. This chapter introduces metabolic cycles is introduced and the inter-
the reader to the biochemical properties of the relation of hexosamine biosynthetic pathway,
major classes of molecules and illustrates their pentose phosphate pathway, and glycolysis is
behavior. presented as well as the influence of fatty acid
In Chapter 3, Bernd Niemann and Susanne oxidation on glucose use and vice versa. Un-
Rohrbach address metabolically relevant cell derstanding of the principles explained in this
biology and illustrate the roles of intracellular chapter is essential to follow the metabolic path
organelles for cardiac metabolism. In this chap- of substrates in an organism.
ter, the roles of all major cellular organelles with Louis Hue, Luc Bertrand, and Christophe
respect to cardiac metabolism are described. The Beauloye then address the principles of how the
1. IntroduCtIon to CArdIAC MEtABolIsM 3
previously described cycles and pathways are Osterholt, we first present a general overview
regulated and how metabolism is controlled. of methods used to investigate cardiac me-
Cardiac metabolism must never stop and needs tabolism. From basic biochemical determina-
to be adjusted to substrate availability, hormonal tions of individual metabolite concentrations
regulation, and workload. The authors elegantly and enzyme a ctivities using spectrophotometry,
describe how metabolic pathways are organized through powerful new tools for broad analyses
and controlled. Furthermore, they discuss how of RNA and protein expression or metabolite
short- and long-term control of enzyme and path- concentration (the “-omics”) up to nuclear and
ways activity is achieved and how flux may be magnetic resonance tracing of metabolic rates,
controlled. With flux control, they distinguish be- the principles are illustrated. We have tried to
tween two general mechanisms: control by sup- illustrate the strengths and the weaknesses of
ply as a “push mechanism” or control by demand the individual methods. As mitochondria have
as a “pull mechanism.” Another way to control moved more and more into the focus of meta-
substrate metabolism is achieved by substrate bolic research, we have addressed those bio-
competition and interaction, which seems to be chemical analyses frequently used in the context
the most sensitive regulation seen in metabolism. of mitochondrial investigations as an example
Chapter 5 offers the reader a thorough under- for the integration of methods.
standing of the regulations and interdependen- We then move to address commonly used
cies of cardiac metabolic pathways and cycles. models to investigate cardiac metabolism. Meta-
The previously mentioned information is bolic measurements are frequently impossible in
strictly focused on processes ongoing in the humans, thus animal models are required. Mod-
mature, adult heart. However, metabolism eling of disease in animal models brings along
undergoes massive changes during develop- advantages and shortcomings. The chapter is
ment. These changes are described by Andrea intended to introduce the reader to surgical, in-
Schrepper in Chapter 6. The adult heart con- terventional, environmental, and genetic animal
sumes preferentially fatty acids followed by low- models and should enable the reader to choose
er amounts of glucose, lactate, and ketone bodies. an appropriate model for cardiac metabolic re-
In contrast, embryonic, fetal, and neonatal hearts; search. The chapter includes models of cardiac
considerably deviate from the adult situation. hypertrophy from different causes, ischemic as
Oxygen availability is frequently limited and well as volume or pressure overload heart fail-
substrate provision differs significantly from the ure models as well as models of diabetes and
adult situation. G lucose is the major substrate in nutritional intervention. Exercise may influ-
these hearts with glycolysis as the main process ence cardiac metabolism as well as infection.
for ATP generation. With birth, the heart has to Furthermore, there are in vitro models as the
adapt quickly to the abundance of fatty acids and isolated Langendorff or the working heart prep-
increased oxygen availability. The change from aration, which are well suited for the investiga-
glucose as the preferred substrate in the fetus to tion of metabolic fluxes in relation to contractile
the adult situation is described in this chapter. function or for the metabolic investigation of
Furthermore in the aging organism, cardiac me- ischema/ reperfusion. Cell culture models are
tabolism changes again and the heart has to cope used more and more to assess signaling mecha-
with increasing limitations in metabolism and nisms in cardiovascular disease, although the
function. The findings in cardiac metabolism in loss of workload-dependent contractile function
the aging heart are also discussed. makes the interpretation difficult at times. Thus,
With Chapters 7 and 8, we enter the realm understanding the limits of these models may
of methods and models. Together with Moritz prove helpful.
4 1. IntroduCtIon to CArdIAC MEtABolIsM
Another physiologic principle, which in itself result from a nutritional “dysbalance,” that is,
is highly interesting and even clinically relevant, the over-reliance on one substrate (mainly fatty
also affects the proper conduct of metabolic acids). Exercise in turn may not only lead to car-
research and the planning of metabolic experi- diac hypertrophy, but affects cardiac substrate
ments. Martin Young describes elegantly the im- metabolism as well as mitochondrial function
pact of diurnal variations in cardiac metabolism in a way that may provide protection against
and how genetically determined cardiac and such metabolic insults. This excellently written
biologic rhythms affect cardiac function and the chapter clearly addresses the influence of nutri-
methods used to investigate them. Cardiac me- tional and exercise-induced changes on cardiac
tabolism not only changes in response to chang- metabolism with respect to acute and chronic
es in environmental conditions or disease, it also consequences.
changes regularly throughout the day. Diurnal Chapter 11 touches on the vast field of isch-
variations are mainly caused by variations in emia, hypoxia, and reperfusion. David Brown,
behavior such as sleep–wake cycle and feeding Monte Willis, and Jessica Berthiaume describe
at different times. They significantly affect both how cardiomyocytes as well as the complete or-
gene and protein expression. These variations gan depend on a continuous coronary flow for
lead to changes in glucose and fatty acid me- proper function. Thus, hypoxia and ischemia
tabolism. Disturbance of diurnal variations may present potentially deadly challenges for the
even lead to heart failure, underscoring their rel- entire organism. Hypoxia is defined as reduced
evance. Frequently, there is little attention paid oxygen availability, which may be, up to a cer-
to diurnal variations in the experimental design, tain degree, tolerated by the heart. In contrast,
yet a different time point of investigation with- ischemia (myocardial infarction) interrupts the
in 1 day may significantly alter the amount of provision of oxygen and nutrients to the heart
protein or RNA to be investigated. Reading this and the removal of carbon dioxide and disposal
chapter not only provides interesting and im- of “waste products” together; and depending
portant information, but also it helps to clarify on the degree of ischemia even completely (low
the relevance of diurnal variation for planning flow- or total ischemia). This has a profound
of experiments. effect on cardiac metabolism. Importantly, the
We then enter a series of chapters address- necessary reperfusion to terminate ischemia
ing states of disease. Marc van Bilsen starts with provokes more changes to cardiac metabolism
the description of the influence of nutrition and and causes damage to the cell by itself, a phe-
environmental factors on cardiac metabolism. nomenon termed reperfusion injury. In the long
As should be clear by now, the heart is able to run, ischemia is the most common cause for the
utilize all possible substrates and has therefore, development of heart failure. In this chapter, the
been termed a metabolic omnivore. Cardiac effects of hypoxia, ischemia, and reperfusion on
metabolism is therefore relatively robust. How- cardiac metabolism and metabolic therapies for
ever, chronic changes in substrate supply lead ischemia-induced heart failure are discussed.
to chronic adaptations of cardiac metabolism, Chapter 12 then addresses heart failure but
which may not always be associated with the this time with pressure overload as the cause.
preservation of normal function. Nutritional T. Dung Nguyen illustrates that cardiac hy-
changes, such as fasting or high-caloric or high- pertrophy and heart failure can be induced by
fat feeding, profoundly affect cardiac metabo- several different mechanisms but pressure over-
lism. The heart and its metabolism is even more load is a major cause. The relation of metabolic
severely affected in conditions such as obesity, remodeling and morphologic remodeling in the
metabolic syndrome, and diabetes, which all heart during the development of heart failure is
rEFErEnCEs 5
discussed and their possible interrelation pre- Finally, Terje Larsen provides a historic over-
sented. While a causal role for impaired cardiac view over the field. Metabolic investigations
metabolism in the development of heart failure have a long tradition and many early discover-
seems not always clear; the observed metabolic ies were necessary to build the foundation for
changes frequently indicate the state of heart fail- today’s investigations of cardiac metabolism.
ure progression (e.g., mitochondrial function). Historically, cardiac metabolism started with
Furthermore, concepts to target cardiac metabo- the ancient Greeks when Aristotle observed that
lism for the treatment of hypertrophy and heart cardiac function is associated with heat and that
failure are presented and their results analyzed. nutrition and heat are connected. Several histor-
A similar target is investigated by Craig Lygate ic findings strongly influenced the development
from a both conceptually and methodologically of the field of metabolism and cardiac me-
different perspective. Energetics address the role tabolism and allowed more and better under-
of high-energy phosphate generation and turn- standing of cardiac function and its coupling
over as assessed by nuclear magnetic resonance to cardiac metabolism. Furthermore, several
spectroscopy. This perspective also assumes methods to perform cardiac metabolic research
a tight link between ATP production and con- have their base on such “historic” work and the
tractile function, but adds the creatine kinase historic findings have been the base for several
system to the picture. Creatine kinase deficiency Nobel prizes in medicine.
has been observed in cardiac hypertrophy and We hope you will find useful information for
heart failure, but the regulation of creatine ki- your endeavor into cardiac metabolism and we
nase is very complex. In Chapter 13, the creatine wish you lots of curiosity and success in your
kinase system is described including various investigations.
findings in hearts with elevated or reduced lev-
els of creatine. Furthermore, energy transfer and
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