Review
Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: Roles in skeletal muscle growth and differentiation

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Abstract

The insulin-like growth factor (IGF) signaling pathway consists of multiple IGF ligands, IGF receptors, and IGF-binding proteins (IGFBPs). Studies in a variety of animal and cellular systems suggest that the IGF signaling pathway plays a key role in regulating skeletal muscle growth, differentiation, and in maintaining homeostasis of the adult muscle tissues. Intriguingly, IGFs stimulate both myoblast proliferation and differentiation, which are two mutually exclusive biological events during myogenesis. Both of these actions are mediated through the same IGF-1 receptor. Recent studies have shed new insights into the molecular mechanisms underlying these paradoxical actions of IGFs in muscle cells. In this article, we provide a brief review of our current understanding of the IGF signaling system and discuss recent findings on how local oxygen availability and IGFBPs act to specify IGF actions in muscle cells.

Introduction

Insulin-like growth factors (IGFs), including IGF-I and IGF-II, are evolutionarily conserved peptide structurally related to insulin. Mature IGF-I and IGF-II consist of A, B, C, and D-domains. The A- and B-domains of IGFs are homologous to those of insulin. Unlike in the case of insulin, the C-domain is not cleaved off in mature IGFs. IGFs contain an additional D-domain, which is not present in insulin (Le Roith et al., 2001).

IGFs are critical for growth and development in all vertebrates studied to date (Wood et al., 2005a). For example, the birth weight of IGF-I or IGF-II knockout mice is about 60% of their wild type littermates (Baker et al., 1993, Liu et al., 1993). Mice with null mutations in both IGF-I and IGF-II have a body weight 30% of their wild type littermates at birth and they invariably died shortly thereafter (Baker et al., 1993, Liu et al., 1993). Over-expression of IGF-I in mice increases the body weight by 30% (Mathews et al., 1988). Likewise, administration of IGF-I peptide to rats increases protein synthesis and body growth (Tomas et al., 1992). IGF-II over-expression resulting from loss of imprinting (LOI) is often associated with somatic overgrowth (Morison et al., 1996, Morison and Reeve, 1998).

In addition to their role in somatic growth, IGFs are important for the development and functional maturation of the central nervous system (CNS), skeletal tissues, and reproductive organs. In humans, a homozygous partial deletion of the IGF-I gene is associated with mental retardation and sensorineural deafness, in addition to severe growth retardation (Woods et al., 1996). In IGF-I knockout mice, there is a significant decrease in auditory neuron number and an increase in apoptosis of cochlear neurons (Camarero et al., 2001). Knockout of the IGF-I gene causes infertility (Baker et al., 1996), and characteristic underdevelopment of muscle tissue is observed in IGF-I null pups (Powellbraxton et al., 1993). Transgenic mice overexpressing IGF-I in the CNS have increased brain growth, neurogenesis, process outgrowth, synaptogenesis, and reduced neuronal apoptosis (D’Ercole et al., 2002). Over-expression of IGF-I in the osteoblasts of transgenic mice leads to improved bone structure, including increased bone density and mineralization (Zhao et al., 2000).

Abnormally high levels of IGFs are found in various tumor cells (LeRoith and Roberts, 2003). Epidemiological studies have suggested high levels of IGF-I as a risk factor in breast, prostate, colon, and lung cancer (LeRoith and Roberts, 2003). Reduced circulating IGF-I levels are associated with type 1 diabetes, and IGF-I treatment improved glucose and protein metabolism and attenuates diabetic cardiomyopathy (Carroll et al., 2000, Norby et al., 2002). Over-expression of IGF-I in mouse pancreatic β cells leads to improvement of type 1 diabetes (George et al., 2002). IGF-I treatment increases insulin sensitivity and improves glycemic control in patients with type 2 diabetes (Moses et al., 1996).

At the cellular level, IGFs induce a variety of cellular responses, including cell proliferation, differentiation, migration, and survival. IGFs exert these biological actions primarily through the binding and activation of the type I IGF receptor (IGF-IR). The IGF-IR has two α subunits and two β subunits linked by disulfide bonds. The α subunit contains a cysteine-rich ligand-binding site. The β subunit has tyrosine kinase activity. The IGF-IR exhibits high sequence and structural similarity with the insulin receptor (IR) (De Meyts and Whittaker, 2002). Given the significant structural similarity between IGFs and insulin, and their respective receptors, it is not surprising that these ligands can cross-activate the receptors when added at high concentrations in cell culture studies. IGF-1R-IR hybrid receptors have also been found, although their functional importance remains poorly understood (Taguchi and White, 2008).

Ligand binding of the IGF-IR induces its autophosphorylation. The activated IGF-IR in turn activates multiple intracellular signal transduction cascades, including the phosphatidylinositol 3-kinase (PI3K)-Akt cascade and the Raf-Mek-Erk1/2 cascade (Dupont and LeRoith, 2001, White, 2003), through the adaptor molecules. IRS-1, a well-studied adaptor protein, has multiple tyrosine residues, which are used as ‘docking’ sites for downstream signaling molecules. For instance, phosphorylation of these tyrosine residues results in the association of IRS-1 with the Src homology 2 (SH2) domains of other cytoplasmic signaling proteins, including PI3K and growth factor receptor-bound protein 2 (Grb2). Activated PI3K synthesizes membrane associated phosphorylated inositols, which in turn activate phosphoinositol-dependent kinases (PDKs). PDKs then activate other protein kinases including Akt/Protein Kinase B (Cianfarani et al., 2007). The activated IGF-IR also recruits the guanine-nucleotide-exchange factor Sos to IRS-1 through the SH2 domain of the adaptor Grb2 (Dupont and LeRoith, 2001). This leads to the activation of the small G-protein Ras, which activates the protein serine kinase Raf and the Erk signaling cascade (Fig. 1, left panel).

The new-born IGF-IR knockout mice weigh about 45% of their wild type littermates, and they die shortly after birth (Baker et al., 1993, Liu et al., 1993). IGF-IR conditional knockout in the liver decreased the capacity for liver regeneration (Desbois-Mouthon et al., 2006). Selectively disrupting the IGF-IR gene in mouse osteoblasts caused a significant decrease in bone volume, connectivity, and trabecular number (Zhang et al., 2002). Inactivation of the IGF-1R gene in the mouse brain impaired remyelination in response to neurotoxicant-induced demyelination (Mason et al., 2003). Deletion of the IGF-IR in pancreatic β cells caused defects in glucose-stimulated insulin secretion and impaired glucose tolerance (Kulkarni et al., 2002). Conditional IGF-IR inactivation in adipose tissue did not affect adipogenesis but resulted in increased adipose tissue mass instead (Kloting et al., 2008). Intriguingly, IGF-IR deletion in adipose tissue led to elevated IGF-I concentration in circulation and had a systemic effect on somatic growth (Kloting et al., 2008).

Recent genetic studies in Xenopus and zebrafish suggest that the structure and function of the IGF-IR is evolutionarily conserved (Eivers et al., 2004, Pera et al., 2001, Richard-Parpaillon et al., 2002, Maures et al., 2002, Schlueter et al., 2006, Schlueter et al., 2007). Using antisense morpholino oligonucleotide (MO)-based target gene knockdown approach and by specific inhibiting IGF-1R-mediated signaling using a dominant-negative IGF-IR fusion protein, Schlueter et al. have shown that IGF-IRs in zebrafish are required for embryo viability and proper growth (Schlueter et al., 2006). They further elucidated the cellular actions of this essential pathway (Schlueter et al., 2007). IGF1R inhibition increased caspase activity and induced neuronal apoptosis. Cell cycle analysis demonstrated cell cycle progression defects in IGF-IR-deficient embryos and this action can be un-coupled from its anti-apoptoic action (Schlueter et al., 2007).

The type II or IGF-II receptor (IGF-IIR) is structurally and functionally distinct from the IGF-IR. The IGF-IIR also acts as a mannose-6-phosphate (M6P) receptor. The IGF-IIR/ M6P is a monomeric transmembrane protein with an extracellular domain composed of 15 cysteine-rich repeats. Mammalian IGF-IIR/ M6P has about 100 times higher affinity for IGF-II than IGF-I. The IGF-IIR binds and targets IGF-II for lysosomal degradation (Kornfeld, 1992). Knockout of the IGF-IIR gene or loss of the imprinted IGF-IIR results in fetal overgrowth and perinatal lethality (Lau et al., 1994, Wylie et al., 2003). Recent reports, however, suggest that IGF-II binding to the IGF-IIR can indirectly activate the Erk signaling by triggering sphingosine kinase (SK)-dependent transactivation of sphingosine-1 phosphate (S1P) receptors (El-Shewy et al., 2007).

In addition to IGF ligands and receptors, there is another component in the IGF signaling pathway, the IGF-binding proteins (IGFBPs). IGFBPs are a family of secreted proteins that specifically bind IGF-I and IGF-II with affinities that are equal to or greater than those of the IGF-IR. IGFBPs function as carrier proteins in the circulation and regulate IGF turnover, transport, and half-life of circulating IGFs (Jones and Clemmons, 1995). The IGF/IGFBP complexes also help to prevent potential hypoglycemic effect of circulating IGFs by preventing possible cross-binding of IGFs with the insulin receptor (Rajaram et al., 1997).

There are IGFBPs in mammals (Duan and Xu, 2005, Firth and Baxter, 2002). These IGFBPs share a common domain structure arrangement. They all have a highly conserved N-terminal domain (N-domain) and C-terminal domain (C-domain), and a variable central domain (L-domain). The N- and C-domain contain multiple conserved cysteine residues, which form intra-domain disulfide bonds within the N-domain and C-domain, thereby defining their overall globular structure. The highly variable L-domain is considered as a flexible linker region connecting the N- and C- domain (Chelius et al., 2001, Forbes et al., 1998, Neumann and Bach, 1999). The N-domain contains the high affinity IGF-binding site, but the C-domain also contributes to IGF binding to some degree (Brinkman et al., 1991, Clemmons, 2001, Hobba et al., 1998, Zeslawski et al., 2001). The C-domain of an IGFBP often mediates its interactions with other proteins. For instance, both IGFBP-3 and IGFBP-5 bind to the acid-labile subunit (ALS) through their C-domains (Firth and Baxter, 2002, Guler et al., 1987). The ternary complex (IGF-IGFBP-ALS) greatly increases the half-life of IGFs in circulation (Ueki et al., 2000). The central L-domain is the least conserved and often contains sites for post-translational regulation, including glycosylation, phosphorylation, and proteolysis (Clemmons, 2001, Firth and Baxter, 2002). The post-translational modification is important for IGFBP function in terms of regulating IGF availability.

Despite the significant sequence homology among the six IGFBPs, each IGFBP exhibits distinct structural and biochemical properties (Duan and Xu, 2005). For example, human IGFBP-1 has an arginine–glycine–glutamate (RGD) sequence in their C-domain. The RGD sequence mediates the binding of these IGFBPs to integrins and stimulate cell motility (Jones et al., 1993). Both IGFBP-3 and IGFBP-5 have a nuclear localization sequence (NLS) in their C-domain. Radulescu (Radulescu, 1995) first recognized that the multiple basic residues in the C-domain of human IGFBP-3 and -5 are similar to the bipartite nuclear localization signal (NLS) found in viral and mammalian transcription factors. Schedlich et al. (1998) has shown that this is indeed a functional bipartite NLS because mutation of 228KGRKR232 into MDGEA abolished the nuclear transport of human IGFBP-3. This bipartite NLS is evolutionarily and functional conserved (Dai et al., 2010, Li et al., 2005). Several studies have demonstrated the nuclear localization of IGFBP-3 and IGFBP-5 (Li et al., 1997, Schedlich et al., 1998, Schedlich et al., 2000, Wraight et al., 1998, Xu et al., 2004, Zhao et al., 2006). The functional significance of the nuclear IGFBPs is still under investigation.

As mentioned above, IGFBPs regulate the half-life of circulating IGFs. In addition to their endocrine function, IGFBPs also modulate IGF availability and biological activity in local tissues. Most IGFBPs, including IGFBP-2 to -6, are expressed in peripheral tissues and most mammalian cells express more than one form of IGFBPs (Duan and Xu, 2005, Firth and Baxter, 2002, Jogie-Brahim et al., 2009, Jones and Clemmons, 1995, Yamada and Lee, 2009). IGFBPs can inhibit and/or potentiate IGF actions, depending on the cellular context and experimental conditions. In vascular smooth muscle cell (VSMC), when added together with IGF-I, IGFBP-2 or IGFBP-4 exerts an inhibitory effect on IGF-I-induced DNA synthesis, while IGFBP-5 potentiates the mitogenic effect of IGF-I (Duan and Clemmons, 1998, Hsieh et al., 2003). Some IGFBPs such as IGFBP-3 and -5 have been shown to have intrinsic biological activities that are IGF-independent (Duan and Xu, 2005, Firth and Baxter, 2002, Jogie-Brahim et al., 2009, Jones and Clemmons, 1995, Yamada and Lee, 2009).

The in vivo actions of IGFBPs have been studied by over-expression and knockout approaches using the mouse model. Ubiquitous over-expression of IGFBP-1, -2, -3 and -5 in transgenic mice leads to various degrees of growth retardation (Salih et al., 2004, Silha and Murphy, 2002). Knockout of a single IGFBP gene in mice, however, results in little or very mild phenotypic changes. IGFBP-1 knockout mice, for example, do not exhibit obvious growth changes under normal conditions, but their livers are more sensitive to apoptotic stimuli and show impaired liver regeneration ability after hepatectomy (Leu et al., 2003a, Leu et al., 2003b). The IGFBP-2 null mice have normal total body weight, although these animals have smaller spleen and bigger liver (Wood et al., 2000). IGFBP-2 deficient male, but not female, mice have reduced cortical bone area and decreased trabecular bone volume fraction (DeMambro et al., 2008). IGFBP-5 knockout mice have modest defects in mammary gland involution, but their body growth, selected organ weights, and body composition are essentially normal (Ning et al., 2007). These findings have lead to the notion that functional compensation by other members of the IGFBP family may have prevented the manifestation of more dramatic phenotypes in these single IGFBP knockout mice. In support of this view, elevated levels of IGFBP-1, IGFBP-3, IGFBP-5, and IGFBP-4 are found in the IGFBP-2-null mice (DeMambro et al., 2008, Wood et al., 2000). Mice null for IGFBP-3, -4, and -5 showed significantly diminished postnatal growth and enhanced glucose metabolism (Ning et al., 2006). These triple knockout mice also demonstrated significantly smaller quadriceps muscle. Another complication factor is the presence of IGFBP proteases. This has been highlighted by recent studies on IGFBP-4. Although a large number of in vitro studies have shown IGFBP-4 to be an inhibitory IGFBP, knockout of the IGFBP-4 gene in mice reduces, rather than increases, prenatal growth (Ning et al., 2008).

Recent studies in zebrafish have revealed important and new insights into the functions of IGFBPs during embryogenesis. The ex utero development and transparent embryos of the zebrafish model facilitate non-invasive in vivo imaging and experimental manipulation (Eisen, 1996). Zebrafish possess all the essential components of the IGF signaling pathway, including igf-1, igf-2, igf-1r, and igfbp genes (Ayaso et al., 2002, Eivers et al., 2004, Maures et al., 2002, Maures and Duan, 2002, Wood et al., 2005a; Zou et al., 2009). The expression of IGFBPs are highly tissue and stage specific (Kajimura et al., 2005, Li et al., 2005, Wood et al., 2005b; Kamei et al., 2008, Zhou et al., 2008, Wang et al., 2009, Dai et al., 2010). MO-based targeted knockdown of zebrafish IGFBP-2 resulted in cardiovascular defects, including reduced blood cell number and circulation, cardiac dysfunction, and angiogenic defects associated with sites of IGFBP2 expression in the brain (Wood et al., 2005b). IGFBP-3 deficiency resulted in delayed pharyngeal skeleton morphogenesis and impaired inner ear development (Li et al., 2005).

In developing zebrafish and in adult fish, hypoxia strongly induced the expression of IGFBP-1 (Kajimura et al., 2006, Maures and Duan, 2002). Hypoxia also caused significant growth and developmental retardation. Using the zebrafish model, we tested the hypothesis that elevated IGFBP-1 mediates hypoxia-induced embryonic growth retardation and developmental delay by binding to and inhibiting the activities of IGFs using loss- and gain-of-function approaches. Knockdown of IGFBP-1 using antisense MOs significantly alleviated the hypoxia-induced growth retardation and developmental delay. Over-expression of IGFBP-1 caused growth and developmental retardation under normoxia. Furthermore, re-introduction of IGFBP-1 to the IGFBP-1 knocked down embryos restored the hypoxic effects on embryonic growth and development (Kajimura et al., 2005). These results have provided strong evidence that IGFBP-1 plays a key role in mediating hypoxia-induced growth and developmental retardation in zebrafish embryos. Interestingly, knockdown of IGFBP-1 did not alter growth and development rate under normoxia. This lack of effect is in agreement with the observation that IGFBP-1 mRNA and protein levels are low under normal oxygen conditions. Therefore, the growth and developmental inhibition by IGFBP-1 may be in an “off” mode when there is ample oxygen, thus favoring fast growth and development. A more recent study has revealed that zebrafish has two IGFBP-1 genes- igfbp-1a and igfbp-1b (Kamei et al., 2008). Interestingly, these two genes display distinct temporal expression pattern in response to hypoxia during embryogenesis and exhibit different biochemical properties (Kamei et al., 2008).

Taken together, these studies demonstrate that IGFBPs are expressed in spatially and temporally restricted fashions and they each play distinct roles in regulating tissue formation and growth through ligand-dependent and possibly ligand-independent mechanisms.

Section snippets

Skeletal muscle cells and myogenesis

Skeletal muscle is composed of large multinucleated cells with an elongated shape (Fig. 1). These muscle cells are often referred to as muscle fibers. There are two broad types of voluntary muscle fibers: slow twitch and fast twitch, which are innervated by different motor neurons (Pette, 2002). Slow twitch fibers contract for long periods of time but generate less force, while fast twitch fibers contract more rapidly and powerfully but fatigue very rapidly. Each skeletal muscle fiber is a

Conclusion remarks

The IGF signaling pathway is an evolutionarily conserved signaling pathway that consists of multiple IGF ligands, receptors, IGFBPs, and the intracellular signal transduction network. Studies in a variety of vertebrate species suggest that the IGF signaling pathway plays a critical role in regulating skeletal muscle growth and differentiation, as well as in maintaining its homeostasis in adults. Recent studies have revealed that oxygen tension plays a critical role in specifying the responses

Acknowledgments

The authors thank Mr. John Allard for proof reading this manuscript. This study was supported by NIH Grant2RO1HL60679 and NSF Research Grant IOB0110864 to C.D. S.G. is supported by a fellowship from China Scholarship Council.

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