5 Exercise and the Growth Hormone-

Insulin-Like Growth Factor-l Axis

Alon Eliakim, MD, Jo Anne Brasel MD,

and Dan M. Cooper, MD
CONTENTS
INTRODUCTION
THE GH-IGF-l AXIS
ACUTE EXERCISE AND THE GH-IGF-l AxIS GROWTH HORMONE
INSULIN-LIKE GROWTH FACTORS (IGFs)
INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS (IGFBPs)
EXERCISE TRAINING AND THE GH-IGF-l AXIS
REFERENCES

INTRODUCTION
Naturally occurring physical activity in humans plays a profound role in tissue anabo-
lism, growth, and development, yet little is known about the mechanisms that link pat-
terns of exercise with tissue anabolism. Anabolic effects of exercise are not limited to
individuals engaged in competitive sports who are particularly focused on improvements
in strength or cardiovascular functions. For example, limb immobilization, neural injury,
and prolonged bed rest cause reduction of muscle mass and bone density even in indi-
viduals who live a sedentary lifestyle (1). These observations imply that a sizeble ana-
bolic stimulus arises from a relatively modest physical activity of daily living. Conversely,
excessive exercise may have adverse effects. For example, Theintz et al. (2) recently
reported a reduction in the growth potential of female adolescent gymnasts engaging in
intense training.
The magnitude and tissue specificity of anabolic effects of exercise likely change
with maturation and aging. It is striking that naturally occurring levels of physical activ-
ity, energy expenditure, and muscle strength exhibit some of their most rapid increases
during childhood and adolescence. This particular combination of rapid growth and
development, high levels of naturally occurring physical activity, and spontaneous,
puberty-related increases in anabolic hormones (growth hormone [GH), insulin-like

From: Contemporary Endocrinology: Sports Endocrinology

Edited by: M. P. Warren and N. W. Constantini © Humana Press Inc., Totowa, NJ

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78 Eliakim, Brasel, and Cooper

growth factor-l [IGF-I], and sex steroids) suggests the possibility of integrated mecha-
nisms linking exercise with a variety of anabolic responses. This chapter will focus on
the relationship between fitness and components of the GH-IGF-I axis, and the effect of
exercise and exercise training on circulating and local (Le., muscle) component of this
system.

THE GH-IGF-l AXIS

The GH-IGF-I axis regulates many essential life processes, including growth, devel-
opment, metabolic, and reparative processes, and may affect several other physiologic
activities (e.g., aging). During the past several decades, the understanding of this axis
has increased markedly as various components of the axis have been identified and char-
acterized and their molecular and clinical regulation have been clarified.
The axis is composed of hormones, growth factors, binding proteins, and receptors.
The understanding of the axis must, therefore, consider each individual component and
the interaction between them under both normal physiologic and pathological condi-
tions. The axis starts in the central nervous system (eNS), which secretes a series of
neurotransmitters (catecholamines, serotonin and cholinergic agents) that cause the
hypothalamus to synthesize growth hormone-releasing hormone (GHRH) and soma-
tostatin (SMS). GHRH stimulates the anterior pituitary to synthesize and secrete GH. In
contrast, SMS directly inhibits GH secretion. However, SMS is produced in many other
tissues as well, and exerts many different biologic activities, most of which are not related
to the GH-IGF-I axis.
GH is the major secretory product of the somatotroph axis. One of GH's most impor-
tant actions is the stimulation of IGF-I synthesis. However, other effects of GH on
metabolism, body composition, and tissue differentiation are independent of IGF-I. GH
exerts direct feedback effect on the two hypothalamic hormones that control its secre-
tion. Tissue GH effects are mediated by the interaction between GH and the GH recep-
tor. The GH receptor contains an intracellular and extracellular transmembrane domains.
The extracellular domain is identical in structure to GH binding protein (GHBP) (3).
Therefore, a unique feature of this axis is that the measurable circulating GHBP levels
likely reflect GH receptor number and overall tissue responsiveness to GH.
IGF-l is part of the insulin-related peptides. As noted earlier, the endocrine form,
secreted mainly by the liver, is GH-dependent. However, the paracrine and autocrine
forms are only partially regulated by GH. Although IGF-I can act in an endocrine man-
ner, its action probably occurs primarily as a result of paracrine or autocrine secretion
and regulation. IGF-I actions are numerous and reproduce most, but not all, of the ana-
bolic and growth-promoting effects of GH. IGF-I stimulates SMS secretion and inhibits
GH by a negative feedback mechanism (4), but it is not clear whether circulating or
central IGF-I is responsible for this feedback mechanism.
The majority of circulating IGF-I is bound to one of six IGFBPs. The most abundant
circulating BP during adult life is IGFBP-3, which is synthesized mainly in the liver,
and is GH-dependent. When bound to IGF-I, it complexes with an acid-labile subunit to
form the circulating complex that carries most of the IGF-I in the serum. As noted
earlier, some of these binding proteins are GH-dependent (e.g., IGFBP-3), but others,
such as IGFBP-I and 2, are insulin-, rather than GH-, dependent (being high when insu-
lin levels are low). The interaction between IGF-I and its binding proteins is even more