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Cellular and molecular regulation of muscle growth and development in meat animals^1,2

Department of Animal Science, University of Minnesota, St. Paul 55108

	Abstract

Top Abstract INTRODUCTION ANABOLIC STEROIDS MYOSTATIN AND TGF-β SUMMARY LITERATURE CITED

 
Although in vivo and in vitro studies have established that anabolic steroids, transforming growth factor-β (TGF-β), and myostatin affect muscle growth in meat-producing animals, their mechanisms of action are not completely understood. Anabolic steroids have been widely used as growth promoters in feedlot cattle for over 50 yr. A growing body of evidence suggests that increased muscle levels of IGF-I and increased muscle satellite cell numbers play a role in anabolic steroid enhanced muscle growth. In contrast to anabolic steroids, the members of the TGF-β-myostatin family suppress muscle growth in vivo and suppress both proliferation and differentiation of cultured myogenic cells. Recent evidence suggests that IGFBP-3 and IGFBP-5 play a role in mediating the proliferation-suppressing actions of both TGF-β and myostatin on cultured myogenic cells. Consequently, this review will focus on the roles of IGF-I and IGFBP in the cellular and molecular mechanisms of action of anabolic steroids and TGF-β and myostatin, respectively.

Key Words: muscle • anabolic steroid • myostatin • insulin-like growth factor-I • insulin-like growth factor binding protein • transforming growth factor-β

	INTRODUCTION

Top Abstract INTRODUCTION ANABOLIC STEROIDS MYOSTATIN AND TGF-β SUMMARY LITERATURE CITED

 
Both in vivo and in vitro studies have shown that anabolic steroids, transforming growth factor-β (TGF-β) and myostatin affect muscle growth in meat-producing animals. Although the mechanisms of action of these muscle growth regulators are not completely understood, a growing body of evidence suggests that the IGF-IGFBP system is involved.

Insulin-like growth factors stimulate proliferation and differentiation of myogenic cells. Additionally, IGF stimulates protein synthesis rate and suppresses protein degradation rate in myogenic cells. Insulin-like growth factor-I is produced locally in muscle and many other tissues. It is currently believed that locally produced IGF-I in skeletal muscle plays a predominant role in supporting normal muscle growth (Sjogren et al., 1999). In vivo, IGF are found in association with a family of high-affinity binding proteins (IGFBP-1 through -6) that affect their biological activity (Baxter, 2000). Insulin-like growth factor binding proteins affect IGF activity by binding to both IGF-I and -II with high affinity and either inhibiting or enhancing their ability to bind to the type I IGF receptor that is responsible for many of their biological effects (Baxter, 2000). In addition to this IGF-dependent mechanism of action, both IGFBP-3 and IGFBP-5 are believed to affect cells via IGF-independent mechanisms involving binding to specific cell surface receptors, transport into the cell, or both (Hwa et al., 1999; Baxter, 2000; Cobb et al., 2004).

It is well established that the anabolic effects of GH on muscle and bone are mediated by IGF-I. More recently, several lines of evidence have indicated that IGF-I and IGFBP also may play important roles in mediating the effects of anabolic steroids, TGF-β and myostatin, also known as growth and development factor-8, on muscle growth in meat-producing animals. The purpose of this review is to summarize these studies.

	ANABOLIC STEROIDS

Top Abstract INTRODUCTION ANABOLIC STEROIDS MYOSTATIN AND TGF-β SUMMARY LITERATURE CITED

 
It is well established that both androgenic and estrogenic steroids significantly enhance feed efficiency, rate of gain, and muscle growth of feedlot cattle, and, consequently, anabolic steroid implants have been widely used as growth promoters for several decades. Implants combining estrogen and androgen are more effective than either androgens or estrogens alone in stimulating muscle growth of steers (Hancock et al., 1991; Hayden et al., 1993; Johnson et al., 1996). Despite general agreement on the effectiveness of anabolic steroids, there has been no consensus as to the cellular mechanism(s) responsible for the anabolic effects of either estrogenic or androgenic steroids.

Role of Satellite Cells in Anabolic Steroid-Enhanced Muscle Growth
The number of muscle fibers in meat-producing animals is essentially fixed at birth; thus, postnatal muscle growth results from hypertrophy of existing muscle fibers. This fiber hypertrophy requires an increase in the number of myonuclei present in the fibers; however, the nuclei present in muscle fibers are unable to divide, so the nuclei must come from outside the fiber. The source of the nuclei needed to support fiber hypertrophy is mononucleated myogenic cells, satellite cells, located on the periphery of the fiber. Muscle satellite cells play a crucial role in postnatal muscle growth by fusing with existing muscle fibers and providing the nuclei required for postnatal fiber growth (Moss and Leblond, 1971; Campion, 1984). Thus, it is significant that the semi-membranosus muscles of yearling steers implanted with a combined trenbolone acetate (TBA) and estradiol-17β (E₂) implant contain a greater number of satellite cells than do the corresponding muscles of nonimplanted steers (Johnson et al., 1998a). Additionally, many studies in both humans and animals have shown that testosterone treatment increases muscle fiber diameter and the number of myonuclei present in muscle fibers in a dose-dependent manner (Bhasin et al., 2001; Sinha-Hikim et al., 2002, 2003). Subsequent studies showed that testosterone treatment caused a dose-dependent increase in the absolute number of satellite cells and the percentage of satellite cells relative to myofiber nuclei present in muscle (Sinha-Hikim et al., 2003). These results indicate that an increase in the number of satellite cells available to fuse with existing muscle fibers contributes significantly to anabolic-steroid-induced muscle growth in humans, laboratory animals, and meat-producing animals.

Effect of Anabolic Steroids on Circulating and Muscle IGF-I Levels
Treatment of yearling steers and sheep with a combined TBA and E₂ implant increases circulating IGF-I levels (Johnson et al., 1996, 1998b; Dunn et al., 2003; Pampusch et al., 2003a); however, studies in which hepatic IGF-I production has been knocked out, resulting in a 75% reduction in circulating IGF-I level, suggest that hepatic sources of circulating IGF-I may not play a major role in growth (Sjogren et al., 1999; Yakar et al., 1999). Instead, local production of IGF-I in skeletal muscle is currently thought to play a predominant role in supporting normal muscle growth through autocrine and (or) paracrine mechanisms (Sjogren et al., 1999). Studies in humans have shown that testosterone treatment increases IGF-I mRNA levels in skeletal muscle (Gayan-Ramirez et al., 2000; Lewis et al., 2002). Similarly, comparison of IGF-I mRNA levels in the splenius muscle of castrated and intact twin lambs showed greater levels of IGF-I mRNA in the muscle of intact sheep (Mateescu and Thonney, 2005). Additionally, treatment with a TBA and E₂ implant has been shown to increase IGF-I mRNA levels in LM of yearling steers as compared with nonimplanted control steers (Johnson et al., 1998b; Dunn et al., 2003; Pampusch et al., 2003a; White et al., 2003). Evaluation of the time course of changes in muscle IGF-I mRNA levels relative to the time of TBA and E₂ implantation showed that muscle IGF-I mRNA levels were increased by 7 d postimplantation and continued to increase to 3 times preimplant levels 28 d after implantation (Pampusch et al., 2003a). Trenbolone acetate and E₂ implantation did not affect myostatin, IGFBP-3, or hepatocyte growth factor mRNA levels in LM (Pampusch et al., 2003a). Based on these studies, it appears that anabolic steroid treatment increases muscle IGF-I levels, and it is likely that this may be at least partially responsible for the increased number of satellite cells, increased myofiber nuclei, increased hypertrophy, and increased muscle growth observed in anabolic steroid-treated animals and humans.

Recent studies show that human skeletal muscle produces 3 isoforms of IGF-I via alternative splicing: IGF-IEa, IGF-IEb, and IGF-IEc (Hameed et al., 2003). Insulin-like growth factor-IEa is similar to the hepatic iso-form that ultimately gives rise to circulating IGF-I. Insulin-like growth factor-IEc [often called mechano growth factor (MGF)] has a different C-terminal AA sequence than IGF-IEa (Hameed et al., 2003). Although both of these isoforms are ultimately processed into the same mature IGF-I peptide, there is evidence that the isoform expressed may be important in regulating muscle growth in various situations. Expression of MGF is rapidly induced following muscle damage or mechanical stress and reportedly activates quiescent satellite cells (Hill and Goldspink, 2003). Overexpression of MGF in C2C12 cells resulted in increased proliferation and suppressed differentiation, whereas overexpression of IGF-IEa stimulated differentiation and a lesser increase in proliferation (Cheema et al., 2005). In vitro studies also suggest that expression of IGF-IEa and MGF are differentially regulated. The C2C12 myogenic cell line constitutively expresses IGF-IEa, and although expression is increased by a single stretch, repeated cyclic stretch decreases expression (Cheema et al., 2005). In contrast, little constitutive MGF expression is observed in C2C12 cells, but expression is increased by a single stretch and by repeated cyclic stretch (Cheema et al., 2005). Additionally, a peptide comprised of the 24 C-terminal AA of the E-domain of MGF reportedly has biological activity that is independent of binding to the IGF-I receptor (Ates et al., 2007; Mills et al., 2007). Recently, it also has been reported that muscle MGF expression was increased after GH treatment of GH-deficient lit/lit mice (Iida et al., 2004), raising the possibility that MGF expression in muscle may be increased by growth promoters. Studies assessing the effects of anabolic steroids on muscle IGF mRNA levels have not determined which IGF-I isoforms are produced in response to anabolic steroid treatment, and this information is potentially of interest.

Effect of E₂ and Trenbolone on IGF-I mRNA in Bovine Satellite Cell Cultures
Several lines of evidence suggest that the effects of anabolic steroids on muscle IGF-I mRNA are direct. Both androgen and estrogen receptors have been identified in muscle fibers and satellite cells (Meyer and Rapp, 1985; Bechet et al., 1986; Sinnett-Smith et al., 1987; Sauerwein and Meyer, 1989; Doumit et al., 1996; Kahlert et al., 1997; Lemoine et al., 2002a,b, 2003; Altuwaijri et al., 2004; Kamanga-Sollo et al., 2004; Sinha-Hikim et al., 2004; Mateescu and Thonney, 2005), and Wu et al. (2007) recently identified androgen response elements on the upstream promoter of the human IGF-I gene. Additionally, in vitro studies show that E₂ or trenbolone treatment of cultured bovine satellite cells causes a dose-dependent increase in IGF-I mRNA level (Kamanga-Sollo et al., 2004). Neither E₂ nor trenbolone treatment affected abundance of myostatin, IGFBP-3, or hepatocyte growth factor mRNA in cultured bovine satellite cells (Kamanga-Sollo et al., 2004). Viewed together, these results strongly indicate that E₂ and trenbolone directly increase abundance of IGF-I mRNA in bovine satellite cells.

Effect of E₂ and Trenbolone on Proliferation in Bovine Satellite Cell Cultures
Attempts to demonstrate a stimulatory effect of anabolic steroids on proliferation of myogenic cells have yielded inconsistent results (Powers and Florini, 1975; Thompson et al., 1989; Doumit et al., 1996; Lee, 2002). It is our belief that this may be because IGFBP present in the serum component of the culture medium may suppress the action of IGF-I produced in response to steroid treatment. This belief is based on our observation that IGFBP-3, the most abundant IGFBP-3 present in serum, suppresses the biological actions of IGF-I in cultured myogenic cells (Xi et al., 2004; Pampusch et al., 2005). Consequently, we used immunoaffinity chromatography to remove IGFBP-3 from sera and added this IGFBP-3-free serum to culture media used to assess the effects of E₂ and trenbolone on proliferation of bovine satellite cell cultures. In these experiments, both E₂ and trenbolone stimulated approximately a 50% increase in ³H-thymidine incorporation in bovine satellite cell cultures (Kamanga-Sollo et al., 2004). Moreover, JB1, a peptide that inhibits IGF-I action by binding to the type I IGF receptor without activating it (Pietrzkowski et al., 1992), suppressed much of the E₂ or trenbolone-stimulated activity (our unpublished data). This suggests that increased expression of IGF-I is at least partially responsible for the increased proliferation observed in response to E₂ or TBA treatment of cultured bovine satellite cells.

	MYOSTATIN AND TGF-β

Top Abstract INTRODUCTION ANABOLIC STEROIDS MYOSTATIN AND TGF-β SUMMARY LITERATURE CITED

 
Myostatin (i.e., growth and development factor-8), a member of the TGF-β super family, is predominantly expressed in developing and in adult skeletal muscle. Myostatin-null mice have significantly increased muscle mass due to increased muscle fiber number (hyperplasia) and fiber size (hypertrophy; McPherron et al., 1997). In cattle, naturally occurring mutations that cause production of inactive myostatin result in a condition called double muscling, in which muscle mass is greatly increased (Grobet et al., 1997). Additionally, cell culture studies have shown that myostatin suppresses both proliferation and differentiation of cultured muscle cell lines and primary myogenic cells (Grobet et al., 1997). Myostatin also reportedly negatively regulates satellite cell activation and self-renewal and has been suggested to be involved in muscle satellite cell quiescence (McCroskery et al., 2003). Transforming growth factor-β₁, a TGF-β superfamily member closely related to myostatin, also has been shown to inhibit both proliferation and differentiation of cultured myogenic cells (Pampusch et al., 1990; Hathaway et al., 1991; Kamanga-Sollo et al., 2003). Studies in our laboratory have shown that cultured porcine embryonic myogenic cells (PEMC) produce both myostatin and TGF-β₁ mRNA (Xi et al., 2007a). Because myostatin suppresses both proliferation and differentiation of myogenic cells, the increased muscle fiber number and size observed in myostatin-null mice could result from increased proliferation, differentiation, or both, of myogenic cells pre-or postnatally. Myostatin- or TGF-β-induced suppression of muscle precursor cell proliferation during critical points in embryonic development could limit the number of myoblasts available to form muscle fibers and, thus, ultimately limit the number of muscle fibers (Lee, 2004). Moreover, because muscle satellite cell proliferation and fusion with existing fibers are responsible for postnatal muscle fiber hypertrophy (Moss and Leblond, 1971; Campion, 1984), the increased muscle fiber size in myostatin-null mice suggests that myostatin may play a significant role in satellite cell activation, proliferation, or both. This hypothesis is supported by reports that myostatin upregulates p21 and down-regulates cyclin-dependent kinase-2, suppressing proliferation in cultured satellite cells (McCroskery et al., 2003). Additionally, muscles of myostatin mutant mice reportedly have more satellite cells per unit of fiber length and a greater proportion of activated satellite cells than muscles of wild-type mice (McCroskery et al., 2003). Furthermore, cultured satellite cells from myostatin-null mice proliferate more rapidly than do satellite cells from wild-type mice (McCroskery et al., 2003). Based on the preceding findings, it appears that the proliferation-suppressing actions of myostatin, TGF-β, or both, play a major role in regulating muscle growth.

Although a great deal is known about the effects of myostatin and TGF-β on proliferation and differentiation of myogenic cells, substantially less information is available about their mechanism of action. Bioactive TGF-β is a homodimer that initially binds to the type II TGF-β receptor, forming a complex that then recruits and binds to the type I TGF-β receptor(s). The type II TGF receptor phosphorylates itself and the type I TGF-β receptor(s), which then phosphorylates Smad2 and Smad3 (R-Smads). Phosphorylated R-Smads form a heteromeric complex consisting of 2 phosphorylated R-Smads and Smad4, and this complex is translocated into the nucleus, where it is involved in regulating the expression of specific genes (Massague, 2000; Moustakas, 2002; Derynck and Zhang, 2003; Itoh et al., 2003). It was recently reported that myostatin binds to the type 2 activin receptors, primarily the activin type IIb receptor, in skeletal muscle (Lee and McPherron, 2001). Although less well characterized, the interaction of myostatin with the activin receptor family appears to be analogous to the interaction of TGF-β₁ with its receptors and also results in the phosphorylation of Smad2 and Smad3. Inhibitory Smad6 can suppress activation of Smad2 and Smad3 by binding to the type I receptor and preventing Smad2 and Smad3 binding and phosphorylation (Massague, 2000; Moustakas, 2002; Derynck and Zhang, 2003; Itoh et al., 2003). Both R-Smads and Smad4 are expressed in most cell types, whereas expression of inhibitory Smads (I-Smads) is highly regulated by extracellular signals (Derynck and Zhang, 2003). Co-repressors, such as Ski and Ski-related novel protein N (SnoN) also can suppress the ability of phosphorylated R-Smad-Smad4 complex to activate TGF-β target genes (Colmenares and Stavnezer, 1989; Xu et al., 2000; Luo, 2004). In contrast, the p38 mitogen-activated protein kinase (p38 MAPK) was reported recently to enhance the proliferation-suppressing action of both myostatin (Philip et al., 2005) and TGF-β (Stuhlmeier and Pollaschek, 2004; Kamaraju and Roberts, 2005) by phosphorylating selected Ser residues in the middle of the linker region of Smad2 and Smad3 that are distinct from the residues phosphorylated by TGF-β R1 (Kamaraju and Roberts, 2005).

There is growing evidence that phosphorylated Smad3 suppresses myogenic differentiation by binding to both MyoD and MEF2c and interfering with their transcription activity (Liu et al., 2001, 2004). In contrast, numerous studies have shown that the ability of both TGF-β (Lutz and Knaus, 2002; Moustakas et al., 2002) and myostatin (Thomas et al., 2000; Joulia et al., 2003; McCroskery et al., 2003; Lee, 2004) to suppress proliferation involves increased levels of p21, decreased levels of cyclin-dependent kinase-2, and decreased phosphorylation of retinoblastoma protein. Thus, proliferation and differentiation appear to be affected via different mechanisms.

Effects of TGF-β and Myostatin on Expression of IGFBP-3 and IGFBP-5 in Myogenic Cell Cultures
Insulin-like growth factor binding proteins-3 and -5 are both produced by cultured embryonic myogenic cells and muscle satellite cells (Hembree et al., 1996; Johnson et al., 1999; Yi et al., 2001) and suppress proliferation of myogenic cells by both IGF-dependent and IGF-independent mechanisms (Pampusch et al., 2003b, 2005; Xi et al., 2004, 2006). Treatment of PEMC cultures with either TGF-β₁ or myostatin causes a significant increase in the concentration of IGFBP-3 protein in medium conditioned for 18 h; however, the magnitude of the myostatin-induced increase is less than that observed with TGF-β₁ treatment (Kamanga-Sollo et al., 2003). Changes in IGFBP-3 concentrations in conditioned medium could result from either increased expression or decreased degradation. Consequently, we examined the effect of both TGF-β₁ and myostatin treatment on IGFBP-3 mRNA levels in PEMC. Insulin-like growth factor binding protein-3 mRNA levels are 3 to 4 times greater in TGF-β₁-treated PEMC cultures than in control cultures (Kamanga-Sollo et al., 2003). Similarly, myostatin treatment causes an approximate doubling of IGFBP-5 mRNA levels in treated cultures as compared with control cultures (Kamanga-Sollo et al., 2005). Thus, although both myostatin and TGF-β₁ increase expression of IGFBP-3 mRNA in PEMC cultures, TGF-β₁ treatment causes a significantly greater increase than does myostatin treatment (Kamanga-Sollo et al., 2003, 2005).

In addition to increasing IGFBP-3 and IGFBP-5 expression, both TGF-β₁ and myostatin suppress IGF-I- and LR3-IGF-I-stimulated proliferation in PEMC cultures. Immunoneutralization of IGFBP-3 or IGFBP-5 resulted in 50 to 70% and 30%, respectively, decreases in the ability of TGF-β₁ and myostatin to suppress either IGF-I or LR3-IGF-I-stimulated proliferation (Kamanga-Sollo et al., 2003, 2005). Immunoneutralization of both IGFBP-3 and IGFBP-5 in TGF-β₁ or myostatin-treated PEMC cultures restored both IGF-I and LR3-IGF-I-stimulated proliferation rates to >90% of the levels observed in control cultures receiving no TGF-β₁ or myostatin treatment (Kamanga-Sollo et al., 2005). Furthermore, the effects of antibodies that immunoneutralize porcine IGFBP-3 and antibodies that immunoneutralize porcine IGFBP-5 appear to be additive, suggesting that they may function via different mechanisms (Kamanga-Sollo et al., 2005). Long-R3-IGF-I is an IGF-I analog that has very low affinity for the IGFBP but retains its ability to bind to the type I IGF receptor and thereby stimulate proliferation (Kubler et al., 2002). Consequently, suppression of LR3-IGF-I-stimulated proliferation by IGFBP-3, IGFBP-5, or both, is believed to result from IGF-I-independent association of IGFBP-3 with cell surface receptors rather than binding and inactivation of IGF-I. Thus, the observation that immunoneutralization of IGFBP-3, IGFBP-5, or both, suppresses the ability of myostatin or TGF-β₁ to inhibit LR3-IGF-I-stimulated proliferation in PEMC cultures indicates that IGF-I-independent actions of IGFBP-3, IGFBP-5, or both, play a role in myostatin and TGF-β₁-induced suppression of proliferation in these cultures.

Potential Mechanisms by Which IGFBP-3 and (or) IGFBP-5 Mediate the Proliferation-Suppressing Activity of TGF-β and Myostatin on PEMC
Altering the Levels and (or) Activities of Intermediates in the TGF-β or Myostatin Signaling Pathway.
Even though immunoneutralization of IGFBP-3 and -5 increases proliferation rates in TGF-β₁ or myostatin-treated PEMC cultures to near those of control cultures not treated with TGF-β₁ or myostatin, phosphorylated Smad2 and phosphorylated Smad3 levels in these cultures are not affected and remain elevated (Kamanga-Sollo et al., 2003, 2005). Thus, the mechanisms by which IGFBP-3 and IGFBP-5 mediate TGF-β₁ and myostatin-induced suppression of myogenic cell proliferation do not appear to involve receptor-mediated phosphorylation of Smad2 or Smad3. Because I-Smads interfere with the ability of the TGF-β receptor to phosphorylate Smad2 and Smad3, the fact that immunoneutralization of IGFBP-3 and -5 does not affect phosphorylated Smad levels strongly indicates that I-Smads are not responsible for the reduced proliferation-suppressing activity observed when IGFBP-3 and (or) IGFBP-5 are immunoneutralized. Additionally, these data show that the interaction of TGF-β₁ or myostatin with their receptors is not affected by immunoneutralization of IGFBP-3 and IGFBP-5 (Kamanga-Sollo et al., 2003, 2005).

Co-repressors, such as Ski and SnoN, suppress the ability of the phosphorylated R-Smad-Smad4 complex to activate TGF-β target genes (Colmenares and Stavnezer, 1989; Xu et al., 2000; Luo, 2004). Consequently, it is possible that IGFBP-3 and (or) IGFBP-5 facilitate the proliferation-suppressing action of TGF-β₁ and myostatin by downregulating the production of these co-repressor molecules. Thus, changes in the levels, activities, or subcellular locations of these molecules could explain the reduced proliferation-suppressing activity of TGF-β₁ or myostatin despite unchanged levels of phosphorylated Smad2 and phosphorylated Smad3. Overexpression of the co-repressor, Ski, reportedly dramatically increases muscle growth in mice (Sutrave et al., 1990). Additionally, levels of Ski and the related co-repressor, SnoN, are increased in cancer cells that are refractory to the antiproliferative effects of TGF-β₁. In these cells, localization as well as expression levels of Ski and SnoN are reportedly altered (Reed et al., 2001; Medrano, 2003; Zhang et al., 2003), and it has been suggested that changes in the nuclear vs. cytoplasmic localization of these molecules may affect their activity. Consequently, IGFBP-3- or IGFBP-5-induced alterations in either the level or subcellular location of co-repressors, such as Ski and SnoN, may facilitate the proliferation-suppressing actions of TGF-β and myostatin in PEMC.

Recently, p38 MAPK has been reported to enhance the proliferation-suppressing action of both myostatin (Philip et al., 2005) and TGF-β (Stuhlmeier and Pollaschek, 2004; Kamaraju and Roberts, 2005) by phosphorylating selected Ser residues in the middle of the linker region of Smad2 and Smad3 that are distinct from the residues phosphorylated by TGF-βR1 (Kamaraju and Roberts, 2005). Moreover, both IGFBP-3 and IGFBP-5 reportedly increase p38 MAPK activity in MCF-10A breast epithelial cells and intestinal smooth muscle cells, respectively (Kuemmerle and Zhou, 2002; Martin et al., 2003). Consequently, IGFBP-3- and (or) IGFBP-5-induced activation of p38 MAPK may enhance the proliferation-suppressing action of TGF-β₁ and my-ostatin on PEMC and porcine muscle satellite cells (PMSC).

Nuclear Localization
Insulin-like growth factor binding protein-3 has been localized in the nucleus of numerous cell types including porcine skeletal muscle (Li et al., 1997; Schedlich et al., 1998, 2000; Hampel et al., 2005; Santer et al., 2006; Xi et al., 2007b). Treatment with TGF-β causes a significant increase in the proportion of IGFBP-3-positive nuclei (Jaques et al., 1997; Schedlich et al., 1998; Wraight et al., 1998; Xi et al., 2007b). Additionally, IGFBP-3 reportedly interacts with transcription regulators, such as the retinoid-X receptor (Liu et al., 2000) and RNA polymerase II binding subunit 3 (Oufattole et al., 2006), indicating that nuclear IGFBP-3 may be involved in altering transcription. Consequently, TGF-β₁-induced translocation of IGFBP-3 into the nucleus may play a role in TGF-β₁-induced suppression of proliferation in myogenic cells. Additionally, IGFBP-5 has also been localized in the nucleus of cultured cells (Schedlich et al., 1998, 2000; Schneider et al., 2002; Xu et al., 2004) and was shown recently to interact with the 4 and a half LIM-only protein 2 (Amaar et al., 2002).

Interaction with the Low-Density Lipoprotein Receptor-Related Protein-1-₂M Receptor
Initial studies identified a 400-Kd receptor present on most cells and showed that this receptor, originally designated the type V TGF receptor (TβR-V), bound both TGF-β and IGFBP-3 at specific but different sites (Huang et al., 2003; Tseng et al., 2004). Subsequent studies identified this receptor as the previously characterized low-density lipoprotein receptor-related protein receptor (Huang et al., 2003). Leal et al. (1997, 1999) have reported that TβR-V is a putative IGFBP-3 receptor and that it mediates IGF-independent suppression of proliferation by IGFBP-3. This report is supported by studies showing that IGFBP-3 has little effect on proliferation of cells that express low levels of TβR-V, whereas stable transfection of these cells so that they constitutively express TβR-V renders them sensitive to suppression of proliferation by IGFBP-3 (Huang et al., 2003; Tseng et al., 2004). Although binding of both TGF-β and IGFBP-3 to TβR-V suppresses proliferation, binding of TGF-β does not suppress proliferation to the same extent as does binding of IGFBP-3 (Huang et al., 2004; Tseng et al., 2004). Consequently, IGFBP-3 may facilitate the proliferation-suppressing actions of TGF-β₁ on PEMC cells by binding to TβR-V. Immunoneutralization of IGFBP-3 potentially renders it unable to bind to TβR-V and reduces the ability of TGF-β to suppress proliferation.

Although some or all of the above processes may be involved, the mechanism by which IGFBP-3 mediates the proliferation-suppressing activity of TGF-β₁ and myostatin in PEMC is currently unknown. Even less is known about the mechanism by which IGFBP-5 mediates the proliferation-suppressing activity of these growth factors. Consequently, further research is needed to elucidate the role of IGFBP-3 and IGFBP-5 in mediating TGF-β₁ and myostatin actions on muscle.

	SUMMARY

Top Abstract INTRODUCTION ANABOLIC STEROIDS MYOSTATIN AND TGF-β SUMMARY LITERATURE CITED

 
Although both in vivo and in vitro studies have shown that anabolic steroids and myostatin and TGF-β significantly affect muscle growth in meat-producing animals, their mechanisms of action are not clear. Recent evidence has indicated that IGF-I and IGFBP play a role in mediating the actions of anabolic steroids and TGF-β and myostatin, respectively. Further investigation into the mechanisms by which IGF-I and IGFBP mediate the actions of anabolic steroids and TGF-β and myostatin on muscle will ultimately lead to a better understanding of the mechanism of action of these important muscle growth regulators in meat-producing animals.

	Footnotes

 
¹ Presented at the ADSA-PSA-AMPA-ASAS Joint Annual Meeting, Growth and Development Symposium: Transcriptional factors and cell mechanisms for regulation of growth and development with application to animal agriculture, San Antonio, TX, July 8 to 12, 2007.

² Some of the research presented in this review was supported by National Research Initiative Competitive Grants 99-35206-7935, 2000-35206-9342, 2006-35206-16632, and 2006-35206-16663 from the USDA Cooperative State Research, Education, and Extension Service.

³ Corresponding author: wdayton{at}umn.edu

Received for publication July 25, 2007. Accepted for publication August 3, 2007.

	LITERATURE CITED

Top Abstract INTRODUCTION ANABOLIC STEROIDS MYOSTATIN AND TGF-β SUMMARY LITERATURE CITED

 


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