Absence of growth hormone-induced avian muscle growth in vivo

Absence of Growth Hormone-Induced Avian Muscle Growth In Vivo R. VASILATOS-YOUNKEN1 Department of Poultry Science, The Pennsylvania State University, University Park, Pennsylvania 16802 A primary lesion would appear to be the inability of GH to induce significant increases in circulating IGF-I concentrations in sexually immature, growing poultry. This is the case despite clear evidence of GH binding to hepatic receptors, GH-induced tyrosine phosphorylation of Janus kinase 2 (JAK2), and GH-induced expression of hepatic IGF-I mRNA and protein. Factors that should be explored with respect to this apparent discrepancy are discussed, including the regulation of IGF-I release, uptake, and interaction with cell-associated IGF binding proteins or receptors. In addition to its growth-promoting effects via IGF-I, GH has direct metabolic effects that are expressed as changes in circulating regulatory hormone and metabolite concentrations. The possibility that such changes may influence IGF-I release and action is also proposed.

(Key words: growth hormone, insulin-like growth factor-I, muscle, satellite cells, signal transduction) 1999 Poultry Science 78:759–768

agents, and will be a particular focus of this review. Because of space limitations, the scope of this review will not encompass in ovo strategies to manipulate subsequent posthatch growth in poultry, a substantial field of endeavor with significant promise (Hargis et al., 1991).

INTRODUCTION In the realm of animal agriculture, where research involving muscle growth and development has obvious application to muscle food production, the growth hormone (GH)/insulin-like growth factor (IGF) axis has greatest relevance in the context of normal, growing, pituitary-intact animals, the logical target for potential growth-enhancing strategies. This paper will attempt to deal with the role of the GH-IGF axis as it relates to posthatch muscle growth in poultry in this context. Also, as emphasized earlier in this symposium, as well as in previous reviews (Dayton and Hathaway, 1991; Dodson et al., 1996), myofiber number is established prior to hatch, and subsequent growth occurs by means of fiber hypertrophy involving proliferation, differentiation, and fusion of specialized myogenic stem cells (satellite cells) with existing muscle fibers. Satellite cells therefore represent the source of nuclei for early postnatal muscle growth, and persist throughout life to be recruited during tissue regeneration in mature muscle. As such, they are the logical target cell for muscle anabolic

PHYSIOLOGY OF THE GH-IGF-I AXIS The general physiology of the GH-IGF-I axis has been delineated for some time, and is beyond the scope of this paper to comprehensively review. The reader is referred to avian-specific (Scanes and Lauterio, 1984; Scanes et al., 1984; Harvey et al., 1991), as well as broader overviews of this topic (Laron, 1982). Briefly, GH is secreted by somatotrophs of the anterior pituitary gland under the influence of both stimulatory [growth hormone releasing factor (GRF) and thyrotropin-releasing hormone (TRH)] and inhibitory [somatostatin (SRIF)] hypothalamic factors. A distinctive feature of the

Abbreviation Key: bHLH = basic helix-loop-helix; BP = binding proteins; c = chicken; ED50 = effective dose 50; FGF = fibroblast growth factor; GH = growth hormone; GRF = growth hormone releasing factor; IGF = insulin-like growth factor; JAK2 = Janus kinase 2; MHC = myosin heavy chain; MRF = myogenic regulatory factor; SLD = sex-linked dwarf; SRIF = somatostatin; TRH = thyrotropin releasing hormone.

Received for publication August 1, 1998. Accepted for publication October 20, 1998. 1To whom correspondence should be addressed: [email protected]

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ABSTRACT Growth hormone (GH) clearly has the potential to dramatically enhance skeletal muscle accretion in red meat animals such as swine. It is generally accepted that this anabolic effect is mediated by insulinlike growth factor-I (IGF-I), a potent stimulator of proliferation and differentiation of satellite cells that are important for myofiber hypertrophy and for regeneration in postnatal muscle tissue. All available evidence suggests that the capacity for IGF-I-mediated actions of GH on avian myogenic cells is intact, and recent evidence is accumulating that GH may even have direct effects on avian skeletal muscle satellite cell proliferation and differentiation. However, with little exception, exogenous GH does not improve skeletal muscle mass, carcass protein, or any measure of muscle anabolism in domestic poultry.

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There is considerable evidence that circulating IGF-I is at least partially dependent upon GH, and derived from the liver in the chicken. The sex-linked dwarf (SLD) chicken (see Decuypere et al., 1991, for review) exhibits a lack of target tissue GH binding (Leung et al., 1987b) due to a variety of molecular defects in the GH-R (Burnside et al., 1992; Benedicte et al., 1993; Agarwal et al., 1994). The SLD has plasma IGF-I concentrations that are reduced to approximately one-third those in normal birds (Scanes et al., 1989; Vasilatos-Younken et al., 1997), in conjunction with undetectable hepatic, but normal extrahepatic (except for enhanced testicular) IGF-I mRNA expression (Tanaka et al., 1996). [Note:The persistence of some circulating IGF-I in the SLD despite absent hepatic expression of the gene would also suggest that: 1) a significant portion of circulating IGF-I is derived from extrahepatic tissues that are GHindependent in the chicken, and 2) hepatic expression is largely GH-dependent. The latter is further supported by the fact that circulating IGF-I concentrations are only partially reduced (to approximately 35 to 50% of normal) in hypophysectomized chickens (Scanes et al., 1986; Lazarus and Scanes, 1988; Proudman et al., 1989). Complicating the regulation of IGF-I activity is the recognition that other related peptides (IGF-II, insulin) as well as IGF-I can bind to any of three related tissue receptors (Type I or IGF-I receptor; Type II/cationindependent mannose-6-phosphate or IGF-II receptor; and the INS or insulin receptor) whose affinities differ for each ligand (Cohick and Clemmons, 1993). In contrast to mammals, IGF-II does not bind to the Type II receptor in poultry, and it is generally considered that effects of IGF in birds are mediated exclusively by the Type I receptor (McMurtry et al., 1997). Exclusive binding to the Type I receptor has been specifically demonstrated in both chicken (Duclos et al., 1991) and turkey myogenic (satellite) cells (Minshall et al., 1990). In addition to target tissue receptors, IGF circulate bound to a family of six IGFBP (1 through 6) that reduce the clearance of IGF from the circulation, and modulate IGF action. IGFBP-3, which is GH-dependent, is the major IGFBP involved in transport of IGF-I in the circulation, and 94% of plasma IGF-I in the chicken is in bound form (McMurtry et al., 1997). Alternatively, all IGFBP are synthesized in tissues, and IGFBP-5, which has the highest affinity of all IGFBP for the IGF (50-fold > the IGF-I receptor at physiological pH; Cohick and Clemmons, 1993), is expressed during myoblast differentiation (James et al., 1993). The chicken cDNA for IGFBP5 has been cloned, sequenced, and determined to encode a mature protein with calculated molecular mass of 28.2 kDa (Allander et al., 1997), which was identified in both chick embryonic myoblast cultures and post-hatch (6and 7-wk-old) chicken skeletal muscle (James et al., 1993; Allander et al., 1997). It is noteworthy that IGFBP-5 mRNA is depressed in response to hypophysectomy, whereas GH markedly stimulates expression (GosteliPeter et al., 1994). In addition to IGFBP-5, IGFBP-2 (Ernst

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circulating profile of GH in the chicken resulting from the coordinated actions of these factors is relatively high amplitude peaks that occur at regular intervals (approximately 90 min) during early posthatch development when growth rate is rapid. These peaks diminish in amplitude to low, virtually undetectable levels at later ages when growth rate has slowed (see VasilatosYounken and Scanes, 1991 for review). Of note is that diminution of high amplitude GH peaks occurs at later ages in male than in female broiler chickens, coincident with the development of sexual dimorphism in body size and muscle deposition (Johnson, 1988). In GH target tissues such as the liver, GH binds to specific plasma membrane receptors (GH-R) in a 1:2 stoichiometry, so that, at biologically effective concentrations of GH, a GH:GH-R dimer is formed (Cunningham et al., 1991) that is essential for signal transduction and biological action (Fuh et al., 1992). High concentrations of GH induce binding in a 1:1 ratio, with impairment of further signal transduction. Subsequent to effective dimer formation, signalling events involve recruitment of a member of the Janus-activated kinase family, JAK2 tyrosine kinase, which binds to the receptor and, in turn, results in tyrosine phosphorylation of the GH-R and JAK2 itself (Argetsinger et al., 1993; Darnell et al., 1994). This initiating event then leads to tyrosine phosphorylation of a variety of protein kinase substrates, including several members of the STAT family of transcriptional regulators that translocate to the nucleus, bind to DNA, and activate transcription of certain genes (Gronowski and Rotwein, 1994; Campbell et al., 1995; Wood et al., 1995; Xu et al., 1996). (See Carter-Su et al., 1996, for review of molecular mechanisms of GH action). In addition to binding of GH to target tissue receptors, circulating binding proteins for GH (GHBP) have been identified in a variety of species, including the chicken (Vasilatos-Younken et al., 1991), and arise from alternative splicing of a primary transcript in rodents (Baumbach et al., 1989; Smith et al., 1989) or proteolytic cleavage in the rabbit and human (Leung et al., 1987a; Sotiropoulos et al., 1993). The origin of chicken GHBP is not clear, as a truncated (0.7 kb) transcript resulting from alternative usage of a functional polyadenylation signal embedded in the coding sequence for the chicken GH-R has been reported (Oldham et al., 1993). Although this truncated transcript appears to be translated, a physiological role for the putative translation product has not been determined, and its predicted size is not consistent with apparent molecular weight for chicken circulating GHBP reported to date (VasilatosYounken et al., 1991). The growth-promoting actions of GH postnatally are believed to be mediated primarily by IGF-I. Although most tissues in the body synthesize IGF-I, circulating levels are presumed to be hepatically derived in response to GH, and released into the circulation to act on other tissues, including skeletal muscle, in an endocrine manner (see Cohick and Clemmons, 1993; and McMurtry et al., 1997 for reviews).

SYMPOSIUM: MUSCLE GROWTH AND DEVELOPMENT

et al., 1990), as well as three distinct IGFBP, including a prominent 30.8-kDa form, were identified in turkey satellite cell cultures (McFarland et al., 1993). The IGFBP are found both in extracellular fluids, and in association with cells, and have the potential to alter the partitioning of IGF-I between membrane receptors, extracellular fluids, and cell surface-associated IGFBP (McCusker et al., 1991; McCusker and Clemmons, 1997). It is suggested that cell-associated IGFBP increase IGF binding to cells, whereas soluble, extracellular IGFBP decrease binding (McCusker and Clemmons, 1997). It is conceivable, then, that factors that regulate the profile and distribution of IGFBP also may impact on IGF-I biological action.

MUSCLE GROWTH IN RESPONSE TO EXOGENOUS GH

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the latter associated with reduced carcass fat deposition (Chung et al., 1985; Etherton et al., 1986; 1987; Campbell et al., 1989; Evock et al., 1991; Fabry et al., 1991). In a comprehensive dose response study, Thiel et al. (1993) demonstrated increases in weights of individual muscles of up to 47% in response to porcine GH treatment, with total carcass muscle yield enhanced 36%, and adipose tissue content reduced 74% compared to controls. Of note in this and other studies (Etherton et al., 1987; Beerman et al., 1990) is that improvements in muscle yield at even low GH dosages are close to maximal, whereas adipose tissue and circulating IGF-I responses are dose-responsive up to even the highest GH dosages evaluated. It was suggested that mechanisms by which GH increases muscle growth may be regulated differently than those that are considered direct effects of the hormone (e.g., effects on lipogenesis) (Etherton et al., 1987).

Characteristics of GH-Induced Muscle Growth

Exogenous GH dramatically alters the efficiency and magnitude of skeletal muscle deposition in red meat animals, most notably swine. It has been emphasized in the literature that GH is less efficacious in promoting muscle growth in very young animals, which may reflect the inherent high capacity of protein accretion in the neonate or relative GH independence of early postnatal growth (Bell et al., 1998). Also, because its mechanism of action is at least partly dependent upon its effects as a repartitioning agent, allowing for proportionately more substrate to be made available for muscle vs adipose tissue accretion, the effectiveness of GH in promoting muscle growth is greater in animals after endogenous nutrient partitioning is shifted towards proportionately greater fat deposition, which occurs with increasing age, as observed in swine (Etherton et al., 1987; Etherton et al., 1993). This relationship has been reviewed for the broiler chicken (Vasilatos-Younken, 1995), and would occur after approximately 4 to 5 wk of age. An additional consideration with regard to accretion of lean tissue in response to GH is that, although the distribution of amino acid utilization is not altered, the magnitude of apparent utilization (i.e., tissue accretion rate) is so dramatically enhanced by GH that amino acid requirements of GH-treated swine are increased by almost 70% (Caperna et al., 1995). Even recognizing that the efficiency of protein utilization is increased by GH as well (Caperna et al., 1991), such dramatic increases in amino acid utilization raise questions concerning optimal levels of dietary amino acids to meet requirements of GHtreated meat animals.

When GH is overexpressed during embryonic development in mice, enhanced muscle mass is observed in the adult, which reflects increased fiber number, but no differences in fiber type (Hikida et al., 1995). When administered during postnatal development, however, GH clearly increases muscle mass due to an increase in muscle fiber hypertrophy only, again with no effect on fiber type distribution; this has been consistently observed across species, including in pigs (Beerman et al., 1990; Solomon et al., 1994; Ono et al., 1995; Sorensen et al., 1996), cattle (Vestergaard et al., 1995; Ono et al., 1996), and rodents (Aroniadou-Anderjaska et al., 1996; Cartee et al., 1996). The increase in fiber diameter occurs with no change in the length of the individual sarcomere unit (Fabry et al., 1991), and collectively translates to increased muscle cross-sectional area, as reported for the Longissimus muscle in pigs (Etherton et al., 1987; Evock et al., 1991; Fabry et al., 1991; Solomon et al., 1994). Consistent with the lack of an effect of GH on muscle fiber type, myosin heavy chain (MHC) isoform distribution and MHC mRNA expression are not altered by GH (Czerwinski and Martin, 1994; Welle and Thornton, 1997). It has been suggested that fiber types differ in their responsiveness to GH, and that this profile differs among species (Ono et al., 1995); however, when data are evaluated collectively, there is some evidence that small muscle fibers (in terms of crosssectional area) are more responsive to GH than large fibers (Solomon et al., 1994; Ono et al., 1996; Sorensen, et al., 1996). An additional relevant feature of GH administration to red meat animals is an increase in fractional protein synthesis rates in tissues such as liver and muscle (e.g., Longissimus) (Eisenman et al., 1989; Seve et al., 1993). This increase is apparently due to increased ribosomal capacity (i.e., increased RNA content) of these tissues (Pell and Bates, 1987; Evock et al., 1991; Seve et al., 1993), and is reflected in dramatic increases in tissue accretion rates of amino acids by GH-treated pigs compared to control

Muscle Growth Responses to GH in Red Meat Animals Administration of GH to growing pigs consistently improves daily gain, feed efficiency, and muscle growth,

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Recognition of Factors Influencing the Response to GH

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animals (Caperna et al., 1995). The efficiency of utilization of dietary protein is also improved by GH (as much as 66% overall), over a range of dietary protein intakes (Caperna et al., 1991).

MECHANISM OF GH-INDUCED MUSCLE GROWTH

IGF-I Actions in Skeletal Muscle

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The growth-promoting effects of GH in mammals are considered to be mediated largely by IGF-I. The effects of IGF-I on skeletal muscle growth have been recognized for many years (Dodson et al., 1985), and comprehensive reviews for both nonagricultural (Florini et al., 1996) and agricultural species (Dodson et al., 1996) have been recently published. In general, it is well established that IGF-I stimulates myoblast and satellite cell proliferation, as well as terminal myogenic differentiation (see Florini et al., 1996, for review), although not at the same time. The effect of IGF-I on myogenic differentiation involves induction of myogenesis genes. As discussed earlier in this symposium, these genes are expressed only in skeletal muscle and encode proteins that function as myogenic regulatory factors (MRF), transcription factors that share a highly conserved basic helix-loop-helix (bHLH) domain that mediates DNA binding, and a myogenic regulatory motif that is unique to the MRF and required for myogenic activity. The MRF form functional heterodimers with other bHLH transcription factors, the E-proteins (e.g., E47, E2-2, and HEB), which then bind to E-box sequences (CANNTG-) within the promoter region of muscle-specific genes and induce expression of muscle-specific proteins. The MRF include MyoD, myf-5, MRF-4, and myogenin (Ludolph and Konieczny, 1995), and myogenin in particular appears to be obligatory for the effects of IGF-I on myogenesis (Florini and Ewton, 1990). One of the most dramatic illustrations of the potential for IGF-I to enhance muscle growth was the work of Coleman et al. (1995), who used the skeletal a-actin gene to direct expression of human IGF-I in cultured myoblasts and in striated muscle of transgenic mice. Expression of the hybrid gene in the C2C12 myoblast cell line increased expression of MRF (including MyoD and myogenin) and contractile protein mRNA, and caused early alignment and fusion of myoblasts into differentiated myotubes. Directed muscle-specific expression of the transgene in mice elevated muscle IGF-I concentrations 47-fold, with no increase in circulating IGF-I levels, and caused marked hypertrophy of all classes of myofibers. Also of note was that cultured myoblasts expressing the hybrid gene (i.e., IGF-I derived via autocrine-paracrine mechanisms) exhibited higher levels of expression of muscle-specific mRNA than cells exposed to higher concentrations of exogenous IGF-I in the culture medium, possibly due to increased expression of IGFBP-5 observed in the cells over-expressing IGF-I. In established chicken myofiber cultures derived from embryonic myoblasts, IGF-I stimulates both hyperplasia and fiber hypertrophy, the latter associated with increased

protein synthesis and decreased degradation, as well as large increases in MHC content, and in the number of myonuclei per fiber length (Vandenburgh et al., 1991). In satellite cells derived from breast muscle of posthatch chickens, IGF-I alone induced a three- to fivefold increase in thymidine incorporation into DNA (Duclos et al., 1991; Wilkie et al., 1995), with an effective dose (ED50) in the physiological range (10 ng/mL). Proliferation of turkey embryonic myoblasts and satellite cells was also stimulated by IGF-I; however, in contrast to the above studies with chicken satellite cells, fibroblast growth factor (FGF) was required together with IGF-I for this proliferation response to occur (McFarland et al., 1993). Indirect evidence of a role for IGF-I in avian satellite cell proliferation is also provided by reduced BrdU-labelling of nuclei in satellite cells isolated from 5-d-old SLD chickens (Goddard et al., 1996), which are known to express significantly reduced circulating IGF-I concentrations, in comparison to normals. Differentiation of turkey embryonic myoblasts but not satellite cells was also induced by IGF-I (McFarland et al., 1993). The inability of exogenous IGF-I to stimulate satellite cell differentiation was suggested to be due to masking of this effect by high endogenous production of IGF-I in cells from posthatch tissue. An additional observed effect of IGF-I, which is pertinent to the overall response in myofiber growth, is stimulation of amino acid transport and protein synthesis, and inhibition of protein degradation in chicken muscle satellite cells (Duclos et al., 1993). In the same study, recombinant chicken GH had no direct effect on basal amino acid transport in these cells. Despite the above in vitro evidence that IGF-I can enhance growth of avian skeletal muscle, exogenous IGF-I administered to normal chickens failed to enhance body weight gain or breast muscle weight (Huybrechts et al., 1992; Tixier-Boichard et al., 1992). This is not surprising in that free IGF-I is rapidly cleared from the circulation (see above), and tissues that are more highly perfused, such as visceral organs, are likely to respond more than skeletal muscle (Mathews et al., 1988). Coordinated increases in IGFBP or muscle-specific expression of IGF-I may be required to realize any growth-promoting effects on muscle (see above re: Coleman et al., 1995). Not only does exogenous IGF-I fail to increase avian muscle growth, but slightly decreased weight of the breast muscle of SLD chickens (Tixier-Boichard et al., 1992). In a recent study using homologous (i.e., chicken) peptide, IGF-I was associated with a significant decrease in weight of the Gastrocnemius and Pectoralis muscles and an increase in muscle free 3-methylhistidine concentrations of normal chickens, suggestive of increased skeletal muscle breakdown (Czerwinski et al., 1998). In this study, circulating insulin concentrations were significantly reduced in IGF-I treated birds, which may account for the increase in muscle breakdown, as insulin is a potent inhibitor of proteolysis, and may be permissive, along with amino acids, for stimulation of protein synthesis by IGF-I (Jacob et al., 1996).

SYMPOSIUM: MUSCLE GROWTH AND DEVELOPMENT

Mediation of GH Effects on MuscleEndocrine Route of IGF-I Action

Mediation of GH Effects on MuscleAutocrine/Paracrine Route of IGF-I Action In pigs administered GH, in which circulating IGF-I was increased, hepatic and adipose tissue but not skeletal muscle IGF-I mRNA were also increased (Coleman et al., 1994). In light of these results, an autocrine-paracrine mechanism for IGF-I effects on skeletal muscle were dismissed, due to lack of GH-induced IGF-I mRNA enhancement in the Longissimus muscle. More recently, however, expression of muscle IGF-I mRNA was found to be GH responsive in a muscle-specific manner, as expression was enhanced in liver and Semitendinosus, but not in the Longissimus muscle of pigs treated with GH, despite increased GH-R mRNA in all three tissues (Brameld, et al., 1996). Additional evidence for an autocrine-paracrine response to GH was observed in rats treated with anti-GH antiserum, in which total serum IGF-I as well as hepatic IGF-I mRNA were unaffected, yet body weight and total protein content of specific muscles were significantly decreased (Palmer et al., 1993). These responses would suggest either a direct effect of GH on muscle, or an autocrine-paracrine mechanism of IGF-I action on muscle growth. Evidence also exists for the possibility of autocrineparacrine responses to GH in poultry. Chicken breast muscle expresses GH-R mRNA beginning early in posthatch development, which is markedly increased at sexual maturity (Oldham et al., 1993; Halevy et al., 1996), and GH has been demonstrated to activate (tyrosine phosphorylate) JAK2 tyrosine kinase in chicken breast muscle during this period (Zhou et al., 1998). Further, GH induced IGF-I mRNA in chicken satellite cells in culture (Halevy et al., 1996), and IGF-I protein concentrations in both breast and Gastrocnemius muscle were increased by pulsatile GH administration, in the absence of any significant elevation in circulating IGF-I (Rosselot et al., 1995). Alternatively, expression of IGF-I message in skeletal muscle of the GH-R-deficient, SLD chicken was equal to that of normal birds (Goddard et al., 1996; Tanaka et al., 1996), suggesting that local IGF-I production by muscle is GH-independent. In the study by Tanaka et al. (1996), hepatic expression was high in normals and undetectable in SLD birds at 4 wk of age (Tanaka et al., 1996). It should be cautioned, however, that mRNA expression was found not to be highly correlated with IGF-I protein concentration in extrahepatic tissues of commercial broiler chickens administered GH (Rosselot et al., 1995), or in mammalian models (Lajara et al., 1989).

Direct Effects of GH on Muscle There is accumulating evidence that GH may have direct effects on avian satellite cell growth processes. At low GH concentrations (2 to 10 ng/mL), GH-R mRNA

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The general consensus regarding muscle growth associated with administration of exogenous GH in mammals is that this effect is mediated largely by enhanced circulating IGF-I produced by the liver in response to GH. Circulating IGF-I concentrations are significantly increased in pigs treated with GH (Etherton et al., 1987; Campbell et al., 1989; Seve et al., 1993; Coleman et al., 1994). However, administration of GH to sexually immature, growing poultry has little, inconsistent, or no effect on circulating IGF-I concentrations (Cogburn et al., 1989; Rosebrough et al., 1991; Bacon et al., 1995; Moellers and Cogburn, 1995; Rosselot et al., 1995), particularly when more accurate homologous immunoassays for avian IGF-I (McMurtry et al., 1994) are employed. In the study of Moellers and Cogburn (1995), a pulsatile pattern of GH administration, which significantly elevated circulating GH concentrations, failed to alter plasma IGF-I. However, continuous delivery of the same daily dosage of GH failed to elevate plasma GH above controls, but was associated with a significant, though relatively small increase in plasma IGF-I, raising questions as to the provocative agent responsible for the plasma IGF-I increase. Circulating IGF-I does appear to be more responsive to GH in adult birds, as several-fold increases in plasma-IGF-I were obtained in adult, layer strain chickens, although dosages used were extraordinarily high (100 mg/d; approximately 50,000 mg GH/kg BW/d, based on information provided in tables; Radecki et al., 1997). It is difficult to explain the lack of increased circulating IGF-I concentrations in response to GH in the growing chicken. Chicken liver expresses significant levels of GH-R mRNA beginning at early ages (2 wk), with marked expression evident in sexually mature birds (Burnside and Cogburn, 1992; Oldham et al., 1993). Although measurable specific binding of GH is very low and difficult to demonstrate in birds prior to sexual maturity, recent studies verify that early steps in the GH signal transduction pathway in liver are intact in sexually immature, growing birds. Zhou et al. (1998) recently demonstrated induction of hepatic JAK2 protein with chronic cGH infusion, and maximal tyrosine phosphorylation of the kinase within 10 min of an i.v. cGH pulse in late-posthatch chickens. Consistent with this, pulsatile in vivo infusion of cGH produced significant increases in hepatic IGF-I message and protein concentrations (Rosselot et al., 1995). In addition, in vitro studies verify that GH directly stimulates IGF-I production by chicken hepatocytes, and the peptide is released into the medium by cultured cells (O’Neill et al., 1990). Thus, all components of the pathway necessary for a circulating IGF-I response to GH administration in the normal, growing chicken appear functional, and the inability of GH to evoke such a response in vivo is a conundrum.

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expression was increased, specific binding of cGH was exhibited, and thymidine incorporation (DNA synthesis) was enhanced in chicken satellite cells (Halevy et al., 1996). In the same study, GH inhibited gene expression of the MRF myogenin and expression of muscle-specific proteins in a dose-dependent manner, effects consistent with inhibition of satellite cell differentiation, and opposite to known effects of IGF-I on these processes (Halevy et al., 1996). It was suggested that this inhibition of differentiation may promote enhanced satellite cell proliferation, thereby allowing more nuclear material to be generated for addition to existing myofibers. In a subsequent study, co-incubation of a low level of GH together with IGF-I did not enhance DNA synthesis in chicken satellite cells above that induced by GH alone, and the time course for induction in the presence of GH or IGF-I was similar, suggesting that cGH effects were independent of IGF-I (Hodik et al., 1997).

With little exception, GH does not improve skeletal muscle mass, carcass protein percentage, or any measure of muscle accretion in sexually immature, growing poultry (Leung et al., 1986; Burke et al., 1987; VasilatosYounken et al., 1988; Cogburn et al., 1989; Cravener and Vasilatos-Younken, 1989; Rosebrough et al., 1991; Bacon et al., 1995; Moellers and Cogburn, 1995) or in adult chickens (Radecki et al., 1997). In fact, in some studies, breast muscle, the largest skeletal muscle depot in the bird, tended to be reduced by GH treatment (VasilatosYounken et al., 1988; Cravener and Vasilatos-Younken, 1989). The exception was observed in prepubescent broiler chickens administered 50 or 250 mg cGH/kg BW/d, s.c. by osmotic minipumps, in which breast muscle weight was increased compared to that of vehicle-infused controls (Scanes et al., 1990). Although not yet sexually mature, birds used in this study were older when final effects of GH were assessed (12 to 15 wk), and may be one factor accounting for the positive response not observed in other studies. Curiously, the increase in muscle mass at the higher cGH dosage was associated with a significant decrease in weight of the abdominal fat pad, whereas, at the lower dosage, the increase in muscle mass was in conjunction with increased abdominal fat, suggesting differences not only in regulatory mechanisms, but the dose-responsiveness of such mechanisms in controlling growth vs metabolic effects of GH.

SUMMARY AND CONCLUSIONS Abundant research has documented the impressive potential for GH to enhance skeletal muscle deposition in agricultural (red) meat animal species. Despite evidence that the initial components of the GH-IGF-I axis are intact, and that IGF-I does directly induce myogenic cell proliferation and differentiation in

ACKNOWLEDGMENTS The author is grateful to R. M. Leach, Jr., for his patience and invaluable advice on preparation of this review, and his keen ability to make a point. Appreciation is also expressed to M. Edwards for tireless trips to the library and meticulous technical corrections.

REFERENCES Agarwal, S. K., L. A. Cogburn, and J. Burnside, 1994. Dysfunctional growth hormone receptor in a strain of sexlinked dwarf-chicken: Evidence for a mutation in the intracellular domain. J. Endocrinol. 142:427–434. Allander, S. V., M. Coleman, H. Luthman, and D. R. Powel, 1997. Chicken insulin-like growth factor binding protein (IGFBP)-5: Conservation of IGFBP-5 structure and expression during evolution. Comp. Biochem. Physiol. 116B: 477–483. Argetsinger, L. S., G. S. Campbell, X. Yang, B. A. Witthuhn, O. Silvennoinen, J. N. Ihle, and C. Carter-Su, 1993. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 74:237–244.

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In Vivo Muscle Responses to GH in Poultry

poultry, with limited exception it has not been possible to demonstrate enhanced muscle deposition in response to GH in vivo in normal, growing, pituitary-intact birds. If an endocrine route for the IGF-I-mediated effects of GH on muscle does function endogenously in poultry, and there is sufficient evidence that exogenous GH binds to hepatic receptors and induces IGF-I gene and protein expression, then the central question becomes why circulating concentrations are not ultimately enhanced. In that case, issues such as mechanism(s) for release of IGF-I into the circulation, IGF-I clearance rates under exogenous GH regimens, profiles of circulating, extracellular free and cell surface-associated IGFBP in response to GH, and threshold levels of hepatic IGF-I necessary to provoke detectable increases in circulating IGF-I become needed areas for exploration. In addition to its growth-promoting effects via IGF-I, GH has known direct metabolic effects (detectable through changes in circulating levels of hormones such as insulin, glucagon, thyroid hormones, and of metabolites). The possibility that one or more of these metabolic changes may impact on IGF-I release and action in poultry is an additional area that should be considered. It has been suggested that broilers are close to their maximum genetic potential for growth, and that this limits any further benefit of supplemental GH. However, the inability of exogenous GH to improve growth performance even in slow-growing, randombred meat-type chickens demonstrates that this is not the case (Peebles et al. 1988). It is the opinion of this author that GH plays an important and complex role in avian posthatch growth, but that the intricacies of how GHIGF-I growth-promoting effects are regulated must be understood before the riddle of why exogenous GH fails to induce muscle growth in poultry is solved.

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