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Endocrinology. 2011 Jan; 152(1): 172–180.
Published online 2010 Dec 8. doi:  10.1210/en.2010-0488
PMCID: PMC3219050

Endocrine Actions of Myostatin: Systemic Regulation of the IGF and IGF Binding Protein Axis


Myostatin’s inhibitory actions on striated muscle growth are believed to be directly mediated by locally produced myostatin and possibly by IGF binding proteins (IGFBPs). We therefore measured skeletal muscle, heart, and liver expression, in neonates and adults, and circulating levels of various IGF axis components (IGF-I, IGFBP-1 to IGFBP-3, and acid labile subunit) in wild-type and mstn−/− mice. Compared with wild type, differences in muscle expression were tissue specific, although IGF-I receptor expression was higher in all mstn−/− neonatal tissues and in adult gastrocnemius. Liver expression of several components also differed between genotype as IGF-I receptor, IGFBP-3 and IGFBP-5 expression was higher in mstn−/− neonates and IGF-I and IGFBP-3 in adults. Circulating IGF-I levels were also higher in mstn−/− adults, whereas IGFBP-1 and IGFBP-2 levels were lower. Comparing IGF-I:IGFBP molar ratios suggested that the relative IGF-binding capacity was potentially lower in mstn−/− mice, and thus, total and “free” IGF-I levels may be elevated. This in turn may increase negative feedback control on GH, because mstn−/− liver weights were lower. Bone growth was similar in both genotypes, suggesting that changes in circulating IGF-I may be more important to muscle, whose mass is enhanced in mstn−/− mice, than to bone. Myostatin receptors, but not myostatin itself, are expressed in the liver. Changes in hepatic production of circulating IGF axis components could therefore result from the loss of endocrine myostatin. Thus, myostatin may inhibit striated muscle growth directly at the cellular level and indirectly through systemic effects on the IGF axis.


Hepatic production, circulating levels and bioavailability of IGF-I are elevated in myostatin null mice suggesting that the muscle-specific factor functions as a hormone.

The extreme muscularity and cardiac physiological hypertrophy associated with a myostatin null phenotype is believed to result from the loss of the myokine’s direct effects on muscle development and on different growth processes. These include myoblast proliferation and differentiation and myotube protein synthesis (1,2). However, it may also involve systemic interactions, because myostatin is readily detected in circulation at concentrations that exceed its bioeffectiveness in vitro (3,4). Zimmers et al. (3) also demonstrated that the systemic administration of myostatin, through the sc implantation of CHO cell tumors overexpressing myostatin, both increases circulating myostatin and decreases skeletal muscle mass, suggesting that locally produced myostatin may not be the sole means of controlling striated muscle development. Nevertheless, systemic responses to myostatin ablation have not been described to date, and the relative contribution of endocrine vs. autocrine myostatin to these processes is still unknown.

In contrast to myostatin, the IGF-I and IGF-II stimulate striated muscle growth and development (5,6). Several studies also suggest that myostatin and the IGFs interact at many levels to coordinate these processes. These include the differential regulation of intracellular signaling pathways (7,8,9,10,11), as well as the expression of IGF binding protein (IGFBP)-3 and IGFBP-5 (12). In fact, the inhibitory effects of myostatin or TGFβ on myoblast proliferation are mediated in part by these IGFBPs and are attenuated when IGFBP-3 is immunoneutralized (13,14). Furthermore, nuclear localization of IGFBP-3, which itself is associated with myoblast growth inhibition (15,16), is stimulated by TGFβ (17). We therefore hypothesized that the muscle growth inhibitory actions of myostatin, whether from autocrine or endocrine sources, may be mediated in part by attenuating aspects of the IGF axis.

Our study suggests that myostatin influences the expression of several IGF axis components in different skeletal muscle groups and in the heart. More importantly, however, it suggests that circulating myostatin influences the hepatic production of these components that in turn may influence striated muscle growth. Thus, myostatin regulates cardiac and skeletal muscle development directly and possibly by controlling the systemic production and bioavailability of the IGFs as well as tissue sensitivity to these growth factors.

Materials and Methods


C57 BL/6 wild-type (WT) and myostatin null (mstn−/−) mice were housed and bred in the Experimental Animal Laboratory Building, Washington State University, in environmentally controlled rooms with 12-h daily light. They were fed ad libitum and were used in strict accordance to protocols preapproved by the Institutional Animal Care and Use Committee of Washington State University.

Quantifying expression and circulating levels of IGF axis components

Total RNA was isolated from the following WT and mstn−/− mouse tissues: neonatal (day of birth) heart, liver, and leg skeletal muscle and adult (7 month old) heart, liver, and skeletal muscle (gastrocnemius and pectoralis). Extractions were performed with Trizol (Invitrogen, Carlsbad, CA) according to the manufacturers protocols, and RNA quality was verified by agarose gel electrophoresis. After deoxyribonuclease I (Ambion, Inc., Austin, TX) treatment, cDNA was synthesized with 0.5 μg total RNA, oligo d(T)18 primers, and the SuperScript III First-Strand Synthesis System (Invitrogen). Samples were diluted individually into iQ SYBR Green Supermix stocks before aliquoting in duplicate and adding the primers (400 nm final concentration for each) (Table 11).). Glyceraldehyde-3-phosphate dehydrogenase was used as a reference gene for skeletal muscle and liver, whereas β-actin was used for cardiac muscle. Amplicons were subjected to melt curve analysis and agarose gel electrophoresis to determine specificity and to check for genomic DNA contamination. An iCycler iQ Real-Time PCR Detection System (Bio-Rad, Hercules, CA) was used to amplify samples for 50 cycles of the following: 94 C for 30 sec, 55 C for 30 sec, and 72 C for 30 sec.

Table 1
Primer sequences and annealing temperatures

Circulating levels of IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 and the acid labile subunit (ALS) were determined using homologous ELISAs. Validation of the IGF-I, IGFBP-3, and ALS assays were previously described (18). The IGFBP-1 assay was constructed using capture and detection antibodies (MAB 1240 and BAF 1240, respectively) and recombinant mouse IGFBP-1, all from R&D Systems (Minneapolis, MN). No cross-reactivity to human GH, insulin, IGF-I, IGF-II, or IGFBP-1, IGFBP-2, IGFBP-3, or IGFBP-4 was detected. Similarly, no cross-reactivity was detected with mouse IGF-I, IGF-II, or IGFBP-2 or IGFBP-3. Assay sensitivity was 0.1–25 ng/ml with intra- and interassay variations of less than 5 and less than 10%, respectively. The IGFBP-2 assay was also constructed with R&D reagents (MAB 7971 for capture, BAF 797 for detection), and specificity was similarly validated against the same human and mouse proteins. Assay sensitivity was 0.2–25 ng/ml with intra- and interassay variations of less than 5 and less than 10%, respectively.

Tibia epiphyseal plate width measurement

Tibia were removed, cleaned of muscle, and immersed in distilled deionized H2O. Two cuts parallel to the bone and across the lateral and medial condyles were then performed with a razor blade to expose the epiphyseal plates. Bones were then dehydrated by immersion in acetone for 45–60 min and stained in freshly made 1.5% AgNO3 for 1 min followed by a 10-sec exposure to strong light, all as described (19). Stained tibias were stored in 70% ethanol before visualization at ×100.

Statistical analysis

Levels of gene expression were quantified using the Q-Gene method (20). Differences between means were determined by an ANOVA coupled to Fisher’s projected least significant difference test or by a student’s t test when appropriate, and statistical significance is defined as P ≤ 0.05.


Skeletal muscle expression

Growth of fetal tissues in utero is largely controlled by IGF-II, not IGF-I (21), which is consistent with higher IGF-II expression in all neonatal tissues examined (Figs. 1–3,, A). In both WT and mstn−/− mice, muscle expression of IGF-I, IGF-I receptor (IGF1R), and IGFBP-3 was higher in neonates than adults, and the relative differences (i.e. general patterns) between muscle groups were similar (Fig. 1A1A).). However, IGFIR and IGFBP-3 expression was higher in skeletal muscle from mstn−/− neonates, and IGFIR and IGFBP-5 expression was higher in the gastrocnemius of mstn−/− adults (Fig. 1B1B),), a mixed muscle type with approximately 33% oxidative fibers (type I or IIA) (22). IGF-I expression was surprisingly lower in gastrocnemius (P ≤ 0.05) and pectoralis (not significant) of mstn−/− adults, although the significance of this is questionable, considering the very low absolute levels of expression, especially compared with the 10-fold or higher expression levels of IGFBP-3 and IGFBP-5 (Fig. 1A1A).). By contrast, the only difference between WT and mstn−/− pectoralis, a predominantly type II glycolytic muscle, was a lower IGFBP-3 expression in mstn−/− mice (Fig. 1B1B).). The IGF axis, therefore, appears to be differentially regulated by myostatin in these muscle groups.

Figure 1
Skeletal muscle expression of IGF/IGFBP axis components in WT and myostatin null (mstn−/−) mice. Gene expression was quantified using “real-time” RT-PCR and RNA isolated from skeletal muscle (SM) of neonatal legs and adult ...
Figure 2
Cardiac muscle expression of IGF/IGFBP axis components in WT and myostatin null (mstn−/−) mice. Gene expression was quantified using “real-time” RT-PCR and RNA isolated from neonatal and adult hearts. All samples were run ...
Figure 3
Liver expression of IGF/IGFBP axis components in WT and myostatin null (mstn−/−) mice. Gene expression was quantified using “real-time” RT-PCR and RNA isolated from neonatal and adult hearts. All samples were run in duplicate, ...

Heart expression

Unlike skeletal muscle, IGF-I expression was similar in neonatal and adult hearts of both WT and mstn−/− mice (Fig. 2A2A).). This suggests that although IGF-I expression tapers with age in skeletal muscle, its role in cardiac muscle is maintained. Levels of IGF1R and IGFBP-3 and IGFBP-5 were significantly higher in neonates of both WT and mstn−/− mice, and the relative differences between neonates and adults were similar. However, neonatal IGF-II and IGF1R expression was higher in mstn−/− than WT hearts, whereas the lower IGF1R expression in adult mstn−/− hearts was the only noted difference among adults (Fig. 2B2B).

Liver expression and circulating levels

Although myostatin circulates, direct evidence of endogenous endocrine action has not been demonstrated. We therefore measured the expression of “muscle relevant” IGF axis components in the liver, because it does not express myostatin. We also measured circulating levels for some of these factors. The relative differences in expression varied between WT and mstn−/− mice, because IGF1R and IGFBP-3 and IGFBP-5 were all higher in mstn−/− neonates compared with adults, although expression was similar in WT neonates and adults (Fig. 3A3A).). This was due to significantly higher levels of neonatal IGF1R and IGFBP-3 and IGFBP-5 expression in mstn−/− livers (Fig. 3B3B)) rather than to lower expression in adult mstn−/− livers. In adults, expression of IGF-I and IGFBP-3 in mstn−/− livers was higher than in WT livers. These results together suggest, for the first time, that endocrine myostatin negatively regulates the hepatic expression of IGF-I and other IGF axis components in neonatal and adult livers.

The liver is the primary source of circulating IGF-I, the IGFBPs 1 to 3 and the ALS, which stabilizes the tertiary complex composed of an IGF, IGFBP-3 or IGFBP-5, and the ALS (23). Differences in the hepatic expression of some IGF axis components imply that circulating levels for these or other components may also be altered. Indeed, the IGF-I concentration was approximately 50% higher in mstn−/− adults, whereas those for IGFBP-1 and IGFBP-2 were reduced by 67 and 30%, respectively (Table 22).). Expressing the molar concentrations of each IGFBP and the ALS to that of IGF-I suggests that the putative IGF-binding capacity of mstn−/− serum may have been reduced when compared with that of WT serum. For example, WT concentrations of IGFBP-1 and IGFBP-2 were 1 and 39%, respectively, of WT IGF-I, whereas they were only 0.2 and 19% of the mstn−/− IGF-I concentrations. Thus, the relative level of “free” IGF-I is higher in mstn−/− mice. The reduction in IGFBP-1 is particularly noteworthy, because the actions of this specific IGFBP are purely antagonistic and are associated with catabolic states.

Table 2
Circulating levels of IGF axis components

Bone growth and liver weights

Differences in body and heart weights between WT and mstn−/− mice are not readily distinguished until approximately 100 d of age, and both are significantly smaller in mstn−/− neonates (2). Thus, these differences develop postnatally as IGF-I hepatic expression and circulating levels rise. The increased systemic tone of the IGF axis could therefore have influenced the growth of nonmuscle tissues in mstn−/− mice. Measurements of aggregate bone growth, tail length, and tibia length, as well as an indicator of bone growth rate, the tibial epiphyseal plate width, were identical in WT and mstn−/− mice of different ages (Fig. 44,, A–C). Thus, the noted differences in striated muscle mass and systemic IGF tone were not accompanied by changes in bone growth. However, they were associated with lower liver weights in mstn−/− mice of various ages (Fig. 4D4D).). This is consistent with the negative feedback role of hepatic-produced IGF-I on circulating GH, which in turn regulates liver size (24). Due to asymmetric muscle growth in mstn−/− mice, tibia length, or tail length, rather than body weight, were used to normalize liver weights. These results, however, did not differ from nonnormalized data.

Figure 4
Bone and liver growth in WT and mstn−/− mice. Tail length (A), tibial length (B), tibial epiphyseal plate width (TEPW) (C), and liver weight (D) were measured in WT and mstn−/− mice of different ages. Only the lines in ...


Previous studies noted that the relative difference in mass between the glycolytic type II muscle groups of WT and mstn−/− mice is greater than that of oxidative type I and that myostatin inhibits development of the former group (25,26,27). Our studies demonstrate that expression of IGF axis components (see Table 33)) differs significantly between oxidative (gastrocnemius) and glycolytic (pectoralis) muscles, although it is difficult to determine whether this contributed to the differential growth of fiber types in mstn−/− mice. Nevertheless, our results suggest that myostatin differentially regulates the expression of IGF axis components in each muscle group.

Table 3
Differences in mRNA levels of IGF axis components

General patterns of expression were similar in neonates and adults of both genetic backgrounds. Thus, the relative changes that normally occur with age also occur in mstn−/− mice. The expression of IGF1R was, in general, higher in mstn−/− tissues, suggesting that increased IGF tissue sensitivity, but not local IGF-I expression per se, may contribute to the rapid striated muscle growth that occurs in young mstn−/− mice (Fig. 44)) (2). This rapid growth could result from increased myosatellite cell proliferation (28,29) or from increased protein synthesis, because IGF-I stimulates both. Contributions of myosatellite cells remain controversial, however, as Amthor et al. (30) suggest that postnatal muscle growth in mstn−/− mice is influenced primarily by increased protein synthesis.

Relative expression patterns in skeletal vs. cardiac muscle were similar in neonates but not adults, suggesting that myostatin’s age-dependent regulation of IGF axis components differs between muscle types. The 50 and 200% higher IGF-II and IGF1R expression levels, respectively, in neonatal hearts of mstn−/− mice could have contributed to the cardiac hypertrophy that develops postnatally (2). By contrast, the only significant difference between mstn−/− and WT adult hearts was a slightly lower IGF1R expression in mstn−/− hearts. It is unlikely, therefore, that alterations in locally produced IGF axis components help to maintain cardiac muscle hypertrophy in adult mstn−/− mice. Local and circulating IGF-I both contribute to physiological hypertrophy of the heart (31,32,33), which requires a functional IGF1R (34). We therefore measured hepatic expression and circulating levels of muscle-relevant IGF axis components.

The noted differences in hepatic expression and/or circulating levels of different IGF axis components are consistent with anabolic growth. This includes increased levels of circulating IGF-I and decreased levels of IGFBP-1 and IGFBP-2, the “catabolic IGFBPs,” and a putative reduction in serum IGF-binding capacity (Table 22).). Most importantly, this is the first evidence of endogenous myostatin having true endocrine function. It is also consistent with the systemic administration of myostatin stimulating cachexia (3) and suggests a novel role for the myokine: the negative regulation of circulating IGF-I and tissue IGF sensitivity. Indicators of skeletal growth were unaffected by the approximately 50% increase in serum IGF-I. This is not surprising, because several studies indicate that bone growth is far more dependent upon local rather than hepatic IGF-I production (24). By contrast, liver weights were smaller in mstn−/− mice. This is consistent with elevated serum IGF-I and negative feedback control of pituitary GH, which in turn controls liver size, not IGF-I (24,35,36).

The liver expresses high levels of myostatin/activin receptors and provides a potential feedback loop between striated muscle, which secretes myostatin, and the liver, which maintains circulating IGF-I (24). The several differences in hepatic expression of IGF axis components, among WT and mstn−/− neonates and adults, indicate that endocrine myostatin regulates the IGF axis at different developmental stages. It also suggests that circulating IGF-I may be more important to the growth of muscle than bone. In fact, linear bone growth is uncompromised even with 65–75% reductions in circulating IGF-I (37), whereas by contrast, circulating IGF-I and striated muscle growth are highly correlated (31,32,38). Increasing hepatic production and circulating IGF-I by 54%, similar to the increase reported herein, had no effect on bone growth but increased skeletal and cardiac muscle mass by 33 and 15%, respectively (39). Thus, the “double-muscled” mstn−/− phenotype likely develops from the loss of myostatin’s direct effects on striated muscle as well as its indirect effects on hepatic IGF-I production.

Changes in IGF-I bioavailability may be equally important to changes in circulating levels as Yakar et al. (40) demonstrated that total IGF-I may not necessarily correspond to changes in growth. However, IGF-I distribution between binary and ternary complexes was identical in control and igfbp3−/− mice despite enhanced growth and reduced total IGF-I in the latter. In fact, body, liver, and muscle weights were all increased as with mstn−/− mice, although not to the same degree. This indicates that IGF-I partitioning between specific IGF:IGFBP complexes, not just between binary and ternary, regulates IGF biological activity. It also suggests that growth is enhanced with increased free IGF-I or in the IGF-I:IGFBP-3 ratio. These results are similar to those presented here, because the estimated binding capacity of mstn−/− serum is reduced compared with WT serum, whereas growth and the IGF-I:IGFBP-3 ratio are both elevated. Thus, changes in IGFBP production and IGF bioavailability may help mediate myostatin’s effects on striated muscle growth.

Organismal growth is largely influenced by GH-stimulated IGF-I production in the liver (Fig. 5A5A),), which in turn regulates somatic tissue growth (41,42). Several recent studies, especially those using transgenic and knockout mice (e.g. liver IGF-I deficient mice, IGFBP or ALS null mice, etc.), question the relative significance of circulating IGF-I and suggest alternatively that local IGF-I production has a more substantial impact on growth (43). Our study indicates that hepatic production and bioavailability of IGF-I is enhanced in mstn−/− mice (Fig. 5B5B).). Thus, we hypothesize that endocrine myostatin negatively regulates hepatic IGF-I production. This is supported by the fact that muscle expresses comparatively very low levels of GH receptors (44,45,46), regardless of species, which reflects the tissue’s partial reliance on circulating IGF-I and the potential need to control it. GH may also inhibit myostatin protein expression (47,48), whereas conversely, myostatin down-regulation of hepatic IGF-I would presumably attenuate the negative feedback control on GH. In fact, activin and myostatin share receptors and activin inhibits GH release and somatotrope proliferation via Pit-1 activation (49,50). Myostatin may therefore additionally regulate the GH/IGF axis by directly modulating pituitary GH release and/or synthesis.

Figure 5
Myostatin and control of the systemic IGF/IGFBP axis. A, In the somatomedin model of growth regulation, pituitary GH stimulates the synthesis and release of IGF-I in the liver and in peripheral tissues. IGF-I in turn activates different growth processes ...

The endocrine phenotype described could have arisen from pleiotropic and indirect effects of developing in a mstn−/− environment. We believe this unlikely because myostatin freely circulates (3,4), its ectopic administration has systemic effects (3,51,52), and its receptors are expressed in the liver (53,54). Furthermore, overexpressing an activin reduces organismal growth and hepatic expression and circulating levels of IGF-I (53,55). Future studies are nevertheless needed to determine whether myostatin directly effects hepatic and pituitary production of these components (Fig. 5C5C).). The autocrine effects of myostatin are well documented (1) and are likely to be the primary means of myostatin action on striated muscle. Our results support the notion, however, that myostatin is a legitimate endocrine factor, because removing it or administering it systemically induces physiological responses in nonmuscle tissues. They also suggest that it may contribute to the homeostatic regulation of the GH/IGF-I axis that may include direct effects on the liver.


This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR051917 and by the National Science Foundation Grant 0840644 (to B.D.R.).

Disclosure Summary: The authors have nothing to disclose.

First Published Online December 8, 2010

Abbreviations: ALS, Acid labile subunit; IGF1R, IGF-I receptor; IGFBP, IGF binding protein; WT, wild type.


  • Rodgers BD, Garikipati DK 2008 Clinical, agricultural, and evolutionary biology of myostatin: a comparative review. Endocr Rev 29:513–534 [PMC free article] [PubMed]
  • Rodgers BD, Interlichia JP, Garikipati DK, Mamidi R, Chandra M, Nelson OL, Murry CE, Santana LF 2009 Myostatin represses physiological hypertrophy of the heart and excitation-contraction coupling. J Physiol 587:4873–4886 [PMC free article] [PubMed]
  • Zimmers TA, Davies MV, Koniaris LG, Haynes P, Esquela AF, Tomkinson KN, McPherron AC, Wolfman NM, Lee SJ 2002 Induction of cachexia in mice by systemically administered myostatin. Science 296:1486–1488 [PubMed]
  • Souza TA, Chen X, Guo Y, Sava P, Zhang J, Hill JJ, Yaworsky PJ, Qiu Y 2008 Proteomic identification and functional validation of activins and bone morphogenetic protein 11 as candidate novel muscle mass regulators. Mol Endocrinol 22:2689–2702 [PubMed]
  • Adams GR 2002 Invited Review: autocrine/paracrine IGF-I and skeletal muscle adaptation. J Appl Physiol 93:1159–1167 [PubMed]
  • Catalucci D, Latronico MV, Ellingsen O, Condorelli G 2008 Physiological myocardial hypertrophy: how and why? Front Biosci 13:312–324 [PubMed]
  • Amirouche A, Durieux AC, Banzet S, Koulmann N, Bonnefoy R, Mouret C, Bigard X, Peinnequin A, Freyssenet D 2009 Down-regulation of Akt/mammalian target of rapamycin signaling pathway in response to myostatin overexpression in skeletal muscle. Endocrinology 150:286–294 [PubMed]
  • Frost RA, Lang CH 2007 Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass. J Appl Physiol 103:378–387 [PubMed]
  • Leger B, Derave W, De Bock K, Hespel P, Russell AP 2008 Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylation. Rejuvenation Res 11:163B–175B [PubMed]
  • Morissette MR, Cook SA, Foo S, McKoy G, Ashida N, Novikov M, Scherrer-Crosbie M, Li L, Matsui T, Brooks G, Rosenzweig A 2006 Myostatin regulates cardiomyocyte growth through modulation of Akt signaling. Circ Res 99:15–24 [PMC free article] [PubMed]
  • Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ 2009 Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol 296:C1258–C1270 [PubMed]
  • Dayton WR, White ME 2008 Cellular and molecular regulation of muscle growth and development in meat animals. J Anim Sci 86:E217–E225 [PubMed]
  • Kamanga-Sollo E, Pampusch MS, White ME, Hathaway MR, Dayton WR 2005 Insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5 mediate TGF-β- and myostatin-induced suppression of proliferation in porcine embryonic myogenic cell cultures. Exp Cell Res 311:167–176 [PubMed]
  • Kamanga-Sollo E, Pampusch MS, White ME, Dayton WR 2003 Role of insulin-like growth factor binding protein (IGFBP)-3 in TGF-β- and GDF-8 (myostatin)-induced suppression of proliferation in porcine embryonic myogenic cell cultures. J Cell Physiol 197:225–231 [PubMed]
  • Oufattole M, Lin SW, Liu B, Mascarenhas D, Cohen P, Rodgers BD 2006 Ribonucleic acid polymerase II binding subunit 3 (Rpb3), a potential nuclear target of insulin-like growth factor binding protein-3. Endocrinology 147:2138–2146 [PubMed]
  • Weinzimer SA, Gibson TB, Collett-Solberg PF, Khare A, Liu B, Cohen P 2001 Transferrin is an insulin-like growth factor-binding protein-3 binding protein. J Clin Endocrinol Metab 86:1806–1813 [PubMed]
  • Xi G, Hathaway MR, White ME, Dayton WR 2007 Localization of insulin-like growth factor (IGFBP)-3 in cultured porcine embryonic myogenic cells before and after TGF-β1 treatment. Domest Anim Endocrinol 33:422–429 [PubMed]
  • Hwang DL, Lee PD, Cohen P 2008 Quantitative ontogeny of murine insulin-like growth factor (IGF)-I, IGF-binding protein-3 and the IGF-related acid-labile subunit. Growth Horm IGF Res 18:65–74 [PMC free article] [PubMed]
  • Interlichia JP, Williams NG, Rodgers BD 2010 A rapid, valid and inexpensive assay for measuring epiphyseal plates in mouse tibia. GH IGF Res 20:171–173 [PMC free article] [PubMed]
  • Muller PY, Janovjak H, Miserez AR, Dobbie Z 2002 Processing of gene expression data generated by quantitative real-time RT-PCR. Biotechniques 32:1372–1374, 1376, 1378–1379 [PubMed]
  • Roberts CT, Owens JA, Sferruzzi-Perri AN 2008 Distinct actions of insulin-like growth factors (IGFs) on placental development and fetal growth: lessons from mice and guinea pigs. Placenta 29(Suppl A):S42–S47 [PubMed]
  • Delp MD, Duan C 1996 Composition and size of type I, IIA, IID/X, and IIB fibers and citrate synthase activity of rat muscle. J Appl Physiol 80:261–270 [PubMed]
  • Firth SM, Baxter RC 2002 Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824–854 [PubMed]
  • Ohlsson C, Mohan S, Sjögren K, Tivesten A, Isgaard J, Isaksson O, Jansson JO, Svensson J 2009 The role of liver-derived insulin-like growth factor-I. Endocr Rev 30:494–535 [PMC free article] [PubMed]
  • Girgenrath S, Song K, Whittemore LA 2005 Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle. Muscle Nerve 31:34–40 [PubMed]
  • McPherron AC, Lawler AM, Lee SJ 1997 Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387:83–90 [PubMed]
  • Hennebry A, Berry C, Siriett V, O'Callaghan P, Chau L, Watson T, Sharma M, Kambadur R 2009 Myostatin regulates fiber-type composition of skeletal muscle by regulating MEF2 and MyoD gene expression. Am J Physiol Cell Physiol 296:C525–C534 [PubMed]
  • McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R 2003 Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol 162:1135–1147 [PMC free article] [PubMed]
  • McCroskery S, Thomas M, Platt L, Hennebry A, Nishimura T, McLeay L, Sharma M, Kambadur R 2005 Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice. J Cell Sci 118:3531–3541 [PubMed]
  • Amthor H, Otto A, Vulin A, Rochat A, Dumonceaux J, Garcia L, Mouisel E, Hourdé C, Macharia R, Friedrichs M, Relaix F, Zammit PS, Matsakas A, Patel K, Partridge T 2009 Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity. Proc Natl Acad Sci USA 106:7479–7484 [PMC free article] [PubMed]
  • Colao A 2008 The GH-IGF-I axis and the cardiovascular system: clinical implications. Clin Endocrinol 69:347–358 [PubMed]
  • Climent V, Marín F, Picó A 2007 Pharmacologic therapy in growth hormone disorders and the heart. Curr Med Chem 14:1399–1407 [PubMed]
  • Pérez-Berbel P, Climent VE, Picó A, Marin F 2008 Short- and long-term effects of growth hormone on the heart. Int J Cardiol 124:393–394 [PubMed]
  • Kim J, Wende AR, Sena S, Theobald HA, Soto J, Sloan C, Wayment BE, Litwin SE, Holzenberger M, LeRoith D, Abel ED 2008 Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol Endocrinol 22:2531–2543 [PMC free article] [PubMed]
  • Zindy F, Lamas E, Schmidt S, Kirn A, Brechot C 1992 Expression of insulin-like growth factor II (IGF-II) and IGF-II, IGF-I and insulin receptors mRNAs in isolated non-parenchymal rat liver cells. J Hepatol 14:30–34 [PubMed]
  • Villafuerte BC, Koop BL, Pao CI, Gu L, Birdsong GG, Phillips LS 1994 Coculture of primary rat hepatocytes and nonparenchymal cells permits expression of insulin-like growth factor binding protein-3 in vitro. Endocrinology 134:2044–2050 [PubMed]
  • Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D 2002 Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 110:771–781 [PMC free article] [PubMed]
  • Velloso CP 2008 Regulation of muscle mass by growth hormone and IGF-I. Br J Pharmacol 154:557–568 [PMC free article] [PubMed]
  • Liao L, Dearth RK, Zhou S, Britton OL, Lee AV, Xu J 2006 Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency. Endocrinology 147:3877–3888 [PubMed]
  • Yakar S, Rosen CJ, Bouxsein ML, Sun H, Mejia W, Kawashima Y, Wu Y, Emerton K, Williams V, Jepsen K, Schaffler MB, Majeska RJ, Gavrilova O, Gutierrez M, Hwang D, Pennisi P, Frystyk J, Boisclair Y, Pintar J, Jasper H, Domene H, Cohen P, Clemmons D, LeRoith D 2009 Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. FASEB J 23:709–719 [PMC free article] [PubMed]
  • Daughaday WH, Hall K, Raben MS, Salmon WJ, Brande JL, van, den, Wyk Jv 1972 Somatomedin: proposed designation for sulphation factor. Nature 235 [PubMed]
  • Kaplan SA, Cohen P 2007 The somatomedin hypothesis 2007: 50 years later. J Clin Endocrinol Metab 92:4529–4535 [PubMed]
  • LeRoith D 2008 Clinical relevance of systemic and local IGF-I: lessons from animal models. Pediatr Endocrinol Rev 5(Suppl 2):739–743 [PubMed]
  • Hill DJ, Freemark M, Strain AJ, Handwerger S, Milner RD 1988 Placental lactogen and growth hormone receptors in human fetal tissues: relationship to fetal plasma human placental lactogen concentrations and fetal growth. J Clin Endocrinol Metab 66:1283–1290 [PubMed]
  • Frick GP, Tai LR, Baumbach WR, Goodman HM 1998 Tissue distribution, turnover, and glycosylation of the long and short growth hormone receptor isoforms in rat tissues. Endocrinology 139:2824–2830 [PubMed]
  • Hirano T 1991 Hepatic receptors for homologous growth hormone in the eel. Gen Comp Endocrinol 81:383–390 [PubMed]
  • Liu W, Thomas SG, Asa SL, Gonzalez-Cadavid N, Bhasin S, Ezzat S 2003 Myostatin is a skeletal muscle target of growth hormone anabolic action. J Clin Endocrinol Metab 88:5490–5496 [PubMed]
  • Oldham JM, Osepchook CC, Jeanplong F, Falconer SJ, Matthews KG, Conaglen JV, Gerrard DF, Smith HK, Wilkins RJ, Bass JJ, McMahon CD 2009 The decrease in mature myostatin protein in male skeletal muscle is developmentally regulated by growth hormone. J Physiol 587:669–677 [PMC free article] [PubMed]
  • Childs GV, Unabia G 1997 Cytochemical studies of the effects of activin on gonadotropin-releasing hormone (GnRH) binding by pituitary gonadotropes and growth hormone cells. J Histochem Cytochem 45:1603–1610 [PubMed]
  • Gaddy-Kurten D, Vale WW 1995 Activin increases phosphorylation and decreases stability of the transcription factor Pit-1 in MtTW15 somatotrope cells. J Biol Chem 270:28733–28739 [PubMed]
  • Artaza JN, Reisz-Porszasz S, Dow JS, Kloner RA, Tsao J, Bhasin S, Gonzalez-Cadavid NF 2007 Alterations in myostatin expression are associated with changes in cardiac left ventricular mass but not ejection fraction in the mouse. J Endocrinol 194:63–76 [PubMed]
  • Reisz-Porszasz S, Bhasin S, Artaza JN, Shen R, Sinha-Hikim I, Hogue A, Fielder TJ, Gonzalez-Cadavid NF 2003 Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin. Am J Physiol Endocrinol Metab 285:E876–E888 [PubMed]
  • Brown CW, Li L, Houston-Hawkins DE, Matzuk MM 2003 Activins are critical modulators of growth and survival. Mol Endocrinol 17:2404–2417 [PubMed]
  • Coerver KA, Woodruff TK, Finegold MJ, Mather J, Bradley A, Matzuk MM 1996 Activin signaling through activin receptor type II causes the cachexia-like symptoms in inhibin-deficient mice. Mol Endocrinol 10:534–543 [PubMed]
  • Brown CW, Houston-Hawkins DE, Woodruff TK, Matzuk MM 2000 Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nat Genet 25:453–457 [PubMed]

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