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ISBN: 978-0-12-803991-5
ISSN: 1877-1173
Nadia Agha
Department of Health and Human Performance, Laboratory of Integrated Physiology,
University of Houston, Houston, Texas, USA
Jacob Allen
Department of Kinesiology and Community Health, University of Illinois at Urbana-
Champaign, Urbana, Illinois, USA
Philip J. Atherton
MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical,
Metabolic and Molecular Physiology, University of Nottingham, Royal Derby Hospital
Centre, Derby, United Kingdom
Frank W. Booth
Department of Biomedical Sciences; Department of Nutrition and Exercise Physiology;
Department of Medical Pharmacology and Physiology, and Dalton Cardiovascular Research
Center, University of Missouri, Columbia, Missouri, USA
Marni D. Boppart
Department of Kinesiology and Community Health, and Beckman Institute for Advanced
Science and Technology, University of Illinois, Urbana, Illinois, USA
Claude Bouchard
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge,
Louisiana, USA
Heather Carter
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
Chris Chen
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
Matthew J. Crilly
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
Michael De Lisio
Department of Kinesiology and Community Health, University of Illinois, Urbana, Illinois,
USA
Christian A. Drevon
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine,
University of Oslo, Oslo, Norway
Kristin Eckardt
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine,
University of Oslo, Oslo, Norway
xiii
xiv Contributors
Jürgen Eckel
Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center (DDZ),
Auf‘m Hennekamp, and German Center for Diabetes Research (DZD e.V.), Düsseldorf,
Germany
Brian S. Ferguson
Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, USA
Nuria Garatachea
Faculty of Health and Sport Science, University of Zaragoza, Huesca, Spain
Laurie J. Goodyear
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, and Department
of Medicine, Brigham, and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts, USA
Rachel Graff
Department of Health and Human Performance, Laboratory of Integrated Physiology,
University of Houston, Houston, Texas, USA
Sven W. G€ orgens
Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center (DDZ), Auf‘m
Hennekamp, Düsseldorf, Germany
Anthony C. Hackney
Department of Exercise and Sport Science; Department of Nutrition, Gillings School of
Public Health, and Curriculum in Human Movement Science, Department of Allied Health
Sciences, University of North Carolina, Chapel Hill, North Carolina, USA
Gilian F. Hamilton
Department of Psychology, The Beckman Institute, University of Illinois at Urbana-
Champaign, Urbana, Illinois, USA
Mark Hargreaves
Department of Physiology, The University of Melbourne, Melbourne, Australia
Katja Heinemeier
Institute of Biomedical Sciences, Faculty of Health and Medical Sciences and Institute of
Sports Medicine, Bispebjerg Hospital, Copenhagen, Denmark
Michael F. Hirshman
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical
School, Boston, Massachusetts, USA
David A. Hood
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
Jørgen Jensen
Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway
Niklas Rye Jørgensen
Department of Clinical Chemistry, Glostrup Hospital and University of Southern Denmark,
Glostrup, Denmark
Contributors xv
Michael Kjaer
Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital and
Centre for Healthy Aging, Faculty of Health and Medical Sciences, University of
Copenhagen, Copenhagen, Denmark
Karsten Krüger
Department of Sports Medicine, University of Giessen, Giessen, Germany
Hawley Kunz
Department of Health and Human Performance, Laboratory of Integrated Physiology,
University of Houston, Houston, Texas, USA
Séverine Lamon
Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and
Nutrition Sciences, Deakin University, Burwood, Victoria, Australia
Amy R. Lane
Curriculum in Human Movement Science, Department of Allied Health Sciences,
University of North Carolina, Chapel Hill, North Carolina, USA
M. Harold Laughlin
Department of Biomedical Sciences; Department of Medical Pharmacology and Physiology,
and Dalton Cardiovascular Research Center, University of Missouri, Columbia,
Missouri, USA
Alejandro Lucia
European University and Research Institute of Hospital 12 de Octubre (“i+12”), Madrid,
Spain
S. Peter Magnusson
Musculoskeletal Rehabilitation Research Unit, Department of Physiotherapy and Institute of
Sports Medicine, Bispebjerg Hospital, Faculty of Health and Medical Sciences, University of
Copenhagen, Copenhagen, Denmark
Chris McGlory
Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada
Jonathan Memme
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
Frank C. Mooren
Department of Sports Medicine, University of Giessen, Giessen, Germany
Joram D. Mul
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical
School, Boston, Massachusetts, USA
Robert C. Noland
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge,
Louisiana, USA
T. Dylan Olver
Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, USA
xvi Contributors
Helios Pareja-Galeano
European University and Research Institute of Hospital 12 de Octubre (“i+12”), Madrid,
Spain
Marion Pauly
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
Bethan E. Phillips
MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical,
Metabolic and Molecular Physiology, University of Nottingham, Royal Derby Hospital
Centre, Derby, United Kingdom
Stuart M. Phillips
Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada
Justin S. Rhodes
Department of Psychology, The Beckman Institute, University of Illinois at Urbana-
Champaign, Urbana, Illinois, USA
Gregory N. Ruegsegger
Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, USA
Aaron P. Russell
Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and
Nutrition Sciences, Deakin University, Burwood, Victoria, Australia
Richard J. Simpson
Department of Health and Human Performance, Laboratory of Integrated Physiology,
University of Houston, Houston, Texas, USA
Kristin I. Stanford
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical
School, Boston, Massachusetts, USA
Yi Sun
Department of Kinesiology and Community Health, University of Illinois at Urbana-
Champaign, Urbana, Illinois, USA
Ryan G. Toedebusch
Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, USA
Elijah Trefts
Department of Molecular Physiology and Biophysics, Vanderbilt University School of
Medicine, Nashville, Tennessee, USA
Liam D. Tryon
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
Thomas Tsiloulis
Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University,
Clayton, Victoria, Australia
Contributors xvii
Anna Vainshtein
Muscle Health Research Centre, School of Kinesiology and Health Science, York
University, Toronto, Ontario, Canada
David H. Wasserman
Department of Molecular Physiology and Biophysics, Vanderbilt University School of
Medicine, Nashville, Tennessee, USA
Matthew J. Watt
Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University,
Clayton, Victoria, Australia
Daniel J. Wilkinson
MRC-ARUK Centre of Excellence for Musculoskeletal Ageing Research, Clinical,
Metabolic and Molecular Physiology, University of Nottingham, Royal Derby Hospital
Centre, Derby, United Kingdom
Ashley S. Williams
Department of Molecular Physiology and Biophysics, Vanderbilt University School of
Medicine, Nashville, Tennessee, USA
Sarah Witkowski
Department of Kinesiology, School of Public Health and Health Sciences, University of
Massachusetts, Amherst, Massachusetts, USA
Jeffrey A. Woods
Department of Kinesiology and Community Health, University of Illinois at Urbana-
Champaign, Urbana, Illinois, USA
Zhen Yan
Department of Medicine; Department of Pharmacology; Department of Molecular
Physiology and Biological Physics, and Center for Skeletal Muscle Research, University of
Virginia, Charlottesville, Virginia, USA
PREFACE
This volume in the series Progress in Molecular Biology and Translational Science
is devoted to the mechanisms regulating molecular and cellular adaptation to
acute and chronic exercise in a variety of settings. Progress in Molecular Biology
and Translational Science provides a forum for discussion of new discoveries,
approaches, and ideas in molecular biology which is what we aimed for in
the development of the volume. We believe that it is a timely contribution
to our understanding of exercise biology. We have been fortunate in being
able to secure contributions from leading scientists and most major labora-
tories that are actively engaged in the study of the molecular mechanisms at
play when people and other living organisms are physically active. The pub-
lication is particularly timely as it occurs just a few months after the leader-
ship of the National Institutes of Health announced that the Common Fund
of NIH will support a 6-year plan to uncover the molecular transducers of
adaptation to physical activity in various tissues and organs.
As the editor of the volume, I am extremely pleased by the distinguished
panel of authors that was assembled for the publication. Sixty-one authors
and coauthors from seven countries have contributed to the volume.
I am very grateful for their willingness to participate in this effort.
I would like to express my gratitude to them not only for their outstanding
science but also for the timely delivery of their contributions. They have
been a delight to work with. Unfortunately, some topics had to be left
out due to the page number limitation but the vast majority of the relevant
topic found a home in the volume.
The leadership of the PMBTS publication series and the staff at Elsevier
have been a delight to work with. I would like to express my thanks to Dr.
Michael Conn, Editor of the PMBTS serial, from Texas Tech University
Health Sciences Center who supported the concept of having a full volume
dedicated to the molecular biology of adaptation to exercise. I also benefited
greatly from the support of Mary Ann Zimmerman, Acquisition Editor, and
Helene Kabes, Senior Editorial Project Manager, all at the Elsevier publish-
ing house. I also want to recognize the diligent work of Roshmi Joy, Project
Manager in the Book Publishing Division at Elsevier. They were all very
supportive at various stages of the development of the publication, and
I would like to express my most sincere thanks to them.
xix
xx Preface
Finally, I would not have been able to undertake the task of serving as
editors for this volume without the outstanding and competent support ini-
tially of Allison Templet and then later of Robin Post of the Pennington
Biomedical Research Center. They worked diligently with each author
in order to ensure that the instructions were well understood by the contrib-
uting authors and that their manuscripts met all the requirements of the pub-
lisher. During the last phase of the production of the volume, Robin worked
diligently on complex scientific material with a dedication to excellence that
made a difference in our ability to deliver a high-quality volume. I feel
greatly indebted to both of them. However, if errors are later discovered
in the volume, they are entirely my responsibility.
CLAUDE BOUCHARD
July 2015
CHAPTER ONE
Contents
1. Introduction 2
2. Sedentary Time, Physical Activity, and Fitness 4
3. Reductionism, Systems Biology, and Integrative Physiology 8
4. Genomic and ENCODE Facts: A Gold Mine for Exercise Biology 10
5. About the Content of the Volume 12
6. Summary and Conclusions 13
References 13
Abstract
This chapter serves as an introduction to the volume focused on the molecular and cel-
lular regulation of adaptation to acute and chronic exercise exposure. It begins with a
definition of the overall content of the “sedens–physical activity–exercise training–
fitness” domain. One conclusion from this brief overview is that past and current studies
have primarily dealt with very limited subsets of the traits and parameters of interest to
exercise biologists. Molecular and cellular studies have focused more on adaptation to
exercise and less on variable levels of cardiorespiratory fitness even though the latter is a
powerful indicator of current and future health status and longevity. In this regard,
molecular profiling of intrinsic versus acquired cardiorespiratory fitness would seem
to be an area of research deserving more attention. Although molecular and cellular
studies are clearly reductionist by nature, they constitute the primary material allowing
systems biology to draw inferences about pathways, networks, and systems. Integrative
physiology can be substantially enriched by taking advantage of the findings and les-
sons from molecular studies and systems biology approaches. DNA sequence variation
within and between populations as well as recent advances in the definition of the func-
tional elements in the human and other genomes offer unique opportunities to pursue
new and more powerful molecular studies, and to reconcile reductionist and integrative
approaches.
Progress in Molecular Biology and Translational Science, Volume 135 # 2015 Elsevier Inc. 1
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/bs.pmbts.2015.07.009
2 Claude Bouchard
1. INTRODUCTION
All tissues and organs of the human body are affected by exercise par-
ticularly when it is energetically demanding and sustained. There is an abun-
dant literature on the metabolic and physiological changes taking place in
response to acute endurance, high intensity, and resistance exercise even
though much remains to be learned. Similarly, there is a growing body of data
regarding adaptation of tissues, organs, and systems to regular exercise and
exercise training, particularly with respect to endurance and resistance train-
ing. Although impressive advances have been made on the general topic of
adaptation to exercise, there are still big gaps in knowledge that deserve our
attention. One critical gap in the foundational body of knowledge of exercise
biology is the limited understanding of the universe of molecular transducers
involved in the regulation of adaptation to all forms of acute and chronic
exercise and of the molecular pathways and networks associated with the
health benefits of being physically active. There are many other gaps in
knowledge and a few are of particular interest and are highlighted here.
One blatant weakness is that exercise biology studies by and large cover
only a fraction of the sedens–physical activity–exercise–fitness domain.
Figure 1 provides a schematic overview of the multiple dimensions of this
domain. Included in the diagram are the sedens–physical activity–exercise
training continuum, the fitness traits, the exercise exposure dimensions,
Figure 1 Schematic description of the sedentary behavior, physical activity level, exer-
cise training, and fitness domain with its multiple dimensions and some of its
implications.
Exercise and Integrative Biology 3
the periods of life, health outcomes and aging, and the levels at which exer-
cise biology scientists are investigating adaptation to acute and chronic expo-
sures to exercise. When considering the global domain, it becomes apparent
that exercise biology has thus far mainly focused on limited subsets of con-
ditions and has fallen short of having comprehensively covered the multiple
forms of exercise and fitness that deserve to be thoroughly investigated in
multiple settings and a variety of clinical conditions. For instance, we know
little regarding the impact of spontaneous physical activity or acute and
chronic exposure to low-intensity exercise on multiple tissues and organs.
One obvious conclusion from this quick overview is that the to-do-list of
exercise biology research is extraordinarily long.
A specific area deserving more research is that of the general topic of the
cellular and molecular adaptation to acute and chronic exposures to all types
of exercise.1 As this volume illustrates, we have some understanding of the
cellular and molecular mechanisms associated with adaptation to some
exercise exposures. But it is also clear from the numerous chapters, each
contributed by world-class experts on a given topic, that we have gaping
holes regarding our knowledge of these mechanisms and how they operate
in multiple tissues and organs. Since the physiological responses to acute
exercise exposure and to exercise training are often organ specific,2 defining
the mechanisms underlying tissue and organ specificity should shed light on
the molecular pathways associated with adaptation, maladaptation, or health
benefits. Importantly, even when some of the molecular mechanisms of
adaptation to exercise have been evidenced, they have generally been
investigated under a limited set of exercise conditions such as high-intensity
exercise training or moderate exercise level meeting the current physical
activity guidelines3 and mainly in young adults of European descent. Thus,
there is a need for a massive effort designed to uncover the molecular and
cellular mechanisms underlying tissue and organ adaptation to all forms of
exercise, particularly in light of the importance of regular exercise for the
prevention of common diseases—including diabetes, cardiovascular dis-
eases, cancer, and dementia—and premature death as well as healthy aging.
The same conclusion seemed to have been reached recently by the
leadership of the U.S. National Institutes of Health when they made public
their new physical activity initiative to be funded by the Common Fund
over a six-year period (2016–2022). The focus of this major effort will be
to identify the populations of molecular transducers of adaptation to exercise
in various tissues and organs using a combination of human and animal
model studies.
4 Claude Bouchard
Figure 2 Distribution of VO2max/kg body weight values in 174 sedentary men, 17–35
years of age, from the HERITAGE Family Study (A). Distribution of the VO2max changes in
% of baseline levels in response to a standardized endurance training program of
20 weeks in the same sedentary subjects (B).
other features of the human genome have paved the way for a more pro-
found understanding of the molecular regulation of adaptation in the
broad sense.
one among all affected relatives who was able to compete at the international
level in endurance events. He may have been the only one for which com-
plex cellular regulatory systems allowed him to benefit from a very high
oxygen-carrying capacity while not being unduly clinically affected by his
polycythemia.
REFERENCES
1. Wackerhage H. Molecular Exercise Physiology: An Introduction. Oxen, UK: Routledge;
2014. xiv, 323 pages.
2. Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J.
Organ-specific physiological responses to acute physical exercise and long-term training
in humans. Physiology (Bethesda). 2014;29(6):421–436.
14 Claude Bouchard
3. U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for
Americans: Be Active, Healthy, and Happy!. Washington, DC: U.S. Department of
Health and Human Services; 2008.
3a. Bouchard C, Blair SN, Katzmarzyk PT. Less sitting, more physical activity or higher
fitness? Mayo Clin Proc. 2015. In press.
4. Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. Coronary heart-disease and
physical activity of work. Lancet. 1953;265(6796):1111–1120. conclusion.
5. Morris JN, Crawford MD. Coronary heart disease and physical activity of work; evi-
dence of a national necropsy survey. Br Med J. 1958;2(5111):1485–1496.
6. Paffenbarger Jr RS, Laughlin ME, Gima AS, Black RA. Work activity of longshoremen
as related to death from coronary heart disease and stroke. N Engl J Med.
1970;282(20):1109–1114.
7. Paffenbarger RS, Hale WE. Work activity and coronary heart mortality. N Engl J Med.
1975;292(11):545–550.
8. Paffenbarger Jr RS, Hyde RT, Wing AL, Hsieh CC. Physical activity, all-cause mortal-
ity, and longevity of college alumni. N Engl J Med. 1986;314(10):605–613.
9. Paffenbarger Jr RS, Wing AL, Hyde RT. Physical activity as an index of heart attack risk
in college alumni. Am J Epidemiol. 1978;108(3):161–175.
10. Manini TM, Everhart JE, Patel KV, et al. Daily activity energy expenditure and mortality
among older adults. JAMA. 2006;296(2):171–179.
11. Blair SN, Haskell WL. Objectively measured physical activity and mortality in older
adults. JAMA. 2006;296(2):216–218.
12. Fiuza-Luces C, Garatachea N, Berger NA, Lucia A. Exercise is the real polypill. Phys-
iology (Bethesda). 2013;28(5):330–358.
13. Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time and mortality from all
causes, cardiovascular disease, and cancer. Med Sci Sports Exerc. 2009;41(5):998–1005.
14. Blair SN, Kohl 3rd HW, Paffenbarger Jr RS, Clark DG, Cooper KH, Gibbons LW.
Physical fitness and all-cause mortality. A prospective study of healthy men and women.
JAMA. 1989;262(17):2395–2401.
15. Kokkinos P, Myers J, Faselis C, et al. Exercise capacity and mortality in older men: a
20-year follow-up study. Circulation. 2010;122(8):790–797.
16. Koch LG, Kemi OJ, Qi N, et al. Intrinsic aerobic capacity sets a divide for aging and
longevity. Circ Res. 2011;109(10):1162–1172.
17. Skinner JS, Jaskolski A, Jaskolska A, et al. Age, sex, race, initial fitness, and response to
training: the HERITAGE Family Study. J Appl Physiol. 2001;90(5):1770–1776.
18. Skinner JS, Wilmore KM, Krasnoff JB, et al. Adaptation to a standardized training pro-
gram and changes in fitness in a large, heterogeneous population: the HERITAGE Fam-
ily Study. Med Sci Sports Exerc. 2000;32(1):157–161.
19. Bouchard C, An P, Rice T, et al. Familial aggregation of VO(2max) response to exercise
training: results from the HERITAGE Family Study. J Appl Physiol.
1999;87(3):1003–1008.
20. Bouchard C, Daw EW, Rice T, et al. Familial resemblance for VO2max in the sedentary
state: the HERITAGE family study. Med Sci Sports Exerc. 1998;30(2):252–258.
21. Joyner MJ, Pedersen BK. Ten questions about systems biology. J Physiol.
2011;589(pt 5):1017–1030.
22. Joyner MJ, Limberg JK. Blood pressure regulation: every adaptation is an integration?
Eur J Appl Physiol. 2014;114(3):445–450.
23. Greenhaff PL, Hargreaves M. ‘Systems biology’ in human exercise physiology: is it
something different from integrative physiology? J Physiol. 2011;589(pt 5):1031–1036.
24. Hoppeler H, Baum O, Lurman G, Mueller M. Molecular mechanisms of muscle plas-
ticity with exercise. Compr Physiol. 2011;1(3):1383–1412.
Exercise and Integrative Biology 15
25. Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle
adaptation. Cell Metab. 2013;17(2):162–184.
26. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science
(New York, NY). 2001;291(5507):1304–1351.
27. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human
genome. Nature. 2001;409(6822):860–921.
28. International HapMap Consortium. The International HapMap Project. Nature.
2003;426(6968):789–796.
29. Abecasis GR, Auton A, Brooks LD, et al. An integrated map of genetic variation from
1,092 human genomes. Nature. 2012;491(7422):56–65.
30. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the
human genome. Nature. 2012;489(7414):57–74.
31. Kellis M, Wold B, Snyder MP, et al. Defining functional DNA elements in the human
genome. Proc Natl Acad Sci USA. 2014;111(17):6131–6138.
32. Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA. Clan genomics and the complex
architecture of human disease. Cell. 2011;147(1):32–43.
33. Juvonen E, Ikkala E, Fyhrquist F, Ruutu T. Autosomal dominant erythrocytosis caused
by increased sensitivity to erythropoietin. Blood. 1991;78(11):3066–3069.
34. de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin receptor causes
dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci USA.
1993;90(10):4495–4499.
CHAPTER TWO
Contents
1. Introduction 18
2. Carbohydrate Utilization During Rest and Exercise 19
3. Muscle Glycogen 20
4. Glucose Transport 22
5. Exercise Signals Regulating Glucose Transport 24
5.1 AMPK and LKB1 24
5.2 Ca2 +/Calmodulin-Dependent Protein Kinases 26
5.3 Downstream Signals Mediating Exercise-Stimulated Glucose Transport 27
5.4 AS160 and TBC1D1 27
6. Increases in Insulin Sensitivity for Glucose Transport After Exercise 28
7. Exercise Training: Impact on Healthy People and People with Type 2 Diabetes 29
Acknowledgments 30
References 30
Abstract
Carbohydrates are the preferred substrate for contracting skeletal muscles during high-
intensity exercise and are also readily utilized during moderate intensity exercise. This
use of carbohydrates during physical activity likely played an important role during the
survival of early Homo sapiens, and genes and traits regulating physical activity, carbo-
hydrate metabolism, and energy storage have undoubtedly been selected throughout
evolution. In contrast to the life of early H. sapiens, modern lifestyles are predominantly
sedentary. As a result, intake of excessive amounts of carbohydrates due to the easy and
continuous accessibility to modern high-energy food and drinks has not only become
unnecessary but also led to metabolic diseases in the face of physical inactivity.
A resulting metabolic disease is type 2 diabetes, a complex endocrine disorder charac-
terized by abnormally high concentrations of circulating glucose. This disease now
affects millions of people worldwide. Exercise has beneficial effects to help control
impaired glucose homeostasis with metabolic disease, and is a well-established tool
Progress in Molecular Biology and Translational Science, Volume 135 # 2015 Elsevier Inc. 17
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/bs.pmbts.2015.07.020
18 Joram D. Mul et al.
to prevent and combat type 2 diabetes. This chapter focuses on the effects of exercise
on carbohydrate metabolism in skeletal muscle and systemic glucose homeostasis. We
will also focus on the molecular mechanisms that mediate the effects of exercise to
increase glucose uptake in skeletal muscle. It is now well established that there are dif-
ferent proximal signaling pathways that mediate the effects of exercise and insulin on
glucose uptake, and these distinct mechanisms are consistent with the ability of exercise
to increase glucose uptake in the face of insulin resistance in people with type 2 dia-
betes. Ongoing research in this area is aimed at defining the precise mechanism by
which exercise increases glucose uptake and insulin sensitivity and the types of exercise
necessary for these important health benefits.
ABBREVIATIONS
ADP adenosine diphosphate
AICAR aminoimidazole-4-carboxamide ribonucleoside
AMP adenosine monophosphate
AMPK AMP-activated protein kinase
AS160 Akt substrate of 160 kDa
ATP adenosine triphosphate
CaMKII Ca2+/calmodulin-dependent protein kinase II
GLUT4 glucose transporter type 4
LKB1 liver kinase B1
MIRKO muscle-specific insulin receptor knockout mice
PAS phospho-Akt-substrate
Pi inorganic phosphate
Rab ras homologous from brain
SNARK sucrose nonfermenting AMPK-related kinase
1. INTRODUCTION
The unique ability of humans to perform endurance running has likely
contributed to the evolution of Homo sapiens from other primates.1 High
levels of physical activity were required in order to evade predators as well
as to obtain food. To maintain these high levels of physical activity, the
working skeletal muscles require increased substrates for generation of aden-
osine triphosphate (ATP). A major substrate for the working muscles is car-
bohydrates, with one source being in the muscle itself in the form of
glycogen, and another source glucose coming from the blood. The break-
down of glycogen from the muscle (glycogenolysis) and the regulation of
glucose uptake into the muscle from the blood are highly regulated pro-
cesses, and in this chapter, current knowledge on these functions will be
discussed.
Exercise and Regulation of Carbohydrate Metabolism 19
3. MUSCLE GLYCOGEN
As noted above, glycogen is an essential fuel for energy production in
the contracting skeletal muscles. Glycogen is a branched polymer of glucose
Exercise and Regulation of Carbohydrate Metabolism 21
with a mixture of α-1,4 and α-1,6 linkages between glucose units. The liver
has the highest concentration of stored glycogen; however, skeletal muscle,
as a result of its total weight, is the largest reserve of stored glycogen in the
body. Intramuscular glycogen is associated with several organelles including
the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils.3,12
Granules of glycogen, or glycosomes, are also physically associated with sev-
eral proteins including glycogen phosphorylase, phosphorylase kinase, gly-
cogen synthase, glycogenin, protein phosphatases, and adenosine
monophosphate (AMP)-activated protein kinase (AMPK).3,12 The synthesis
of glycogen involves multiples enzymes, and glycogen synthase is the
rate-limiting enzyme. The breakdown of glycogen (glycogenolysis) is also
controlled by a multienzyme system, and this will be discussed in more
detail below.
Glycogen utilization is rapidly initiated at the onset of exercise and
increases exponentially with exercise intensity.13 Regulation of glycogenol-
ysis is very sensitive to the metabolic rate of skeletal muscle during
exercise.14,15 Glycogen phosphorylase is the enzyme responsible for the
rate-limiting step during muscle glycogenolysis.3,16 At rest, glycogen phos-
phorylase exists primarily in the inactive b form, whereas with the onset of
exercise phosphorylase kinase phosphorylates the b form to the active a
form.3 Phosphorylase kinase activation results from elevated calcium levels
and binding of epinephrine to β-adrenergic receptors on the sarcolemma.
Activation of phosphorylase kinase by stimulation of β-adrenergic receptors
on the sarcolemma is mediated by cyclic AMP. Elevated epinephrine levels
increase glycogen phosphorylase activity and glycogenolysis in perfused rat
hind limbs and glycogenolysis in humans during moderate exercise.16,17
Muscle glycogenolysis does not always correlate tightly with levels of
phosphorylase kinase a.18 This suggested that posttranslational factors
enhance the glycogenolytic rate during various intensities of exercise.
Indeed, AMP and adenosine diphosphate (ADP) levels, and increased levels
of Pi can all allosterically regulate activity of the a and b forms of phosphor-
ylase kinase.3 With increase exercise duration, there is a decrease in glycogen
availability in parallel with decreased phosphorylase activity, while there is
increased availability of other substrates for oxidation, such as plasma glucose
and free fatty acids.
Muscle fiber type can also be a factor in determining the regulation of
muscle glycogenolysis. During moderate intensity exercise, muscle glyco-
genolysis occurs predominantly in type I muscle fibers. As exercise duration
increases or if exercise intensity increases, type I fibers become depleted and
22 Joram D. Mul et al.
4. GLUCOSE TRANSPORT
The other major source of carbohydrate during exercise is circulating
blood glucose. Blood glucose concentrations during exercise are controlled
by a precise regulatory mechanism, and the source of the circulating glucose
is primarily the liver. In the resting state, food consumption also regulates
blood glucose concentrations, and the removal of glucose from the circula-
tion in response to both food consumption and physical exercise is a critical
factor for the maintenance of normal glycemia in humans.
The transport of glucose into skeletal muscle is essential for tissue
homeostasis, and under normal physiologic conditions, the transport process
is rate limiting for glucose utilization.23 Transport occurs by facilitated dif-
fusion, and there is an increase in the maximal velocity of transport without
an appreciable change in the substrate concentration at which glucose trans-
port is half maximal.24 The transport of glucose utilizes specific carrier pro-
teins called glucose transporters, which are a family of structurally related
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