Cellular physiology and metabolism of physical exercise

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Cellular Physiology and Metabolism 
of Physical Exercise
Livio Luzi 
Editor
Cellular Physiology 
and Metabolism 
of Physical Exercise
123
ISBN 978-88-470-2417-5 e-ISBN 978-88-470-2418-2
DOI 10.1007/978-88-470-2418-2
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Editor
Livio Luzi 
Department of Sport Sciences, Nutrition and Health 
University of Milan
Milan, Italy
The contents of the book are partially based on Biologia cellulare nell’esercizio fisico. Livio Luzi
© Springer-Verlag Italia 2010
Dedicated to my father, Mario, 
who died on May 31, 2011
Cellular Physiology and Metabolism of Physical Exercise deals with several areas
of science, including evolution. Physical inactivity is one of the leading causes of
death in industrialized countries. Accordingly, intensive research has been devot-
ed to studies of the regulation of muscle physiology and contraction. In this vol-
ume, these topics are particularly up to date and thoroughly debated. The aim of
this book is to furnish both a basic and an advanced scientific portrait of the cel-
lular physiology of skeletal muscle cells. Basic information includes an overview
of muscle cell morphology, biochemistry, molecular biology, and physiology, with
special emphasis on the cell membrane, energy metabolism, and cell contraction.
Particularly innovative are the chapters dealing with methodologies to study, both
invasively (muscle biopsies) and non-invasively (NMR-spectroscopy, mathemati-
cal modeling), intracellular metabolism and physiology. A specific chapter is ded-
icated to a new frontier of research in the field of sport sciences, namely, the pos-
sibility of correlating specific DNA polymorphisms and athletic performance. The
micro environment of a contractile cell is of pivotal relevance to nutritional status.
For this reason, three chapters are dedicated to “cellular feeding” and related is-
sues. In many countries, the practice of sport is encouraged to prevent and treat
most chronic degenerative diseases. Nonetheless, excess physical activity may al-
so cause health problems. The common mechanism underlining both (positive
and negative) effects is inflammation, which is also treated in a chapter.
Inflammation, along with immune tolerance, is also a relevant issue in the host vs.
graft reaction, the basis of transplant rejection. Whether patients who have under-
gone organ transplantation benefit from exercise is a matter of debate that is treat-
ed herein. Hyperactivity is also profoundly related to disorders of alimentation,
such as anorexia, whose metabolic features are addressed in this book as well. The
non-human primate model is often used in biomedical research to test new drugs.
Modern concepts in suggesting an exercise program consider physical exercise as
a drug, introducing the necessity of studying patterns of physical exercise in an an-
imal model closest to the genus Homo (primates). To do so requires fundamental
knowledge of the basics of exercise physiology in primates. The last chapter of the
book is centered on the fundamentals of exercise physiology in primates, which
necessitated a discussion of how (and, possibly, why) the genus Homo developed
VII
Preface
from Australopithecines some 1.5 million years ago. In conclusion, I believe this
work provides a complete manual for scientists interested in understanding the ba-
sic physiology and clinical relevance of physical exercise. The book’s realization
was made possible by the proactive and factual interaction of the authors (most of
them are or at some time were co-workers of mine), to whom I convey my most
sincere appreciation and acknowledgment.
Milan, November 2011 Livio Luzi
PrefaceVIII
IX
Livio Luzi is presently Professor of Endocrinology at the Università degli Studi di
Milano and Director of the Metabolism Research Center of the Scientific Institute
Policlinico San Donato, Milan, Italy. He graduated with a degree in Medicine cum
laude in 1981, completing his residency in Internal Medicine in 1986. From 1984
through 1987, he was a post-doctoral fellow in Endocrinology and Metabolism at the
Yale University School of Medicine. Returning to Italy, he became an Investigator at
the San Raffaele Research Institute in Milan. In 1993, he moved to the Harvard
Medical School, in Boston, where he had accepted a position as Assistant Professor
of Medicine in the Endocrinology-Hypertension Division of the Brigham and
Women’s Hospital. In 2002, he was appointed Full Professor at the University of
Milan. From 2007 through 2010, he was Dean of the Faculty of Sport Sciences
(Facoltà di Scienze Motorie) of the University of Milan. Currently, he is Coordinator
of the Ph.D. Program in Sport Sciences of the same university. Since 2005, he has
been an Adjunct Professor of the Diabetes Research Institute at the University of
Miami, Florida (USA). He has over 150 publications in the areas of metabolism, di-
abetes, and sport sciences, with an H-index of 40. 
About the Editor
XI
1 Human Evolution and Physical Exercise:
The Concept of Being “Born to Run” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Livio Luzi
1.1 The Concept of Being Born to Run . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 From Five Billion to One Million Years Ago . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3 The Appearance of the Genus Homo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2 Cell Morphology and Function: The Specificities 
of Muscle Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Anna Maestroni
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.2 Striated Skeletal Muscles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.3 Muscle Contraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3 The Cell Membrane of the Contractile Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Gianpaolo Zerbini
3.1 Cell Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.2 The Structure of the Cell Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.3 Functions of the Cell Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.4 Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.5 Membrane Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.6 The Sarcolemma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4 Gene Polymorphisms and Athletic Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Ileana Terruzzi
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4.2 What Happens When the Balance in the Human Body
Is Modified? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4.3 Human Performance Shows a Wide Variety of Responses . . . . . . . . . . . 26
Contents
4.4 Can Genes Predict Athletic Performance? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.5 Genetic Variability Between Individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.6 Genetic Polymorphisms of the Enzymes Involved
in DNA Methylation and Synthesis in Elite Athletes . . . . . . . . . . . . . . . . . . 30
Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
5 Nutrients and Whole-Body Energy Metabolism:
The Impact of Physical Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Stefano Benedini
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
5.2 Energy and ATP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
5.3 Nutrition and Athletic Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.4 Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.5 Leptin and Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.6 Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.7 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
5.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
6 Mitochondrial and Non-mitochondrial
Studies of ATP Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Roberto Codella
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
6.2 In Vivo Magnetic Resonance Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
6.3 Mitochondrial Function Assessed by 31P-MRS . . . . . . . . . . . . . . . . . . . . . . . . . 47
6.4 Measurement of TCA Cycle Flux (VTCA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
6.5 Anaerobic Sources of ATP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
6.6 Integrative View . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
7 Excessive Nutrients and Regional Energy Metabolism . . . . . . . . . . . . . . . . . . . . 55
Gianluca Perseghin
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
7.2 Excessive Ectopic Fat Accumulation and Abnormal
Regulation of Insulin-Dependent Metabolic Pathways . . . . . . . . . . . . . . . 56
7.3 Excessive Ectopic Fat Accumulation as the
Consequence of Increased Adipose-Derived FFA Flux . . . . . . . . . . . . . . . 58
7.4 The Association of Excessive Ectopic Fat Accumulation
and Abnormalities of Energy Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
7.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
8 Muscle Biopsy To Investigate Mitochondrial Turnover . . . . . . . . . . . . . . . . . . . . 67
Rocco Barazzoni
8.1 Skeletal Muscle Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
8.2 Skeletal Muscle Function and Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
ContentsXII
8.3 Mitochondrial Glucose and Fatty Acid Oxidation . . . . . . . . . . . . . . . . . . . . . . 69
8.4 Regulation of Mitochondrial Oxidative Metabolism . . . . . . . . . . . . . . . . . . 69
8.5 Mitochondrial Function and Turnover in Human
Skeletal Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
8.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
9 Introduction to the Tracer-Based Study of Metabolism
In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Andrea Caumo and Livio Luzi
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
9.2 Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
9.3 Mass-BalancePrinciple . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
9.4 A Hydraulic Analogy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
9.5 Steady State and Turnover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
9.6 Clearance Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
9.7 Measurement of Turnover: The Essential Role of Tracer
Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
9.8 Characteristics and Properties of a Tracer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
9.9 The Constant-Infusion Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
9.10 The Single-Injection Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
9.11 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
10 Physical Activity and Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Raffaele Di Fenza and Paolo Fiorina
10.1 Inflammation Is an Important Feature of Metabolic
Diseases and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
10.2 Effect of Physical Activity on Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
10.3 Molecular Effect of Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
10.4 Physical Activity and miRNA: A Unifying Hypothesis . . . . . . . . . . . . . 104
10.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
11 The HPA Axis and the Regulation of Energy Balance . . . . . . . . . . . . . . . . . . . . 109
Francesca Frigerio
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
11.2 Anatomy of the HPA Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
11.3 Physiology of the HPA Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
11.4 Molecular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
11.5 HPA Axis and Energy Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
11.6 The HPA Axis and Non-homeostatic Energy Intake Regulation . 115
11.7 The HPA Axis and Energy Expenditure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
11.8 The Role of Glucocorticoids on Peripheral Organs . . . . . . . . . . . . . . . . . . 116
11.9 HPA Axis and Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
11.10 Glucocorticoids and Doping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
XIIIContents
12 Physical Exercise in Obesity and Anorexia Nervosa . . . . . . . . . . . . . . . . . . . . . . . 123
Alberto Battezzati e Simona Bertoli
12.1 Reduced Physical Activity in Industrialized Countries: 
A Potential Cause of the Obesity Pandemics? . . . . . . . . . . . . . . . . . . . . . . . . . 123
12.2 Reduced Physical Activity: The Cause of Weight Gain
in the Obese? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
12.3 Can Humans Adapt Energy Expenditure to Energy
Intake and Vice Versa? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
12.4 Is Physical Activity a Meaningful Trait in Anorexia
Nervosa? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
12.5 Why Hyperactivity in Anorexia Nervosa? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
12.6 Biological Basis of Activity-Based Anorexia . . . . . . . . . . . . . . . . . . . . . . . . . . 128
12.7 The Neuroendocrine Profile of AN Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
12.8 Is Hyperactivity an Unfavorable Prognostic Behavior? . . . . . . . . . . . . . 129
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
13 Physical Exercise and Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Valentina Delmonte, Vincenzo Lauriola, Rodolfo Alejandro 
and Camillo Ricordi
13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
13.2 Physical Work Capacity Before Transplantation . . . . . . . . . . . . . . . . . . . . . . 134
13.3 Physical Work Capacity After Transplantation . . . . . . . . . . . . . . . . . . . . . . . . 135
13.4 Exercise Therapy for Heart Transplant Recipients . . . . . . . . . . . . . . . . . . . 137
13.5 Exercise Therapy for Lung Transplant Recipients . . . . . . . . . . . . . . . . . . . . 138
13.6 Exercise Therapy for Kidney Transplant Recipients . . . . . . . . . . . . . . . . . 139
13.7 Exercise Therapy for Liver Transplant Recipients . . . . . . . . . . . . . . . . . . . . 140
13.8 Exercise Therapy for Pancreas and Islet Transplant
Recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
13.9 World Transplant Games . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
13.10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
14 The Baboon as a Primate Model To Study the Physiology 
and Metabolic Effects of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Francesca Casiraghi, Alberto Omar Chavez, Nicholas Musi 
and Franco Folli
14.1 Introduction: The Value of Non-human Primates
in Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
14.2 Non-human Primates in Biomedical Research . . . . . . . . . . . . . . . . . . . . . . . . . 149
14.3 The Baboon as a New Model To Study Physical Activity
and the Effects of Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
14.4 Summary . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
ContentsXIV
XV
Rodolfo Alejandro Diabetes Research Institute, University of Miami, 
Miller School of Medicine, Miami, USA
Rocco Barazzoni Department of Medical, Surgical and Health Sciences, 
University of Trieste, Trieste, Italy
Alberto Battezzati International Center for the Assessment of Nutritional 
Status (DiSTAM), University of Milan, Milan, Italy
Stefano Benedini Department of Sport Sciences, Nutrition and Health, 
University of Milan, Milan, Italy
Research Center of Metabolism, IRCCS Policlinico San Donato Milanese, 
Milan, Italy
Simona Bertoli International Center for the Assessment of Nutritional 
Status (DiSTAM), University of Milan, Milan, Italy
Francesca Casiraghi Department of Medicine, Division of Diabetes, 
University of Texas Health Science Center, San Antonio, USA
Andrea Caumo Department of Sport Sciences, Nutrition and Health, 
University of Milan, Milan, Italy
Alberto Omar Chavez Department of Medicine, Division of Diabetes, 
University of Texas Health Science Center, San Antonio, USA
Roberto Codella Department of Sport Sciences, Nutrition and Health, 
University of Milan, Milan, Italy
Valentina Delmonte Diabetes Research Institute, University of Miami, 
Miller School of Medicine, Miami, USA
Contributors
Raffaele Di Fenza Department of Medicine, Istituto Scientifico San Raffaele, 
Milan, Italy
Paolo Fiorina MD PhD Assistant Professor, Harvard Medical School, 
Boston, USA
Department of Medicine, Istituto Scientifico San Raffaele, Milan, Italy
Franco Folli MD PhD Department of Medicine, Division of Diabetes, 
University of Texas Health Science Center, San Antonio, USA 
Francesca Frigerio Novartis Farma S.p.A., Saronno (Varese), Italy
Vincenzo Lauriola Diabetes Research Institute, University of Miami, 
Miller School of Medicine, Miami, USA
Anna Maestroni Complications of Diabetes Unit, Division of Metabolic 
and Cardiovascular Sciences, Istituto Scientifico San Raffaele, Milan, Italy
Nicholas Musi Department of Medicine, Division of Diabetes, 
University of Texas Health Science Center, San Antonio, USA
Gianluca Perseghin Division of Metabolic and Cardiovascular Sciences, 
Istituto Scientifico San Raffaele, Milan, Italy 
Department of Sport Sciences, Nutrition and Health, University of Milan, 
Milan, Italy
Camillo Ricordi Diabetes Research Institute, University of Miami, 
Miller School of Medicine, Miami, USA
Ileana Terruzzi Division of Metabolic and Cardiovascular Sciences, 
Istituto Scientifico San Raffaele, Milan, Italy
Gianpaolo Zerbini Complications of Diabetes Unit, Division 
of Metabolic and Cardiovascular Sciences, Istituto Scientifico San Raffaele, 
Milan, Italy
ContributorsXVI
1.1 The Concept of Being Born to Run
Born to Run was the third album produced by the American singer-songwriter Bruce
Springsteen. It was released by Columbia Records on August 25, 1975. The same ti-
tle was used in the following decades for: at least one novel, an episode in the TV se-
ries Terminator, a book on a Mexican tribe of extreme runners, and it even appeared
on the cover page of Nature, in November 2004. The common denominator of all the
uses of Born to Run is the recognition of the need of humans to run in order to sur-
vive.
1.2 From Five Billion to One Million Years Ago
The present atmosphere of the Earth is composed of 21% oxygen. The remaining
gases are nitrogen (78%), argon (0.9%), carbon dioxide and other trace elements
(0.012%). About 5 billion years ago, at the birth of our planet, the atmosphere con-
tained virtually no oxygen. The advent of the first forms of life on Earth (prokary-
otes, primordial unicellular bacteria) was crucial for the change in composition of the
gas content of the atmosphere. Primordial bacteria were able to carry out photosyn-
thesis, utilizing hydrogen, obtained from water, and CO2 to release oxygen.
Therefore the development of life on Earth was determined by the appearance of or-
ganisms capable of surviving in the absence of oxygen, with their survival exclusive-
ly founded on anaerobic metabolism. The increasing amount of oxygen released by
prokaryotes into the primordial atmosphere favored the development of oxidative re-
actions to produce energy for life, a much more efficient method than anaerobic me-
1L. Luzi (ed.), Cellular Physiology and Metabolism of Physical Exercise
© Springer-Verlag Italia 2012
Human Evolution and Physical Exercise: 
The Concept of Being “Born to Run”
Livio Luzi
1
L. Luzi (�)
Department of Sport Sciences, Nutrition and Health 
University of Milan
Milan, Italy
e-mail: livio.luzi@unimi.it
tabolism. Some 1500 million years ago, the first eukaryotes capable of producing en-
ergy with oxidative metabolism appeared on Earth. Millions of years were then
necessary for the development of multicellular eukaryotes. It is relevant for evolution
in general and for human evolution in particular that in parallel with the appearance
of more complex multicellular organisms much of the Earth’s ecosystem was altered
by dramatic geologic events [1]. The volcanic eruptions, continent shifts, and mete-
oric collisions forced major evolutionary leaps, as only organisms capable of adapt-
ing to the new environment survived. One such adaptation is described by the en-
dosymbiotic theory. Endosymbiosis means “cohabiting within” and in this case
refers to the postulated collaboration/interaction between organisms with different
metabolic capabilities and dimensions, both of which gain an evolutionary advantage
by merging their living environments. As stated, not all organisms were able to tol-
erate an oxidant atmosphere (i.e., an atmosphere increasingly rich in oxygen pro-
duced by photosynthesis). According to endosymbiotic theory, primordial eukaryotes
were able to survive due to their incorporation of prokaryotes bearing much-needed
complementary skills. Peroxisomes and mitochondria are thought to be remnants of
prokaryotes that eventually became eukaryotic organelles, conferring upon their
hosts the cellular machinery needed for oxygen detoxification and energy production
in aerobiosis [2].
1.3 The Appearance of the Genus Homo
Roughly 1.5 million years ago, Homo erectus appeared on the Earth. Our present
genes are similar to those of Homo erectus, Homo habilis, and the first Homo sapi-
ens (200,000 to 100,000 years ago) [3]. Australopithecines were the ancestors of
Homo erectus and their evolution was driven by an important change in the ecosys-
tem: the replacement of woodlands by grasslands and savannas in central Africa [4].
The expansion of savannas caused a fundamental change in the way hominids for-
aged and, consequently, in the quality and caloric content of food as well as the
amount of physical activity required to gather food. In fact, the disappearance of
woodlands induced hominids to cover longer distances in savannas, prompting the
natural selection of individuals with longer lower limbs, the ability to run, better ther-
moregulatory capacity, and with a higher resting and total daily energy expenditure.
Evolutionarily, longer lower limbs and bipedalism facilitated foraging behavior in the
new ecosystem, determining a strong association between changes in body size (and
metabolism) and ranging/foraging patterns [5, 6]. Therefore, the earliest representa-
tive of the human genus, considered to be the African Homo erectus, was indeeed
“born to run,” that is,to cope with an environment strikingly different from the
woodlands where previous hominids had gathered food. Several musculoskeletal
adaptations are representative of the genus Homo, including a large cranial vault, a
prominent nose, a thin mandible, a chin, small teeth, a modified hip joint, and a light
skeleton. These anatomic changes allowed our ancestors to walk and run for long
distances and times, as their bodies were specialized for endurance and physical ac-
tivity [7]. Indeed, humans are specifically adapted to engage in prolonged strenuous
L. Luzi2
muscular activity, such as efficient long-distance bipedal running. This capacity
evolved to allow the running down of game animals by persistent slow but constant
chase over many hours. Central to the success of this strategy were at least four dis-
tinct factors [8]: (1) energetics: the lower cost of running vs. walking (the other hu-
man gait) at speeds above ~2 m/s; (2) skeletal length: as long lower limbs gave Homo
erectus greater speed in chasing and hunting; (3) the development of the central nerv-
ous system: with the differentiation of specific brain areas responsible for equilibri-
um, movement coordination, and postural stabilization; (4) thermoregulation: in
which the human body, unlike that of animal prey, can effectively remove muscle
heat waste. In most animals, a temporary increase in body temperature allows the
storage of muscle heat waste. This enables them to escape from animal predators that
quickly speed after them for a short duration (the method used by nearly all preda-
tors to catch their prey). Unlike other animals that hunt, humans remove body heat
with a specialized thermoregulatory system based on sweat evaporation. One gram
of sweat can remove 2,598 J of heat energy. Another mechanism is increased skin
blood flow during exercise, which allows for greater convective heat loss and is aid-
ed by humans’ upright posture. This skin-based cooling is a function of an increased
number of sweat glands combined with a lack of body hair that would otherwise stop
air circulation and efficient evaporation. Because humans can remove exercise-gen-
erated heat, they can avoid the heat exhaustion that affects animals chased in persist-
ence hunting, and so eventually catch their prey.
The amount of food available was much greater in the savannas than in wood-
lands, mainly due to the higher caloric and protein content of the large herbivores
hunted. This produced an increase in the body size of Homo erectus (∼ 65 kg males
and 52 kg females) compared to previous hominids (e.g., Australopithecines, ∼ 44 kg
males and 31 kg females). The increase in body weight, per se, determined a higher
resting energy expenditure (REE: in Homo erectus, an average of 1565 kcal/day in
males and 1361 kcal/day in females vs. 1130 and 902 kcal/day in males and females,
respectively, of Australopithecus africanus). By adding the calories consumed by
daily activities for Homo erectus to the REE, a total energy expenditure (TEE) of 3165
calories for males and 2141 calories for females can be estimated. These values are
quite similar in each case to those of a 70 kg individual contemporary to us [8].
Did Homo habilis actually hunt quadrupeds, or did our earliest ancestors mere-
ly scavenge meat from lion and other predator kills? Many experts now believe that
Homo habilis scavenged meat from nearby predator kills, chasing away lions with
stones and loud calls. The hominids would then grab choice pieces of meat and re-
treat to a convenient place, far away from predators. There they would eat the fresh
meat, and break up the bones for their marrow. Once their hunger was satisfied, they
would move off, leaving the crushed bones for other predators to scavenge. The ho-
minids would return to the same place on several occasions. However, their visits
were sufficiently infrequent so that carnivores did not hide in wait.
Contemporary humans have a genetic background, body size, resting and total
energy expenditure comparable to Homo erectus. Nonetheless, the environment of
Western countries in which many 21st century humans live has dramatically
changed: (1) there is no longer a need to consume energy for food foraging and hunt-
31 Human Evolution and Physical Exercise: The Concept of Being “Born to Run”
ing; (2) many more calorie-rich and refined foods are available, in virtually unlim-
ited supply; (3) food deprivation and starvation, except during religious fasts, are un-
known (in contrast to the winters and other periods of food scarcity faced by Homo
erectus). As a matter of fact, we are currently benefiting from a major ecosystem
change that started 10,000 years ago, with the agricultural revolution (when popula-
tions of hunters/gatherers settled down and began to raise grains and conserve food
for the winter), and reached its apex at the beginning of the 20th century, with the in-
dustrial revolution and the introduction of machines to help humans perform labor-
intensive and energy-demanding tasks. Therefore, due to the mismatch between our
genetic background (what we are predisposed for) and our new environment (what
we are actually doing), the incidence of diseases such as obesity, type 2 diabetes,
metabolic syndrome, hypertension, cardiovascular events, and some forms of cancer
has increased dramatically, especially in recent decades [9, 10].
The metabolic mechanism utilized by our body to store rather than to burn calo-
ries is insulin resistance. Insulin sensitivity (the opposite of insulin resistance) is de-
fined as the ability of insulin to metabolize a load of glucose (and other energy sub-
strates such as free fatty acids). An impairment of the body’s capacity to metabolize
a glucose load protects the individual from periods of food scarcity, starvation, or a
deficit in carbohydrate or fat intake. Obviously, if evolution selected insulin-resist-
ant humans based on their ability to survive periods of famine, the above-described
changes in the 20th century ecosystem have made modern humans susceptible to hy-
perglycemia, hyperlipidemia, and their pathological consequences, namely diabetes,
obesity, and atherosclerotic disease. In principle, more insulin-sensitive individuals
should be favored today, as they are able to dispose of regular, high-calorie loads in
less time whereas during life on the African savanna they would have been con-
demned to extinction [9]!
The maintenance of normal glycemia is obtained by the balance between insulin
secretion and insulin action, a relationship known as glucose tolerance. In normal in-
dividuals, there is a hyperbolic relationship between insulin secretion and insulin ac-
tion (Fig. 1.1); accordingly, normal glucose tolerance can be obtained over a wide
range of secretory capacity and insulin action. It is also well established that an im-
balance between insulin secretion and insulin action causes hyperglycemia. The se-
cretion of insulin must therefore be considered along with its action in order to de-
termine “the metabolic wellness” of an individual. It is a common belief that today’s
marathon runners are the closest modern humans come to Homo erectus in terms of
lifestyle and metabolism. Marathon runners maintain a normal glucose tolerance by
means of relatively efficient insulin action, tempered by relatively low levels of in-
sulin secretion. In this scenario, hunters/gatherers should have benefited from a very
high level of insulin action matched by a low secretory capacity of the hormone.
There is an apparent discrepancy between the predisposition of our genes to store en-
ergy (the “thrifty genotype” hypothesis [9] and the highly efficient insulin action of
marathon runners (and, probably, of Homo erectus). Thus, an organism predisposed
to saving and storing energy needs constant physical exercise to maintain normal in-
sulin action and proper substrate utilization. Accordingly,a healthy lifestyle is de-
fined by regular physical exercise along with appropriate dietary habits. In other
L. Luzi4
1 Human Evolution and Physical Exercise: The Concept of Being “Born to Run” 5
words, the lack of a physical exercise program renders vain all dietary interventions
(this is basically the clinical “on the field” experience of most physicians).
It is worth noting that it is not only the total amount but also the pattern of insulin
secretion that determines glucose disposal and the effective clearance a glucose
load. First-phase insulin release has been shown to have a consistent role in inhibit-
ing endogenous glucose production following a meal. Early stages of diabetes and
obesity are characterized by a loss of first-phase insulin release and thus by post-
prandial hyperglycemia and a reduction of the thermogenic effect of food. The com-
bination of the two defects leads to diabetes and obesity, respectively (or a combina-
tion thereof). Similar to insulin action, the "blindness" of the β-cell to glucose is
overcome by amino acid administration via a high-protein diet, indicating that pro-
tein homeostasis is the metabolic domain best protected by evolution. In fact, on the
one hand, in most conditions (with the notable exception of obesity) insulin’s action
on protein metabolism is spared (despite a marked impairment of its action on car-
bohydrate and lipid metabolism). On the other hand, amino acids/high-protein diets
are able to restore a normal secretory pattern of insulin secretion, thus overcoming
β-cell blindness to glucose during the early stages of type 2 diabetes mellitus.
Based on these considerations there are two possibilities. One is that current evo-
lutionary pressure will select one or a few protective genes/features of the sedentary
Homo sapiens that will allow humans to evolve such that the insulin sensitivity of fu-
ture generations is much higher that that conferred by our present genes. In other
words, presumably, only individuals with a higher capacity to burn calories and dis-
Fig 1.1 The relationship between insulin sensitivity and beta-cell secretion is well-described by a
hyperbolic function, such that the product of insulin sensitivity times beta-cell secretion tends to re-
main constant. Physical exercise is known to enhance insulin sensitivity. Since less insulin is re-
quired to metabolize glucose, a concomitant reduction in beta-cell secretion takes place. The over-
all effect is as follows: a subject undertaking physical training slides along the hyperbola achieving
a position characterized by elevated insulin sensitivity and low circulating insulin levels
pose of nutrient loads (without needing to perform physical exercise) will be select-
ed for survival by evolution. In this case, we have no choice but to passively wait for
evolution to find a solution (as our ancestors did!).
The other possibility is to change our behavior such that it mimics our ancestors’
way of life in terms of patterns of physical activity and the diet of hunters/gatherers.
That lifestyle was characterized by three cornerstones. First, physical exercise was
performed several hours a day, with different modalities and intensities. In Homo
erectus, walking and running were frequent forms of physical exercise. The behav-
ior of contemporary species of primates has been studied to deduce the physical ex-
ercise patterns and total daily energy expenditure of our ancestors. Although this kind
of information is difficult to extrapolate, based on a total energy expenditure of
2,500–3,500 kcal per day, physical exercise, ranging from active to strenuous, was
likely performed for between 1 and 4 hours daily. Moreover, even during periods of
daily rest and over the year, the average energy expenditure was higher than the pres-
ent-day value, reflecting non-shivering thermogenesis secondary to cold-temperature
exposure. Second, the diet of hunters/gatherers contained a much lower (up to 30%
less) percentage of complex carbohydrates than is consumed today, a higher protein
content (both vegetable and animal protein), and a total fat content similar to today’s
level, with the notable prevalence of mono- and polyunsaturated fats over saturated
fats. Third, of particular relevance was the modality of caloric intake of Homo erec-
tus, characterized by periods of forced starvation (presumably ranging from 1 day to
longer periods). Therefore, periodic fasting was a constant for hunters/gatherers
whereas, unless voluntarily performed, periods of food deprivation are for the most
part completely unknown in modern Western societies. Interestingly, a metabolic
model of fasting is provided by the initial stage of mental anorexia. Patients with this
disease voluntarily reduce their caloric intake while engaging in physical exercise for
several hours a day. Consequently, body weight, total daily energy expenditure, and
blood concentrations of glucose, lipids, and amino acids (with respect to matched
controls) are reduced, resulting in a clinical picture that is the mirror image of type
2 diabetes and metabolic syndrome. This clinical model suggests that our genes pre-
dispose us with the ability to well resist long periods of reduced caloric intake. If we
succeed in changing our lifestyle accordingly, we will eradicate diabetes, obesity, hy-
pertension, metabolic syndrome, cardiovascular disease, and even some forms of
cancer.
References
1. Kasting JF, Siefert JL (2002) Life and the evolution of Earth’s atmosphere. Science 10:1066-
1068
2. Alberts B, Johnson A, Lewis J et al (2002) Molecular biology of the cell. New York, Garland
Science
3. Wood B, Collar M (1999) The human genus. Science 284:65-71
4. Cerling TE (1992) Development of grasslands and savannas in East Africa during the neogene.
Paleogeog Paleoclimatol Paleoecol 97:241-247
5. Leonard WR, Robertson ML (1997) Comparative primate energetics and hominid evolution.
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Am J Phys Anthropol 102:265-281
6. Ulijaszek SJ (2002) Human eating behaviour in an evolutionary ecological context. Proc Nutr
Society 61:517-526
7. Isbell LA, Pruetz JD, Lewis M, Young TP (1998) Locomotor activity differences between
sympatric patas monkeys (Erytrocebus Patas) and vervet monkeys (Cercopithecus aethiops):
implications for the evolution of long hindlimb length in Homo. Am J Phys Antropol 105:199-
207
8. Bramble DL, Lieberman DE (2004) Endurance running and the evolution of Homo. Nature
433:345-353
9. Luzi L, Pizzini G (2004) Born to run: training our genes to cope with ecosystem changes in the
twentieth century. Sport Sci Health 1:1-4
10. Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”. Am
J Hum Genetic 14:353-362
71 Human Evolution and Physical Exercise: The Concept of Being “Born to Run”
2.1 Introduction
Muscles can be of different types. Based on morphology, we can distinguish sev-
eral types:
• Striated skeletal muscles have characteristic cross-striations which are due to
the regular arrangement of contractile elements, the sarcomeres. Striated skele-
tal muscles contract in response to nerve impulses from the motor neurons of
the central nervous system (CNS) or at the conscious level. They are related to
skeletal segments.
• The striated cardiac muscle of the heart is called the myocardium.
Microscopically, cardiac muscle fibers are marked by transverse striae, which
are also present on skeletal muscle fibers, as well as other transverse striations
that make up the joint areas of the fibers. Cardiac muscle contracts independ-
ently of the will.
• Smooth muscles, as their name implies, do not possess cross-striations. They
are generally lighter in color than striated muscles and form the muscular com-
ponent of the viscera. The walls of organs and structures such as the esophagus,
stomach, intestines, bronchi, uterus, urethra, bladder,blood vessels, and the
erector pili in the skin (which control the erection of body hair) all contain
smooth muscle. The contractions of smooth muscles (with very few exceptions)
are involuntary and occur under the control of hormones or external stimuli and
in response to impulses from the autonomic nervous system.
9L. Luzi (ed.), Cellular Physiology and Metabolism of Physical Exercise
© Springer-Verlag Italia 2012
Cell Morphology and Function:
The Specificities of Muscle Cells
Anna Maestroni
2
A. Maestroni (�)
Complications of Diabetes Unit,
Division of Metabolic and Cardiovascular Sciences 
Istituto Scientifico San Raffaele, Milan, Italy
e-mail: maestroni.anna@hsr.it
2.2 Striated Skeletal Muscles
The muscles are covered externally by connective tissue referred to as the epimy-
sium, which surrounds the entire muscle, holding it together. Inside the epimysi-
um are fiber bundles, the fasciculi, wrapped in a sheath of connective tissue. The
connective tissue sheath surrounding each fasciculus is called the perimysium.
Finally, within the perimysium are the muscle fibers, which are the individual
muscle cells. The endomysium, another sheath of connective tissue, surrounds
each muscle fiber. The epimysium, perimysium, and endomysium are connective
structures that together form the tendon (Fig. 2.1).
Muscle fibers range in length from 1 mm to a maximum of 12 cm in the sarto-
rius muscle. Their diameter ranges from a minimum of 10 μm to a maximum of
100-105 μm (average: 10–50 μm). These cellular elements are derived from the fu-
sion of progenitor cells called myoblasts and thus form syncytia. Skeletal muscle
fibers are cylindrical in shape and contain many nuclei (even hundreds) located
near the sarcolemma (the cell membrane of muscle cells). However, the defining
characteristic of muscle fibers is the cross-striations seen on light microscopy.
A gelatin-like substance fills the spaces between the myofibrils. This is the sar-
coplasm and it comprises the cytoplasm of muscle fiber. The sarcoplasm differs
from true cytoplasm in that it contains a large quantity of stored glycogen as well
as the oxygen-binding compound myoglobin, which is quite similar to hemoglo-
bin (Fig. 2.2).
Another special structure of the muscle fiber is the sarcoplasmic reticulum,
which is the smooth endoplasmic reticulum. Its distinct shape can be recognized
in every sarcomere. The sarcoplasmic reticulum is structured as follows: at the
junction between the A and I bands are the terminal cisternae, along which
A. Maestroni10
Fig 2.1 Schematic structure of skeletal muscles
branching tubules are arranged longitudinally, resulting in fenestrated central
cisternae. At the confluence of two terminal cisternae is a tubular formation, the
transverse tubules (T tubules). This sarcolemmal invagination communicates
with the extracellular environment but not with the lumen of the sarcoplasmic
reticulum. The membranes of the two systems are coupled but they are separated
by a gap. Together, these structures are referred to as the triad of the reticulum and
they are involved in modulating the release of calcium ions, which are essential
for muscle contraction.
Each muscle fiber also contains several hundred to several thousand myofibrils:
these are the contractile elements of skeletal muscle. Sarcomeres are the building
blocks of myofibrils (Fig. 2.3). They are composed of thin actin filaments and
thick myosin filaments. A sarcomere is defined as the segment between two neigh-
boring Z-lines (or Z-discs, or Z bodies). In electron micrographs of cross-striated
muscle, the Z-line (from the German Zwischenscheibe, the band in between the I-
bands) appears as a series of dark lines. Surrounding the Z-line is the region of the
I-band (I for isotropic). Following the I-band is the A-band (A for anisotropic).
Within the A-band is a paler region called the H-band (from the German heller,
bright). The names of these bands derive from their properties as seen on polariza-
112 Cell Morphology and Function: The Specificities of Muscle Cells
Fig 2.2 Representation 
of skeletal muscle fibers
tion microscopy. Finally, inside the H-zone is a thin M-line (from the German mit-
tel, middle of the sarcomere) (Fig. 2.4).
Each myosin filament typically comprises about 200 myosin molecules, lined
up end to end and side by side. The myosin molecule is composed of two identi-
cal heavy (larger) chains and two pairs of light (smaller) chains. The heavy protein
chains intertwine to form a tail end, a rigid spiral, and two globular heads. One of
the two light protein chains is associated with one of the heavy-chain heads. The
globular heads of the myosin cross-bridges mediate the interaction with thin actin
filaments during muscle contraction. The myosin filaments are connected from the
M-line to the Z-disc by tinin.
A. Maestroni12
Fig 2.3 Schematic structure of skeletal muscles
Fig 2.4 Schematic 
representation of contracted
and relaxed sarcomeres
2 Cell Morphology and Function: The Specificities of Muscle Cells 13
Actin is a globular protein (G-actin) that combines to form long, thin chains (F-
actin). Two F-actin strands form a helical twist, much like two strands of pearls
twisted together. Each actin molecule has an active binding site that serves as the
point of contact with the myosin filament. 
In addition to actin, the thin filaments of the sarcomere are composed of
tropomyosin and troponin. Tropomyosin is a tubular protein that twists the actin
strands while troponin is a more complex protein made up three subunits (TnC,
TnI, and TnT) and attached at regular intervals to both the actin strands and to
tropomyosin. When calcium is bound to specific sites on TnC, tropomyosin rolls
out of the way of the actin filament’s active sites, thus allowing myosin to attach
to the thin filament and to subsequently produce force and/or movement. In the ab-
sence of calcium, tropomyosin interferes with the action of myosin such that the
muscles remain relaxed.
The individual subunits of troponin serve different functions in muscle contrac-
tion: troponin C binds to calcium ions to produce a conformational change in TnI;
troponin T binds to tropomyosin to form a troponin-tropomyosin complex; and tro-
ponin I binds to actin in thin myofilaments to hold the troponin-tropomyosin com-
plex in place.
Tropomyosin and troponin require the presence of calcium ions to maintain re-
laxation or to initiate contraction of the myofibril, which we examine later in this
chapter. In addition, actin and myosin interactions are regulated by another protein,
nebulin, which serves as an anchoring protein for actin (Fig. 2.5).
2.3 Muscle Contraction
The events that trigger a muscle fiber are complex. The process is initiated by a mo-
tor nerve impulse from the brain or spinal cord. An action potential originating in
the CNS reaches an alpha motor neuron, which then transmits the action potential
down its own axon. The action potential is propagated by the activation of sodium-
dependent channels along the axon toward the synaptic cleft. An influx of Ca2+
causes vesicles containing the neurotransmitter acetylcholine to fuse with the plas-
ma membrane, releasing acetylcholine into the extracellular space between the mo-
tor neuron terminal and the motor end plate of the skeletal muscle fiber.
Fig 2.5 Schematic 
representation of thick 
and thin filaments
Acetylcholine diffuses across the synapse and binds to and activates acetylcholine
receptors on the motor end plate of the muscle cell. Activation of the acetylcholine
receptor opens its intrinsic sodium/potassium channel, causing sodium to rush in
and potassium to trickle out. Since the channel is more permeable to sodium, the
membranes of the muscle fibers becomes more positively charged, triggering an ac-
tion potential. The action potential spreadsthrough the muscle fiber’s network of T-
tubules, depolarizing the inner portion of the muscle fiber. Depolarization acti-
vates voltage-dependent calcium channels in the T-tubule membrane, which are in
close proximity to calcium-release channels in the adjacent sarcoplasmic reticulum.
Activated voltage-gated calcium channels physically interact with and thereby
activate calcium-release channels, causing the sarcoplasmic reticulum to release cal-
cium. The released calcium binds to the troponin C present on the actin thin fila-
ments of the myofibrils. Troponin then allosterically modulates tropomyosin.
Normally, tropomyosin sterically obstructs myosin-binding sites on the thin fila-
ment; however, once calcium binds to troponin C and causes an allosteric change in
the protein, troponin T allows tropomyosin to move, unblocking the binding sites.
Myosin has ADP and inorganic phosphate bound to its nucleotide-binding pock-
et and is in an active state. In this form, it binds to the newly uncovered binding sites
on the thin filament in a process very tightly coupled to inorganic phosphate release,
in which actin serves as a cofactor. Myosin is now strongly bound to actin, with the
release of ADP and inorganic phosphate tightly coupled to the power stroke. During
the latter, the Z-bands are pulled towards each other, thus shortening the sarcomere
and the I-band.
Conversely, ATP binding to myosin allows it to release actin and to remain in
a weak binding state (a lack of ATP makes this step impossible, resulting in the rig-
or state characteristic of rigor mortis). Myosin then hydrolyzes the ATP and uses
the energy to move into the “cocked back” conformation. In vivo studies have con-
firmed model-based predictions regarding movement of the myosin head of skele-
A. Maestroni14
Fig 2.6 The mechanism 
of muscle contraction
tal muscle: during each power stroke the myosin head moves 10–12 nm; however,
there is also in vitro evidence of variations (smaller and larger) in this range of
movement that are specific to the myosin isoform (Fig. 2.6).
Sliding of the filaments occurs as long as ATP is available and calcium is pres-
ent. During the above-described steps, calcium is actively pumped back into the
sarcoplasmic reticulum, which creates a deficiency in the environment around the
myofibrils. As a result, calcium ions are removed from troponin such that the
tropomyosin reverts to its previous state, forming a complex with troponin and
again blocking myosin-binding sites. Myosin is thus unable to bind to the thin fil-
aments, and contraction ceases.
Suggested Reading
Macintosh BR, Gardiner PF, McComas AJ (2006) Skeletal muscle: form and function. Human
Kinetics, Leeds 
Lieber RL (2002) Skeletal muscle structure, function, and plasticity. Lippincott Williams &
Wilkins, Baltimore
152 Cell Morphology and Function: The Specificities of Muscle Cells
3.1 Cell Membranes
The cell membrane was initially considered only as a barrier delimiting the cytoplasm
from the extracellular environment but further research revealed that the cell membrane
has a number of functions that are essential to the cell [1]. Structurally, the cell mem-
brane is formed by a lipid bilayer (Fig. 3.1), with each of the two layers composed of
molecules called phospholipids. The lipid component is, by definition, water-repellent,
while the phosphate component is hydrophilic. The membrane is formed as the phos-
phate moves toward the outer surface of the cell, attracted by the aqueous environment,
which the inwards-oriented lipids seek to escape. An additional and very important
component of this double lipid structure consists of the membrane proteins. 
The organization of the cell membrane is therefore referred to as a “fluid mosaic,”
in which the hydrophobic and hydrophilic components interact with each other in
such a way that membrane fragments are able to detach from the main structure
without creating permanent holes. The membrane surrounding internal organelles,
such as the endoplasmic reticulum, the Golgi apparatus, lysosomes, and vacuoles, in-
teracts with these structures and is crucial to their function [2].
3.2 The Structure of the Cell Membrane 
3.2.1 Lipids 
Lipids are retained on the internal aspect of the cell membrane because of their wa-
ter repellency. Although they may also bond with oxygen molecules, lipids mainly
17L. Luzi (ed.), Cellular Physiology and Metabolism of Physical Exercise
© Springer-Verlag Italia 2012
The Cell Membrane 
of the Contractile Unit
Gianpaolo Zerbini
3
G. Zerbini (�)
Complications of Diabetes Unit
Division of Metabolic and Cardiovascular Sciences 
Istituto Scientifico San Raffaele, Milan, Italy
e-mail: g.zerbini@hsr.it
consist of hydrocarbons. The three main classes of lipids that make up the cell
membrane are fats, phospholipids, and steroids. 
Fats (triacylglycerols) are not true polymers but are nonetheless composed of
large molecules formed from a number of smaller molecules; these are held togeth-
er due to their water-repellent properties. Fat consists essentially of two molecules:
glycerol and fatty acids. Glycerol belongs to the class of alcohols, while fatty acids
are composed of 16–18 carbon atoms. One end of the fatty acid is the carboxylic
group, which is joined to a long hydrocarbon tail. The C-H bonds of the fatty-acid
tail account for the hydrophobicity of fat. 
Fat is formed by the binding of three fatty acids to a glycerol molecule, giving
rise to a bond between the hydroxyl group and the carboxylic group. The fat mol-
ecule thus generated is called triacylglycerol or triglyceride. The fatty acids com-
prising the fat molecule can be identical or different. The length, number, and loca-
tion of the double bonds present in a fatty acid define its physical and chemical
characteristics. Fat may be saturated or unsaturated depending on the structure of
the fatty acids that make up the hydrocarbon tail. The fluidity of the membrane
tends to change according to the prevalence of saturated or unsaturated fats within
the cell membrane [3]. 
Phospholipids are the major component of the cell membrane. They are structural-
ly similar to fat but contain only two fatty acids instead of three. The third hydroxyl
group of glycerol is in this case attached to a negatively charged phosphate group,
which is usually linked to small hydrophilic molecules. Different types of phospho-
lipids can be generated based on the nature of the molecule bound to the phosphate.
Phospholipids contain both a hydrophobic and a hydrophilic region and are thus de-
fined as amphipathic molecules. The hydrophobic component is the hydrocarbon tail,
while the hydrophilic head is formed by the phosphate group and its attachments. The
morphology of phospholipids is such that once they are in contact with water they or-
ganize themselves in clusters in which the hydrophilic side is exposed toward the
aqueous extracellular milieu while the hydrophobic part is aligned inwards. This struc-
ture is called a micelle and it is the main structural component of the phospholipid bi-
layer, comprising the semi-permeable structure characteristic of any cell membrane. 
Steroids consist of cholesterol and include several hormones. The carbon skele-
ton of steroids is arranged in four concentric rings. Cholesterol in particular is a key
element of animal cell membranes and is essential to their stability. All steroids are
formed from a cholesterol precursor. In the cell membrane, cholesterol molecules
are incorporated into the phospholipid bilayer [4].
3.2.2 Proteins 
Proteins alone account for > 50% of a single cell’s dry weight. Although the cell
membrane contains tens of thousands of proteins, each protein can be considered as
a polymer organized from the different sequential arrangements of 20 amino acids.
Membrane proteins may be integral or peripheral.Integral proteins are generally
transmembrane proteins in which the hydrophobic part traverses the cell mem-
brane between its extracellular and intracellular aspects, while the hydrophilic ends
G. Zerbini18
of the protein emerge on either side. Within the membrane, integral proteins are
larger than lipids; some of them diffuse very slowly in this environment while oth-
ers are anchored to the cytoskeleton. Peripheral proteins, as their name implies, are
not located inside the cell membrane but are instead weakly anchored to its outer
surface, often in contact with the external portions of integral membrane proteins. 
3.2.3 Carbohydrates 
Membrane carbohydrates are usually branched oligosaccharides. Those covalent-
ly bonded to lipids form glycolipids while those covalently bonded to proteins
form glycoproteins. The oligosaccharides on the cell surface differ between individ-
uals but also from cell to cell; in the latter case, they can therefore be used as
markers to distinguish one cell from the other. 
3.2.4 Membrane Asymmetry
Membranes are exposed to the extracellular milieu and to the cytoplasm; according-
ly, they have different internal and external surfaces. Since the two lipid layers dif-
fer in their composition, membrane proteins also assume different spatial arrange-
ments. However, carbohydrates are found only on the outer surface of the mem-
brane. 
3.3 Functions of the Cell Membrane 
3.3.1 Transport 
The cell membrane allows the internal and external passage of material. Transport
of the various molecules may be energy-independent or coupled to an energy-de-
pendent reaction or process.
3.3.2 Diffusion
Many small molecules are able to cross the cell membrane simply by moving
across a gradient from an area of higher to one of lower concentration. 
Only molecules small enough to pass through the small pores within the mem-
brane are transported by diffusion. Since no energy is involved to move these mol-
ecules, diffusion tends to be a slow process. The transition of the molecules
through the membrane is also influenced by whether they are lipid-soluble or wa-
ter-soluble. 
3.3.3 Facilitated Diffusion 
Some membrane proteins can form channels that allow water-soluble molecules to
pass through the hydrophobic lipid layer inside the membrane. This is the mecha-
193 The Cell Membrane of the Contractile Unit
nism by which important molecules such as glucose, which supplies energy to the
cell, pass through the membrane. The protein channels allow these molecules to
pass from areas of higher to those of lower concentration. 
3.3.4 Active Transport
For some molecules, a higher concentration must be maintained on one side of the
membrane than on the other. To maintain this concentration gradient requires ener-
gy. Perhaps the best studied model of active transport is the sodium-potassium
pump, but minerals are also moved by this mechanism. 
Nerve cells use pumps to transport ions in order to ultimately transmit their chem-
ical messages. 
3.3.5 Phagocytosis and Pinocytosis
Sometimes the cell must allow the entry of molecules that are too large to pass
through the normal channels of the plasma membrane. In this case, the membrane
surrounds the molecule of interest, forming a vesicle that can be easily transported
inside the cell. Phagocytosis and pinocytosis refer to the vesicle-mediated transport
of solid and liquid molecules, respectively. 
3.4 Immune System 
The proteins that make up the cell membrane are obviously very important for the
immune system. Some of them form channels or transporters, but other are need-
ed for the identification and characterization of the cell. The recognition of self re-
lies on the presence of proteins and glycoproteins on the cell surface. An organ that
is transplanted from one individual to another will be recognized as foreign if the
membrane proteins differ from those of the recipient organism; in such cases, un-
less so-called immunosuppressive drugs are administered to the host, the trans-
planted organ will be rejected. The same mechanism underlies autoimmune dis-
eases such as rheumatoid arthritis and diseases of the thyroid; in both cases, mem-
brane proteins of the human body are mistakenly recognized as foreign and then
rejected.
3.5 Membrane Receptors 
Some transmembrane proteins form membrane receptors, in which case a portion
of the protein is located on the outer surface of the membrane and, based on its
highly specific structure, is recognized by its ligand. The ligand may be a specific
substance, such as a hormone, or a protein present on the membrane of another cell,
as occurs when a killer lymphocyte recognizes a foreign cell. The binding of a hor-
mone to its specific membrane receptor results in aggregation of the receptor-ligand
G. Zerbini20
3 The Cell Membrane of the Contractile Unit 21
complex followed by either on-site degradation of the complex itself or its internal-
ization with further activity inside the cell. 
3.6 The Sarcolemma
The sarcolemma is the cell membrane of a muscle cell (skeletal, cardiac, and
smooth muscle). It consists of the typical plasma membrane but also an outer coat
made up of a thin layer of polysaccharide material containing thin collagen fibrils.
At each end of the muscle fiber, the surface layer of the sarcolemma combines with
a tendon fiber. The tendon fibers finally collect into bundles to form the muscle ten-
don, which inserts into bones. The sarcolemma is specialized to receive and conduct
stimuli. Dysfunctions in the stability of the sarcolemma membrane and its repair
system underlie diseases such as muscular dystrophy [2].
References
1. Hollán S (1996) Membrane fluidity of blood cells. Haematologia 27:109-27
2. Jacobson K, Sheets ED, Simson R (1995) Revisiting the fluid mosaic model of membranes.
Science 268:1441-2 
3. Singer SJ (2004) Some early history of membrane molecular biology. Annu Rev Physiol
66:1-27
4. Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes.
Science 175:720-31
4.1 Introduction
Researchers have long worked to identify and describe the morphologic, anthropo-
metric, physiologic, and functional characteristics of athletes who have reached
high levels in various sports. But year after year, athletic records are broken and the
limits of human performance are continuously redefined.
Despite these increasingly high performance levels, all living organisms are in
a state of homeostasis, in which the body is maintained in a state of biochemical
balance even when subjected to strong environmental stimuli. This adaptive abil-
ity is a primary defense mechanism that the body exploits to protect itself from
changes in the external environment and/or from systematic repetition of stress-
ful physical changes. Since training and exercise in general are stress factors
with demands on the metabolism of protein and energy, the supply of oxygen in
the blood, and all other homeostatic control systems, the body has evolved a
state of readiness allowing it to react even to the demands of extreme physical
performance.
Physical effort, if sufficiently intense, causes a fatigue process that after an ad-
equate and necessary recovery phase prevents the return of energy reserves, protein
synthesis, and numerous regulatory mechanisms to their initial, pre-loading state
but instead brings about a level that is significantly higher, resulting in greater per-
formance capabilities (Fig. 4.1). In fact, during the mandatory recovery phase, not
only is the energy consumed offset but reserves above the initial level are built up
according to a mechanism called “super-compensation”. The ability to adapt to dif-
ferent situations and to different environmental circumstances related to physical
activity is an amazing feature typical of living beings. If the human bodywere not
able to respond positively to all the demands it encounters, such as cold, heat, oxy-
23L. Luzi (ed.), Cellular Physiology and Metabolism of Physical Exercise
© Springer-Verlag Italia 2012
Gene Polymorphisms and Athletic 
Performance
Ileana Terruzzi
4
I. Terruzzi (�)
Division of Metabolic and Cardiovascular Sciences 
Istituto Scientifico San Raffaele, Milan, Italy
e-mail: terruzzi.ileana@hsr.it
gen deprivation, manual work, inactivity, or disease—in other words, all those
sometimes difficult circumstances that life entails—it would face certain death.
4.2 What Happens When the Balance in the Human Body
Is Modified?
The human body is a marvelous machine that will improve or worsen its per-
formance depending on the type, amount, and frequency of the stimuli with which
it is confronted and it will adapt its skills to cope with substantial workloads.
Muscular work involves a coordinated series of intracellular changes that lead to
movements of muscle fibers and, consequently, of the muscles themselves. The hu-
man body’s ability to adapt to muscular work means that its muscles can be trained
to carry out this work and thus to reach a degree of contraction different from the
resting state, resulting in improved neuromuscular response and increased resist-
ance. In fact, muscle development is the natural adaptation of the body to increas-
ing physical activity, with a very complex set of changes. Consequently, the body
is equipped to deal with a stressful event of greater magnitude, as the duly stimu-
lated muscles which periodically undergo effort become stronger each time.
Therefore, systematic training induces the body to successfully confront in-
creasingly higher levels of fatigue through the development of morphologic and
functional changes that are stable over time and depend on the type, intensity, and
duration of the exercise but also on the physiologic characteristics of the individual.
Progress in the body’s performance occurs in response to a training stimulus
that produces an improvement in the starting conditions. Moreover, improvement
requires that the training stimulus consists of a steady and gradual increase based
on a person’s individual organic capability and without interruptions, to avoid
losing the adaptations thus far achieved. Accordingly, a new state of homeostasis
is achieved. In contrast, low-intensity and inconsistent training do not alter either
the quality or the metabolic performance of an athlete (Fig. 4.2).
In recent years, much attention has been paid to the type and amplitude of the
changes that develop with physical exercise, at the cellular and molecular levels,
I. Terruzzi24
Fig 4.1 Schematic 
representation of the 
fluctuation in athletic 
efficiency due to fatigue, 
compensation and 
super-compensation
in order to assess whether there is a correlation between them and the body’s
adaptability and ability to perform.
A series of tests can be used to investigate the physiologic factors that deter-
mine an athlete’s physical and sports performance. For example, the measure-
ment of blood lactate is an indicator of lactic acid metabolism under stress, allow-
ing training loads and recovery to then be modulated accordingly. The determina-
tion of maximal and submaximal O2 consumption is a good indicator of perform-
ance, while the evaluation of slow muscle fiber composition reflects the amount of
muscle strength. All of these tests are very effective for periodic monitoring, which
is extremely important for an athlete in order to assess the results of his or her
training program. A through analysis of the results allows performance to be relat-
ed to training strategies, thus creating a successful training program that provides
optimal results.
However, the chosen indicator serves only to measure that particular parame-
ter, such that a related improvement or deterioration in performance can only be in-
directly inferred. Instead, measurements of the complex processes of exercise-in-
duced stress adaptation are necessary to make the appropriate choice of exercise
and to decide upon the duration and characteristics of its execution, in order to pro-
vide the athlete with the right support and guarantee improved performance. But
can these parameters, which show a significant correlation with performance and
allow estimations of adaptability and performance capabilities, be used to identi-
fy an athlete a priori?
These types of tests are able to measure retrospectively how an athlete re-
sponds to the training stimulus and to determine the effect of that training, but not
254 Gene Polymorphisms and Athletic Performance
Fig 4.2 Human body’s 
adaptations to different 
physical activities
to predict an individual’s response to the stimulus. Will the tested athlete have the
talent to be among the elite? Will he have the skills to better respond to the kind of
training in question? Will she merely be one of the many competitors or will she
be a winner?
4.3 Human Performance Shows a Wide Variety
of Responses
Sports performance and motor ability have always shown a large degree of varia-
tion even between individuals who use the same training protocols. This variabil-
ity can be seen in Fig. 4.3, which shows the running times of the athletes who par-
ticipated in the Vancouver marathon in 1999 (Fig. 4.3, left panel). The distribution
of the arrival times can be explained by a variety of factors—extrinsic and intrin-
sic—that affect the performance of each runner. 
Age (Fig. 4.3, center panel) and sex (Fig. 4.3 right panel) are certainly among
the factors able to determine the different performance responses of each individ-
ual athlete. Figure 4.3 show that, on average, women are slower than men, al-
though it is not clear whether this is reflects anatomic differences between the sex-
es or social and cultural influences. The environment is certainly one of the most
relevant extrinsic factors influencing the development of athletic potential, but it is
equally certain that potential is innate and determined by an individual’s genetic
heritage.
Each of us owes our uniqueness to the information contained in our DNA, the
genetic code that we inherited from our parents and which we pass on to our chil-
dren. What is written in that code determines not only phenotypic traits, such as
hair, eyes, skin color and other physical features, but also our character, our sus-
ceptibility to disease, and our ability to react to stimuli. Of course, the environment
and our life experiences greatly affect the manifestation of this information such
that, depending on the type and amount of stimuli we receive, our response will re-
flect the adaptability with which our DNA has equipped us (Fig. 4.4).
The way we progress as a result of training is certainly due to the presence of
a stimulus that acts by placing our body under stress, but our response to that stim-
I. Terruzzi26
Fig 4.3 Graphical representation of the variability in athletic performance
4 Gene Polymorphisms and Athletic Performance 27
ulus is dictated by the instructions written in our DNA and it is these instructions
that generate different responses to equivalent stimuli. Physical activity induces a
wide variety of biochemical and biophysical responses that act on the organism
and determine a broad range of phenotypic adaptations. The results in terms of per-
formance vary and this variability is particularly observed in athletes, in whom al-
most no measurable differences in performance can distinguish the winner from
his or her competitors. It is clear that some athletes possess an innate talent that
distinguishes them from other competitors who show the same strength of will, the
same effort, and the same perseverance in training: genetics provide the competi-
tors with the opportunity to participate and the winner with the