AN OVERVIEW OF THE GROWTH HORMONE-INSULIN-LIKE GROWTH FACTOR SYSTEM
Insulin-like growth factor I (IGF-I) possesses widespread anabolic and insulin-sensitizing effects, mediated through endocrine (i.e., circulating) as well as paracrine/autocrine (i.e., locally produced) mechanisms. IGF-I serves as ligand for the ubiquitously expressed tyrosine kinase IGF-I receptor (IGF-IR), which upon ligand occupancy by protein phosphorylation activates intracellular signaling cascades, which favor proliferation via the mitogen-activated protein kinase pathway and insulin-like effects via the phosphatidylinositol 3-kinase pathway. Furthermore, IGF-IR activation inhibits apoptosis, hereby linking the IGF-I with the development of neoplasias (13,42).
Growth hormone (GH) is the principal regulator of the hepatic synthesis of IGF-I, IGF-binding protein 3 (IGFBP-3), the major IGF carrier in plasma, and the acid labile subunit (ALS). ALS binds preformed complexes of IGF-I and IGFBP-3 and is responsible for the long turnover of circulating IGF-I (34). However, the hepatic responsiveness to GH is sensitive to nutritional changes (13). During fasting, the liver develops resistance to GH and its ability to synthesize IGF-I becomes markedly reduced (8,13), whereas in obesity, the GH-induced IGF-I generation is increased (44). Nutritionally regulated changes in the hepatic responsiveness to GH appear to be controlled by the portal supply of insulin, which increases GH receptor availability on the hepatocytes (43). The important role of portal insulin supplies is stressed by findings showing that patients with type 1 diabetes, who are C-peptide positive, have higher levels of free and total IGF-I than C-peptide-negative patients with a similar metabolic control (30).
Apart from controlling the hepatic responsiveness to GH, and in this way indirectly the synthesis of IGF-I, insulin may directly influence IGF-I bioactivity by controlling the hepatic synthesis of the insulin-suppressible and IGF-I inhibitory binding protein, IGFBP-1. Insulin promptly inhibits the hepatic synthesis of IGFBP-1 at the transcriptional level, resulting in detectable reductions in circulating IGFBP-1 levels with 60 min after insulin exposure (6). Thus, IGFBP-1 levels are affected primarily by exercise of long duration and during the recovery after short-lasting exercise (see next section).
MEASUREMENTS OF IGF-I
Since the introduction of the first specific immunoassay for IGF-I more than 30 yr ago (25), quantification of immunoreactive IGF-I levels in plasma or serum has constituted the backbone of clinical IGF research. However, as the IGFBP influence the antibody recognition of IGF-I, all immunoassays require dissociation of IGFBP/IGF-I complexes followed by removal or "neutralization" of the IGFBPs before assay. As a result, immunoreactive IGF-I (∼total IGF-I) represents an integrated sum of various IGF-I/IGFBP complexes, which differ with respect to plasma half-life, tissue accessibility, and possible bioactivity (21,22,51). The latter idea was supported by recent experimental studies suggesting that it is the composition of IGFBP/IGF-I complexes and their tissue accessibility rather than the absolute serum levels of IGF-I that determine the endogenous IGF-I bioactivity (74). Whether these experimental findings can be extrapolated to humans remains to be investigated, and it should be acknowledged that quantification of immunoreactive (total) IGF-I levels has yielded important and biologically meaningful information on the IGF system in many clinical conditions.
Assays for free IGF-I were introduced more than a decade ago (23,24,65). Two different approaches have been used. In our laboratory, we separate free from bound IGF-I (or IGF-II) using ultrafiltration by centrifugation, performed at 37°C, followed by immunoassay of ultrafiltered free IGF-I (24). The other methodology is based on a sandwich assay, which uses a solid phase antibody specific for free IGF-I, hereby allowing serum to be incubated directly without prior processing. However, although the capture antibody is specific for free IGF-I, it is able to extract IGFBP-complexed IGF-I during assay incubation, and consequently the sandwich technique is considered to measure truly free plus "readily dissociable" IGF-I. Accordingly, levels as determined by the sandwich assay are higher than those after ultrafiltration (21-23).
The ability of IGF-I to interact with its cell-membrane receptor depends on several aspects, including the free ligand levels, the ligand occupancy (or saturation) of the IGFBP, the ability of the IGFBP to dissociate IGF-I in the neighborhood of the IGF-IR (which depends on the proportion of IGFBP relative to the cell-surface density of the IGF-IR), and the presence of IGFBP proteases. Furthermore, IGF-II-mediated activation of the IGF-IR should be remembered. However, none of the immunoassays (whether it is total or free IGF-I) take the ligand competition between IGFBP and IGF-IR, the presence of IGFBP proteases, or the contribution of IGF-II into account. Therefore, we established a specific IGF-I bioassay based on the kinase receptor activation (KIRA) principle originally described by Sadick (59). In the KIRA assay, cells transfected with the human IGF-IR gene are stimulated with either serum or IGF-I standards for 15 min at 37°C. Then, the samples are aspirated, the transfected cells lysed, and the crude cell lysates transferred to a sandwich assay specific for the phosphorylated IGF-IR. Thus, the IGF-I KIRA assay enables determination of the ability of serum to phosphorylate (i.e., activate) the IGF-IR in vitro during conditions approaching those in vivo (∼bioactive IGF-I) (9). The different IGF-I assay technologies are summarized in Figure 1. For further information on IGF-I assays and their pros and cons, refer to references (9,12,21-24).
It is currently debated whether the actions of IGF-I are maintained primarily by endocrine (i.e., liver-derived/circulating) or locally produced (autocrine/paracrine) IGF-I. Studies in liver IGF-I knockout mice and clinical case reports indicate that peripherally produced IGF-I is the main determinant of somatic growth, whereas the liver is responsible for circulating IGF-I levels, which by negative feedback controls pituitary GH secretion (18,21,41). On the basis of these considerations, there has been an increasing interest in measuring tissue-specific IGF-I levels, and microdialysis appears to provide a suitable methodology. However, the microdialysis technology needs to be refined; the recovery remains problematically low, and the perfusate only yields a limited volume for assay. At the time of writing, there are three microdialysis reports on tissue levels of IGF-I in skeletal muscle/connective tissue (3,17,50); data are summarized in Table 1. The author expects the microdialysis technology to be optimized and increasingly used in the years to come.
THE EFFECT OF EXERCISE ON GH
All types of exercise potently stimulate the secretion of GH, and within 10 to 20 min after the onset plasma GH levels are markedly increased. This physiological response was originally described in 1963 (58), and since then, hundreds of investigations have been published, describing the impact of different types of exercise (endurance and resistance, sprint and marathon running, single and repetitive bouts of exercise, etc.) on the GH secretion in different study populations (young and old, trained and untrained, lean and obese, GH sufficient and GH deficient, etc.). Nevertheless, the precise mechanisms by which exercise elicits an increased secretion of GH remain to be clarified. The secretion of GH appears to be controlled by numerous hypothalamic hormones, neurotransmitters, and circulating factors, among others IGF-I. However, during exercise, circulating IGF-I is virtually unchanged (see next section), indicating that there are no alterations in the negative feedback regulation of the somatotrophs by circulating IGF-I. Consequently, the exercise-induced stimulus for GH appears to be primarily of central origin, probably involving GH-releasing hormone and somatostatin (27). It is beyond the scope of this review to cover the relationship between exercise and GH secretion; this topic has already been extensively reviewed by others (26,27,33,62,73). Instead, previous findings are briefly summarized in Table 2. As illustrated, the GH response to exercise is affected by numerous factors that are often physiologically linked, and consequently it may be difficult to segregate the contribution of the individual factors (for instance age, obesity, and V˙O2max).
THE EFFECT OF EXERCISE ON CIRCULATING IGF-I AND IGFBP
IGF-I is the primary downstream mediator of GH actions, and circulating IGF-I plays an important role in the feedback regulation of GH secretion (21). Consequently, it was obvious to investigate the association between circulating IGF-I and GH during exercise. However, in contrast to the robust stimulation of GH, the acute IGF-I response to exercise appeared less predictable: quantification of immunoreactive (total) IGF-I levels in serum or plasma has yielded inconsistent results, with levels being reported to decline (39), to increase (2,16,60), or to remain unchanged (35,49,63) after the onset of exercise.
In addition, studies of the chronic effects of exercise on the circulating IGF-I have yielded inconsistent results. Early cross-sectional studies reported positive associations between V˙O2max and GH secretion (19,66) and immunoreactive IGF-I levels (19,52), respectively, suggesting that an improvement in fitness would result in a higher serum IGF-I level. However, this hypothesis has only been supported by some longitudinal studies (40,53); by contrast, other studies have observed reductions in immunoreactive IGF-I levels after several weeks of exercise despite an improved physical performance (muscle strength and/or V˙O2max) (19,20,48).
The IGFBP are important modulators of IGF-I actions in vivo (34), and short-term as well as long-term exercise may alter the IGFBP. This is particularly true for IGFBP-1, which consistently increases severalfold during prolonged exercise (10,39) as well as in the recovery period after short-term exercise (69). It is well known that the IGFBP may alter plasma levels of free IGF-I without affecting total IGF-I (21), and accordingly many of the newer exercise studies have included measurements of IGFBP as well as free IGF-I. Proteolysis of IGFBP-3 may also affect levels of free IGF-I (61). However, exercise does not consistently lead to an increased IGFBP-3 proteolytic activity: both increased (46,60) and unchanged (15,35) IGFBP-3 proteolytic activities have been reported in association with exercise. Interestingly, one study found IGFBP-3 proteolysis to depend on the level of fitness, as it was increased in untrained but not in trained subjects (57).
At the time of writing, more than 10 studies have investigated the concomitant changes in "free IGF-I" (i.e., ultrafiltered free IGF-I, ELISA-free IGF-I, or bioactive IGF-I), total IGF-I, and IGFBP. These studies are summarized in Table 3A (acute studies) and Table 3B (long-term studies).
The acute studies (n = 8; Table 3A) cover exercise programs from 30 s to 2 h, and obviously the different training regimens make a direct comparison difficult. However, most studies find that "free IGF-I" (whether measured by ultrafiltration, direct ELISA, or bioassay) remains unchanged during exercise but may decrease during recovery. A notable exception is the study by Bermon et al. (4), who found significant increases in free IGF-I up to 6 h after exercise. As this study contained the oldest group of participants (67-80 yr), it can be speculated that the observed increment in free IGF-I is age specific and that it cannot be extrapolated to younger individuals.
In the acute studies, total IGF-I remains either unchanged or increases after exercise, and the same appears to be true for IGFBP-3. The author believes that the reported increases in total IGF-I observed in some studies are primarily explained by plasma volume changes induced by exercise, which is known to induce rapid changes in plasma volume related to exercise intensity (15). However, in the study by Wallace et al. (69), increases in total IGF-I, IGFBP-3, and ALS occurred in the absence of changes in hematocrit, and based on this observation, the authors suggested that ternary-complexed IGF-I was able to leave and to enter the circulation in relation to exercise. This "dynamic theory" is attractive but needs confirmation.
The long-term studies (Table 3B) cover exercise programs lasting from 3 wk to 6 months. In the four studies carried out in nonprofessionals, free IGF-I generally changed in parallel with total IGF-I, indicating that inclusion of "free IGF-I" does not add novel information. Furthermore, as suggested in the study by Rosendahl et al. (57), untrained subjects respond differently to several weeks of exercise than trained subjects, with an increased IGFBP-3 proteolysis and a longer-lasting suppression of IGF-I levels. The 3-wk professional cycling contest is an exception because total and free IGF-I changed in opposite directions, most likely because it represents an extreme amount of exercise (10). In that study, all athletes completed the race with marked reductions in free IGF-I, which correlated inversely with increases in IGFBP-1. By contrast, total IGF-I increased by approximately 50%, whereas IGFBP-3 remained unchanged, hereby illustrating that the ratio between IGF-I and IGFBP-3 may be a poor indirect estimate of free IGF-I (21). On a molar basis, the increase in total IGF-I levels (∼10 nmol·L−1) exceeded those of IGFBP-1 (∼2 nmol·L−1), making it unlikely that IGFBP-1 can solely explain the reduction in free IGF-I. Accordingly, the authors speculated that after prolonged exercise, there was an increased transport of IGF-I from the circulation to the peripheral tissues, hereby explaining the reduction in free but not total IGF-I (10). Alternatively, because free IGF-I is more sensitive to catabolism (fasting) than total IGF-I (8), the reduction in free IGF-I may be caused by exercise-induced wasting. Supportive of this idea, the cyclists lost body weight during the last part of the race, concomitant with the reduction in free IGF-I (10). Two recent studies confirm that nutritional intake (in particular, calories rather than protein intake) affects the circulating IGF system during exercise. Alemany et al. (2) studied two groups of matched soldiers undergoing an 8-d high-energy expenditure military exercise. The two study groups received an isocaloric, low-energy diet with either low- or high-protein content, but neither of these two diets could abolish the reductions in free and total IGF-I (2). Conversely, overfed subjects (15% positive energy balance) undertaking 7 d of strenuous exercise were able to maintain levels of free and total IGF-I, whereas underfed subjects (33% negative energy balance) showed marked and parallel reductions in serum free and total IGF-I (47).
As illustrated in Table 3A and B, the inclusion of "free IGF-I" (irrespective of methodology) has not substantially altered the impression that the response of IGF-I to exercise is variable and most likely reflects differences in study protocol (exercise intensity and duration) and study populations (baseline level of fitness and age). Furthermore, it seems fair to conclude that the exercise-induced GH peak as a rule does not increase endocrine IGF-I levels. In comparison, subcutaneous injection with recombinant human GH, eliciting similar peak levels but longer-lasting elevations in serum GH than those observed after sprint exercise, was able to increase serum IGF-I levels of free and total IGF-I within 4 h after injection (63).
Numerous studies verify that IGF-I exerts anabolic effects on skeletal muscles (68). Therefore, the observation that it is possible to increase muscle strength, performance, and V˙O2max without concomitant and robust changes in circulating IGF-I indicates that the effect of exercise on muscle strength is mediated via locally produced (i.e., paracrine/autocrine) rather than endocrine IGF-I. Indeed, as excellently reviewed recently, there is solid (albeit primarily experimental) evidence that locally produced IGF-I is more important than endocrine-derived IGF-I (68). For instance, animal experiments have shown that exercise leading to muscle hypertrophy is accompanied by increases in IGF-I DNA, messenger RNA (mRNA), and peptide within the exercising muscle (1). Transgenic overexpression of IGF-I in skeletal muscles leads to significant hypertrophy without affecting circulating IGF-I levels (14), and mice lacking skeletal muscle IGF-IR have hypoplastic muscles, which in contrast to wild-type littermates are not stimulated by GH treatment (38). Interestingly, human studies have confirmed that exercise is accompanied by an increased IGF-I mRNA expression in exercising muscles without concomitant changes in circulating IGF-I levels (29).
A very recent experimental study in liver IGF-I-deficient (LID) mice stresses the importance of locally produced IGF-I (45). In the LID mouse, the hepatic generation of IGF-I has been genetically silenced, and these mice therefore show markedly reduced circulating levels of total IGF-I (approximately 20% of levels in wild-type littermates) and secondary GH hypersecretion. Matheny et al. (45) subjected adult LID mice to 16 wk of endurance training (ladder climbing) and observed changes, which generally resembled those found in wild-type littermates. Thus, training doubled the lifting capacity and increased hind leg muscle mass, IGF-I mRNA, and IGF-IR phosphorylation. On the basis of these studies, the authors concluded that normal muscle performance may be seen even in the setting of severe circulating IGF-I deficiency and that up-regulation of local IGF-I appears to be involved in compensatory growth of muscle in response to endurance exercise. More surprisingly, the same authors (45) found a reduction in the intracellular signaling of GH, indicating that local increases in IGF-I are in fact GH independent. Although this finding appears controversial, earlier studies in hypophysectomized rats and in rats made GH deficient by treatment with neutralizing GH-releasing hormone antibodies support that muscular IGF-I expression may not be strictly GH dependent (75). However, in the author's view, this hypothesis needs further evaluation.
CONCLUSION AND PERSPECTIVES
On the basis of the current literature, it appears that the stimulatory impact of exercise on skeletal muscles is mediated by an augmented pituitary GH secretion, leading to an increased local IGF-I synthesis. This hypothesis may explain why training studies generally have failed to link an improved muscle performance with changes in circulating IGF-I levels. However, it should be acknowledged that a role of circulating IGF-I cannot completely be ruled not. For instance, patients with GH insensitivity (∼Laron syndrome) do respond to subcutaneous IGF-I by an increased muscle mass, although the response was less pronounced than the response observed in GH-deficient subjects treated with GH (5). In the author's view, future research needs to compare circulating versus locally produced IGF-I and their impact on skeletal muscles to elucidate the link between exercise, GH, and muscle hypertrophy. Consequently, to gain more information, we need to optimize methodologies for the measurement of tissue IGF-I levels in humans.
The author has received funding from The Danish Research Council for Health and Disease. The contents of the present review do not constitute endorsement by the American College of Sports Medicine.
Disclosure statement: The author has nothing to disclose.
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