Table of Contents
REVIEW ARTICLE
PIOTR GRONEK1, TADEUSZ RYCHLEWSKI1, RYSZARD SŁOMSKI2,3, KRYSTYNA STANKIEWICZ1, JOANNA LEHMANN1
1 Department of Physiology, Biochemistry and Hygiene, University School of Physical Education, Poznań, Poland
2 Department of Biochemistry and Biotechnology, Agricultural University Poznań
3 Institute of Human Genetics, Polish Academy of Sciences, Poznań
Correspondence should be addressed to: Department of Physiology, ul. Królowej Jadwigi 27/39, 61-871 Poznan, Poland, E-mail: 
Table of Contents
Key words: IGF-1, structure, function, physical training.
Insulin-like growth factors (IGFs) are mitogens for many cell types that play important roles in cell cycle progression, cell proliferation, and tumor progression. This paper discusses the insulin-like growth factor 1 (IGF-1). IGF1 is produced in numerous tissues and affects almost every cell. Major organs that synthesize IGF1 are the liver, heart, lung, placenta, kidney, pancreas, spleen, ovaries, large intestines, brain, small intestines, testes, bone and pituitary. In humans, approximately 10 milligrams of IGF1 are produced per day until the age of about 30 years whereby production decreases with aging. IGF1 is similar to insulin and possesses anabolic and cell growth effects. Insuline-like growth factor 1 is also important for its effect on development of diabetes and other chronic diseases. The major target tissues affected by IGF1 are muscle, cartilage, bone, liver, kidney, nerves, skin and lungs. The placenta is among the tissues that contain a high density of IGF-I receptors. IGF-1 is a 70 amino acidpolypeptide with a molecular mass of 7.6kD coded by the IGF-1 gene that contains 6 exons, 4 of which are alternatively spliced. It is involved in regulation of cell proliferation, differentiation and apoptosis. IGF1 stimulates skeletal muscle hypertrophy and a switch to glycolytic metabolism by activating the calcium calmodulin-dependent phosphatase calcineurin. Genetically determined low IGF-1 levels may lead to reduction in birth weight, length, and head circumference, and to persistent short stature and small head circumference in later life. It might be useful to gene therapy, which seems to be optimistic in the case of damaged muscle and dystrophies. In this brief review we address the advances that have been made in the studies on IGF-1.
Insulin-like growth factor 1 (IGF-1) belongs to a family of peptides that play important roles in mammalian growth and development mediating many of the growth-promoting effects of the growth hormone [64]. Its alternative name is somatomedin C. Investigations of Daughaday et al. [19] showed that the growth hormone (GH) did not directly stimulate the incorporation of sulfate into cartilage through a factor previously termed 'sulfation factor' and known as somatomedin. Recently, three main somatomedins have been recognized: somatomedin C (IGF-1), somatomedin A (IGF-2), and somatomedin B [80]. Human IGF1 is a 70-amino acid polypeptide cross-linked by 3 disulfide bridges, with a molecular mass of 7.6kD [77]. The liver is the primary source of circulating IGF-1 [90, 106]. The plasma concentration of IGF-1 reflects the secretion of the growth hormone (GH) by the pituitary gland.
The IGF-1 gene was mapped in chromosome 12 (Fig. 1). This gene contains 5 exons. Exons 1-4 encode the 195-amino acid precursor (IGF-1B); and exons 1, 2, 3, and 5 encode the 153-residue peptide (IGF1A) [80]. The structure of IGF-1 resembles the structure of IGF2. Smith et al. [92] did not confirm the 5-exon structure but they observed 6 exons, 4 of which were alternatively spliced depending on the tissue type and hormonal environment [92].
Figure 1. IGF-1 gene in genomic localization is found on cytogenetic band 12q23.2
The main functions of IGF-1 are presented in Table 1. IGFs are peptide hormones involved in regulation of cell proliferation, differentiation and apoptosis. IGFs are regulated by endocrine and paracrine processes. Their activity in tissue is determined by local production of IGFs and insulin-like growth factor binding proteins (IGFBPs). IGFs are predominantly bound to binding proteins (IGFBPs) [42, 106]. The insulin-like growth factor binding protein family has grown to six members, ranging in size from 216 to 289 amino acids. Four of these binding proteins are found in the serum. The synthesis of IGFBPs is regulated by IGFs and other growth factors [51]. IGFBP-3 is the predominant binding protein in the serum and it is also a marker of the growth hormone activity [46]. More than 90% of circulating IGF-1 is complexed with IGFBP-3. In fed or diet-restricted humans, administration of IGF-1 for several days appears to increase IGFBP-3 circulation [107].
Over the last few years we have witnessed a renewed interest in the chemistry and biology of the IGFBPs. The IGFBPs have their own intrinsic biological activities, independent of their ability to interact with IGF-I and IGF-II. IGFBPs directly regulate several cellular functions. Based on their primary structures, each IGFBP may be divided into three distinct domains of more or less equal size. The NH2- and COOH-terminal ends are highly conserved and contain 16–18 spatially conserved cysteine residues that form the various intra-domain disulfide bonds. Each IGFBP contains a GCGCCXXC motif and a CWCV sequence within their NH2- and COOH- end, respectively. Implicit in analysis of sequence homology has been the assumption that IGFBPs exhibit similar tertiary structures, including a “universal” IGF-binding domain.
Interaction between IGF-1 and its receptor IGF-1R is specific [109]. The signaling pathway mediated by Insulin-like Growth Factor 1 is shown in Figure 2 and a summary network of the IGF-1a precursor is shown in Figure 3.
The insulin-like growth factor receptor (IGF-1R) belongs to the family of transmembrane protein tyrosine kinases, which include the highly homologous insulin receptor and the insulin receptor related receptors. IGF1 stimulates skeletal muscle hypertrophy and a switch to glycolytic metabolism by activating the calcium calmodulin-dependent phosphatase calcineurin which was observed independently by Semsarian et al. [88] and Musaro et al. [62].
Semsarian et al. observed that skeletal muscle hypertrophy and regeneration were important adaptive responses to both physical activity and pathological stimuli [88].
Table 1. The recent investigations on IGF-1 function
Figure 2. Signaling pathway mediated by Insulin-like Growth Factor 1
Skeletal cells synthesize insulin like growth factors (IGF) and six IGF binding proteins (IGFBP). IGFs are secreted by skeletal cells and their concentrations in the bone environment reach biologically significant levels. Failure to maintain these processes underlies the loss of skeletal muscle mass and strength that occurs with ageing and in myopathies. It has been known that stable expression of a gene encoding insulin-like growth factor 1 (IGF-1) in C2C12 skeletal muscle cells, or treatment of these cells with recombinant IGF-1 or with insulin and dexamethasone, results in hypertrophy of differentiated myotubes and a switch to glycolytic metabolism. When treating them using IGF-1 or insulin and dexamethasone it becomes clear that this mobilizes intracellular calcium, activates the Ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor NF-ATc1.
Figure 3. Summary network of IGF-1a precursor.1 – Insulin-like growth factor precursor 1a; 2 – Insulin-like growth factor receptor 1 precursor; 3 – Insulin-like growth factor binding protein 1 precursor; 4 – Insulin-like growth factor binding protein 3 precursor; 5 – Cation-independent mannose 6 phosphate receptor precursor; 6 – Insulin-like growth factor 2 precursor; 7 – Insulin-like growth factor 1B precursor; 8 – Ciliary neurotrophic factor; 9 – Myogenic factor; 10 – Growth hormone variant precursor; 11 – Interleukin-1 alpha precursor.
Once a plasmid encoding IGF-1 is injected into rat latissimus dorsi muscle it also activates calcineurin, mobilizing satellite cells and causing a switch to glycolytic metabolism. It is proposed that growth-factor-induced skeletal-muscle hypertrophy and changes in the myofibre phenotype, which are mediated by calcium mobilization, are critically regulated by the calcineurin/NF-ATc1 signalling pathway [88].
Expression of a dominant-negative calcineurin mutant also repressed myocyte differentiation and hypertrophy [62]. It was demonstrated that IGF-1 induced expression of transcription factor GATA2, which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of NFATC1 [62].
There are numerous functions of the IGF-1 which have been described. An interesting study was conducted by Aleman et al. [1] which showed that IGF-1 levels were significantly associated with age-related reduction of certain cognitive functions, specifically the speed of information processing. Subjects with higher IGF-1 levels performed better on the Digit Symbol Substitution test and the Concept Shifting Task. The study supported the hypothesis that circulating IGF-1 might play a certain role in the age-related reduction of cognitive functions, specifically the speed of information processing.
Wodds et al. [105] identified homozygosity as responsible for partial deletion of the IGF-1 gene in a patient with severe prenatal and postnatal growth failure, sensorineural deafness, and mental retardation associated with IGF-1 deficiency. Another homozygous mutation in the polyadenylation signal of the IGF-1 gene in a patient with IGF-1 deficiency was identified by Bonapace et al. [9].
Insulin-like growth factor 1 and the receptor of the IGF-1 (IGF-1R) genes were considered to be candidates for insulin resistance, type II diabetes and low birth weight by Rasmussen et al. [75]. In genomic DNA from 82 Danish families with type II diabetes Rasmussen et al. [75] identified several silent and intronic polymorphisms.
Genetically determined low IGF-1 levels may lead to a reduction in birth weight, length, and head circumference, and to persistent short stature and small head circumference in later life [2]. Low IGF-1 levels were studied as a possibility of association between low birthweight and polymorphism of IGF-1. It seems that the consequence of the absence of the wildtype allele may be lower birthweight. An interesting question is whether the IGF-1 gene influences pre- or postnatal growth?
In the study conducted by Vaessen et al. [99] a correlation was observed between low birthweight and polymorphism in the IGF-1 gene that raises a risk of type 2 diabetes and myocardial infarction [99]. Individuals without the wildtype allele had a 215-gram lower birthweight than homozygous for the wildtype allele.
The activity of the hypothalamic–GH—IGF axis declines in midlife, leading to a relative GH and IGF-I deficiency. In conjunction with the many catabolic changes observed during aging, this fall in GH and IGF-I serum levels has been termed somatopause (Fig. 4).
Figure 4. The activity of the hypothalamic–GH—IGF axis declines in midlife, leading to relative GH and IGF-I deficiency.IGF-1 levels is low at birth, increase during puberty and than start to decline during the 2nd-3rd decade of life. X axis: age span [years], Y axis: IGF-1 level [ng/ml]
Out side the muscle fibres residue are local satellite cells. The muscle-specific stem cells proliferate by normal cell division. As the next step some of the created cells fuse with the muscle fiber. Many factors are involved in this process including progrowth and antigrowth regulation factors. Satellite cells respond to IGF-1, and as a consequence there is a greater number of cell divisions; whereas a different growth regulating factor, myostatin, inhibits the process of their proliferation.
If the IGF-1 protein alone is injected to a cell it would dissipate within hours. But once a gene comes to a cell, it should keep functioning for the whole life duration of that cell, and muscle fibers are very long-lived. There are, therefore, many efforts to find a way to deliver the IGF-1 gene directly to muscle tissue [97].
The IGF-1 gene given to mice by the University of Pennsylvania researchers triggered additional production of insulin-like growth factor 1. Muscle strength was maintained and recovery from injury was as efficient as it was at a young age. In the experiment the strength and healing ability was seen throughout the lives of the treated mice. However, their life usually last a few years. It is not known how long the effects might be maintained in humans, or whether there could be as yet some unknown long-term side effects.
Many researchers use viruses as a delivery vector, because they are skilled at transporting genes to the cells. Our research group uses plasmids to carry genes into the cell. However, there are many problems in gene therapy, whether it is virus, adenovirus or plasmid. After injection of AAV-IGF-1 (IGF-1 packed into an adenovirus), one can observe that the muscle overall size and the rate at which they grow is 15-30% greater than normal [97]. When Rosenthal created mice genetically altered for overproduction of IGF-1, the animals developed normally except skeletal muscle which was 20-50% larger that in wild mice [62]. What is important from the cardiologic point of view IGF-1 levels were elevated only in muscles but not in blood. A high plasma level may be connected with cardiac problems and risk of cancer. When AAV-IGF-1 was injected into the murine leg muscle in animals after two-month weight-training, the injected animals gained circa twice as much strength in this muscle as in the uninjected legs in the same animal.
On training completion, the injected muscles lost strength much more slowly than the unenhanced muscle. Unfortunately this knowledge may be used in gene doping, and one can expect that sooner or later we might face some serious problems concerning detection of genetic doping including IGF-1.
Circulating levels of IGF-1 are regulated by insulin and the growth hormone. Malnutrition, fasting, liver disease and other severe diseases are associated with low IGF-1 concentration [16]. IGF-1 concentration decreases with aging [53]. Exercise is another important regulator of IGF-1 levels [60].
Several cross-sectional studies have found significant positive correlations between fitness level and circulating IGF-1 levels [24, 43, 70]. Such a correlation indicates that physical training leads to an increased activity of the IGF system. Higher levels of circulating IGF-1 and increased amplitude of spontaneous GH pulses were found in trained young males as compared with the untrained ones [43, 48, 70]. Studies on animals demonstrated that longer periods of training resulted in increased IGF-1 gene expression in the skeletal muscular tissue [108].
In contrast, several studies on exercise training have reported decreased circulating IGF-1 levels [24, 25, 79]. Eliakim et al. [25] hypothesized that the IGF-1 adaptation to prolonged training consisted of a two-phase response: the first one being the catabolic phase and the second one the anabolic state. Jahreis et al. (1991) found a decreased circulating IGF-1 level after intensive training programme in female gymnasts, in whom energy expenditure exceeded energy intake.
Eliakim et al. [24] suggested that the generally increased circulating IGF-1 levels in fitter subjects might be related to IGFBPs. Increased IGFBP-3 proteolysis was reported after an acute bout of exercise [87]. Changes in IGFBP-3 proteolysis are believed to represent a compensatory mechanism inducing the increase of free IGF-1 concentration by lowering IGFBP-3 ligand affinity and thereby modifying IGF-1 bioavailability by releasing IGF-1 from its 150-kDa complex, consisting of IGF-1, intact IGFBP-3, and an acid-labile subunit [74]. Rosendal et al. [79] speculated that IGFBP-1 and IGFBP-2 had a greater impact than IGFBP-3 on the levels of free and total IGF-1 during an 11-week of exercise program. In this study the decrease of IGF-1 levels was accompanied by upregulated levels of IGFBP-1 and IGFBP-2 despite an increased IGFBP-3 proteolysis in previously untrained subjects. The effect of regularly performed exercise on IGFBPs levels is conflicting. Rosendal et al. [79] suggested an existence of a threshold for relative physiological stress to be exceeded in order for IGFBP-3 proteolysis to occur.
Over the last several years the interest in IGF-1 has evolved from a focus on the levels of free IGF-1, to an interest in a variety of other biological effects. IGF-1 levels correlated with muscle mass in men but not in women in a cross-sectional sample in the New Mexico Aging Process Study. In men, but not in women, higher IGF-I levels protected against loss of lean body mass. Many questions remain to be answered in this field, also including the precise biochemistry of its interactions with IGFBPs, with extra-cellular matrix proteins, with putative receptors, and with intracellular targets; as well as concerning the three-dimensional structure. The potential roles played by the IGF-1 in human diseases (cancer) remain to be elucidated, and new discoveries are likely to lead to a number of novel therapeutic opportunities. Also gene therapy with IGF-1 seems to bring human beings an opportunity to understanding the muscle process better. The subject of therapeutic applications of the IGFs is potentially very broad. Some researchers predict potential benefits associated with the recombinant human IGF-1 (rhIGF-1) or the recombinant human IGF-1/IGFBP-3 complex. The potential availability of rhIGF-1 will open possibilities for therapy for a wide range of conditions and provide an opportunity to clarify physiological endocrine mechanisms in humans.
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