Signal transduction and adaptation to exercise: background and methods.
INTRODUCTION
In this chapter we aim to answer questions such as ‘why and how do we adapt to exer-
cise?’ We begin by highlighting limitations to the classical view of supercompensation in
exercise training, before introducing the signal transduction hypothesis of adaptation.
Related to this we discuss how exercise generates signals that are sensed by sensor pro-
teins, conveyed and computed by signal transduction proteins and how adaption regula-
tors regulate transcription, translation or protein synthesis, protein degradation and other
cellular functions such as the cell cycle. All this makes cells and organs adapt to exercise.
In the second half of the chapter we introduce RT-qPCR, which is a method used to
measure mRNAs, and Western blotting, which is used to measure proteins. The chapter
concludes with a discussion of high throughput approaches, including microarrays and
proteomics, and their application in exercise physiology. To prepare for this chapter you should read Chapter 1, which introduces molecular exercise physiology and basic wet
laboratory research methods, and Chapter 2, which introduces sport and exercise genet-
ics and explains PCR (polymerase chain reaction) which is the basis for RT-qPCR.
WHY DO WE ADAPT TO EXERCISE?
Physiological adaptations are changes that occur within individuals in response to exter-
nal factors such as exercise and other environmental factors, such as altitude. In the
history of adaptation research one early idea is the overload concept proposed by Julius
Wolff, who linked the loading of bones to their adaptation in an 1892 book entitled The
Law of Bone Remodelling (Wolff, 1892). This hypothesis is now known as Wolff’s law. It
can be extended to other organs if the meaning of the term overload is extended beyond
mechanical overload. Stating the overload principle for sport is of course correct but the
overload principle is just stating the obvious, namely that exercise training is required
for adaptation. Moreover it does not explain the mechanisms by which bones or other
organs respond and adapt.
A different theory, viewed by some as a mechanistic explanation of adaptation, is
the so-called supercompensation or overcompensation hypothesis (Koutedakis et al.,
2006). The supercompensation hypothesis is the transposition of the general adap-
tation syndrome proposed by Hans Selye applied to exercise training. It describes a
decline of an often undefined y-axis variable during exercise and its recovery after exer-
cise. The recovery, however, does not just reach pre-exercise levels but overshoots, which
is termed supercompensation. Such supercompensation is regarded as the adaptation
to exercise (Koutedakis et al., 2006), but this does not shed light on the mechanisms
responsible and the whole idea has at least four flaws:
x Supercompensation happens for muscle glycogen after endurance exercise and
feeding (Bergstrom and Hultman, 1966). However the time course for most other
systems before, during and after exercise is different: for example neither mitochon-
dria, capillaries nor neurons are lost during exercise, as would be expected if the
supercompensation hypothesis were true.
x The supercompensation hypothesis is a time course but not a mechanism. Using the
glycogen time course before, during and exercise as an example, it is well demon-
strated that glycogenolysis depletes glycogen during exercise whereas insulin-stim-
ulated glucose uptake and glycogen synthesis are at least partially responsible for
the increase of the glycogen concentration after exercise and carbohydrate intake.
x The supercompensation hypothesis implies that recovery periods are essential for
adaptation. In reality the heart adapts to exercise despite continuous contraction.
Also skeletal muscles adapt to chronic electrical stimulation applied continuously
over several weeks (Henriksson et al., 1989).
x Despite being propagated for decades (Koutedakis et al., 2006) there is little
actual evidence that the supercompensation time course is essential for adap-
tation. In contrast, in this book we quote several hundreds of references that
support the alternative hypothesis that signal transduction pathways mediate
adaptation to exercise.
Because of the above, the supercompensation hypothesis should no longer be
used in an attempt to explain adaptation to exercise. In this chapter we will now
introduce the signal transduction hypothesis of adaptation. According to this
hypothesis, specific sensor proteins detect exercise-related signals, which are then
computed by transduction pathways or networks. These early signals regulate
downstream events including gene transcription, translation or protein synthesis
and protein breakdown. The result is changed organs or organs that have adapted
to exercise.
SIGNAL TRANSDUCTION HYPOTHESIS OF ADAPTATION
All organisms need to survive in an environment that is in constant flux. At a whole-
organism level inputs from the external environment are sensed and information is
relayed via endocrine and nervous systems, which act as specialized adaptation sys-
tems for the whole organism. Within these systems there are specific sensor organs
(e.g. eye, ear) and computing organs (e.g. nervous system) that allow complex mes-
sages to be processed. In order to do so many variables need to be sensed. This input
is then computed and cells and the whole organism adapt accordingly. In addition
to hormonal and neural signals, individual cells contain the necessary machinery to
sense and adapt to changes in their local environment. This intrinsic ability of cells
is elegantly illustrated by the specificity of resistance training, where hypertrophy of
the muscles recruited during training occurs in the absence of measurable effects in
muscles that did not contribute to the exercise. Therefore, exercise-induced muscle
hypertrophy cannot be due to systemic factors such as endocrine hormones. Even
more convincing evidence for the intrinsic adaptability of cells comes from experi-
ments performed on animal tissues ex vivo or cells cultured in vitro. Under these
circumstances the link between individual cells and the organism or organ is severed
completely. Nonetheless, electrical stimulation of skeletal muscle ex vivo or myotubes
in vitro instigates intracellular events that are associated with exercise-induced adapta-
tions such as mitochondrial biogenesis.
In the forthcoming sections we will discuss the intracellular events that link the acute
responses to exercise with long-term adaptation. Conceptually, the cellular events in this
process can be broken down into three major steps:
1 Sensing of exercise-related signals: Sensor proteins detect changes in Ca2
, AMP,
glycogen, pO2
, amino acids, force, neurotransmitters and hormones.
2 Signal transduction: Proteins form pathways and networks that convey and
compute the sensed input.
3 Effector processes: Effector proteins regulate transcription, translation or protein
synthesis, protein degradation and cellular functions such as the cell cycle. This is
the actual adaptation to exercise.
The signal transduction hypothesis of adaptation is illustrated in Figure 3.1 and then
explained in more detail in the following text.
