Published November 24, 2014

MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM—

Mechanism of growth hormone stimulation of skeletal muscle growth in cattle1
H. Jiang*2 and X. Ge*
*Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg 24060

ABSTRACT: Growth hormone, also called somato-
tropin (ST), is a polypeptide hormone produced by the
anterior pituitary. The major functions of GH include
stimulating bone and skeletal muscle growth, lipolysis,
milk production, and expression of the IGF-I gene in the
liver. Based on these functions, recombinant bovine ST
(bST) and recombinant porcine ST (pST) have been used
to improve milk production in dairy cows and lean tis-
sue growth in pigs, respectively. However, despite these
applications, the mechanisms of action of GH are not ful-
ly understood. Indeed, there has been a lot of controversy
over the role of liver-derived circulating IGF-I and local-
ly produced IGF-I in mediating the growth-stimulatory
effect of GH during the last 15 yr. It is in this context
that we have conducted studies to further understand
how GH stimulates skeletal muscle growth in cattle. Our
results do not support a role of skeletal muscle-derived
IGF-I in GH-stimulated skeletal muscle growth in cattle.
Our results indicate that GH stimulates skeletal muscle
growth in cattle, in part, by stimulating protein synthesis
in muscle through a GH receptor-mediated, IGF-I-inde-
pendent mechanism. In this review, besides discussing
these results, we also argue that liver-derived circulating
IGF-I should be still considered as the major mechanism
that mediates the growth-stimulatory effect of GH on
skeletal muscle in cattle and other domestic animals.

Key words: growth hormone, insulin-like growth factor I, cattle, skeletal muscle, liver, satellite cells

© 2014 American Society of Animal Science. All rights reserved. J. Anim. Sci. 2014.92:21–29
doi:10.2527/jas2013-7095
INTRODUCTION
Growth hormone, also called somatotropin (ST),
is a hormone produced by the anterior pituitary. The
best characterized function of GH is stimulating bone
and skeletal muscle growth. The presence of GH in
the body was first indicated by the observation that
chronic injection of a crude extract from bovine pitu-
itaries resulted in gigantism in rats (Evans and Simp-
son, 1931). It is now known that GH is essential for
postnatal growth (Cannata et al., 2010). Mice lacking
GH (Beamer and Eicher, 1976) or its receptor (GHR;
Zhou et al., 1997) are 50% smaller than their wild-
type littermates. Deficiency of GH causes dwarfism in
children (Dattani and Preece, 2004). Administration
of GH to growing pigs increases ADG by 10 to 20%
(Etherton, 2001). Administration of GH also increases
1A symposium held at the Joint Annual Meeting, July 8–12, 2013,
Indianapolis, IN, with publication sponsored by the Journal of Animal
Science and the American Society of Animal Science.
2Corresponding author: hojiang@vt.edu
Received August 30, 2013.
Accepted October 7, 2013.
21
ADG in cattle (Early et al., 1990; Enright et al., 1990;
Dalke et al., 1992; Moseley et al., 1992; Rumsey et al.,
1996; Samber et al., 1996; Elsasser et al., 1998; Tripp
et al., 1998; Vann et al., 1998; Schlegel et al., 2006) al-
though this increase is generally lesser than that in pigs
(Etherton and Bauman, 1998). Besides stimulating
growth, GH stimulates lipolysis, milk production, and
expression of the IGF-I gene. Based on these functions,
recombinant human GH has been used to promote
growth in GH-deficient children (Dattani and Preece,
2004); recombinant bovine ST (bST) and porcine ST
(pST) have been used to increase milk production in
dairy cows (Bauman, 1999) and lean growth in pigs
(Foster, 1999), respectively. However, despite these
applications, the mechanisms of action of GH are not
fully understood. Indeed, there has been much contro-
versy over the role of liver-derived circulating IGF-I
and locally produced IGF-I in mediating the growth-
stimulatory effect of GH. It is in this context that we
have conducted studies to further understand how GH
stimulates skeletal muscle growth in cattle. The pur-
pose of this review is, therefore, to discuss the results
from these and related studies.
22 Jiang and Ge
BASIC MECHANISM OF GH ACTION:
GH Receptor AND SIGNALING
At the cellular level, GH exerts its action by first
binding to the GHR, a single transmembrane domain-
containing protein (Fig. 1). The GHR mRNA is ex-
pressed in many tissues in cattle, including liver, skel-
etal muscle, fat, and mammary gland, with the greatest
level in liver (Lucy et al., 1998; Jiang et al., 1999; Jiang
and Lucy, 2001b). Transcription of the GHR gene is
initiated from multiple transcription start sites, gener-
ating GHR1A, 1B, and 1C mRNA that differ in the 5′
untranslated region but still encode the same amino acid
sequence (Jiang and Lucy, 2001b). Major bovine GHR
mRNA variants are GHR1A, 1B, and 1C mRNA (Fig. 1).
The GHR1A mRNA is only expressed in the liver (Lucy
et al., 1998). The GHR1B and 1C mRNA are expressed
in a wide array of tissues (Jiang et al., 1999; Jiang and
Lucy, 2001b). Liver-specific expression of GHR1A
mRNA is controlled by liver-enriched transcription fac-
tors hepatocyte nuclear factor 4α (HNF-4α; Jiang and
Lucy, 2001a), HNF-4γ, and chicken ovalbumin up-
stream promoter-transcription factor II (COUP-TFII),
also known as NR2F2 (nuclear receptor subfamily 2,
group F, member 2; Xu et al., 2004). Ubiquitous ex-
pression of the GHR1B and 1C mRNA is controlled, in
part, by the ubiquitously expressed transcription factor
Specificity protein 1 (Jiang et al., 2000). Transcription
of the GHR1A mRNA is also controlled by zinc finger
binding protein 89 (ZBP-89; Xu et al., 2006) and sig-
nal transducer and activator of transcription 5 (STAT5;
Jiang et al., 2007). In humans and rodents, there exists
a GH binding protein (GHBP), which lacks the trans-
membrane domain compared with the GHR and, there-
fore, binds GH in the circulation (Baumann, 2002). The
GHBP is generated from the same gene encoding the
GHR through either alternative splicing or proteolysis,
depending on the species (Baumann, 2002). A GHBP
seems to be present in cattle although its identity has not
been fully characterized (Davis et al., 1992; Devolder et
al., 1993).
The GHR is present in the form of homodimer in the
cell membrane (Brown et al., 2005). Binding of GH to the
GHR activates the tyrosine kinase, Janus kinase 2 (JAK2).
Activated JAK2 phosphorylates several cytoplasmic
substrates, including STAT1, 3, and 5, insulin receptor
substrate (IRS), and Src homologous and collagen-like
protein (SHC), each leading to a signal transduction path-
way that results in changes in gene expression or protein
modification (Herrington et al., 2000; Piwien-Pilipuk et
al., 2002). Of these pathways, the JAK2-STAT5 signal-
ing appears to be the primary pathway that mediates GH
regulation of gene transcription (Waxman and O’Connor,
2006).
Figure 1. Molecular biology of the bovine growth hormone receptor
(GHR). The bovine GHR gene contains 9 coding exons, exons 2 to 10.
Transcription is initiated from multiple exon 1s, generating GHR mRNA
with various 5′ untranslated regions. These GHR mRNA variants differ in
tissue specificity and expression levels but encode the same GHR protein,
which has a single transmembrane domain. Expression of the liver-specific
GHR1A mRNA is controlled by the transcription factors hepatocyte nuclear
factor 4α (HNF-4α), HNF-4γ, and chicken ovalbumin upstream promot-
er-transcription factor II (COUP-TF II), which bind to the same response
element, and signal transducer and activator of transcription 5 (STAT5)
and zinc finger binding protein 89 (ZBP-89). Expression of the ubiquitous
GHR1B and GHR1C mRNA is regulated in part by the transcription factor
Specificity protein 1 (Sp1). See online version for figure in color.
BASIC MECHANISM OF IGF-I ACTION:
IGF-I RECEPTOR AND SIGNALING
Insulin-like growth factor-I is important for both pre-
natal and postnatal growth (Stewart and Rotwein, 1996).
In cattle, the IGF-I gene is expressed in many tissues, ex-
pression being most abundant in the liver. Like the GHR
gene, transcription of the IGF-I gene generates multiple
mRNA variants: class 1 and class 2 IGF-I mRNA. Class
1 IGF-I mRNA contain exon 1 as the lead exon, and class
2 IGF-I mRNA contain exon 2 as the lead exon (Wang et
al., 2003b). The 2 classes of IGF-I mRNA encode the same
mature IGF-I polypeptide but differ in translational effi-
ciency (Wang et al., 2003b). Serum IGF-I concentrations
are high, ranging from 50 to 500 ng/mL in cattle (Nikolic
et al., 2001). Based on liver-specific IGF-I knockout mouse
models, 75% of serum IGF-I is produced by the liver (Sjo-
gren et al., 1999; Yakar et al., 1999). Liver IGF-I mRNA
expression and serum IGF-I concentration are stimulated
by GH (Stewart and Rotwein, 1996) and inhibited by feed
restriction (McGuire et al., 1992; Thissen et al., 1994;
Wang et al., 2003a). In the circulation, more than 80% of
the IGF-I is estimated to be present in ternary complexes
with IGFBP-3 or IGFBP-5 and acid-labile subunit, which
serve to prolong the half-life of IGF-I in blood (Boisclair
et al., 2001). Some circulating IGF-I is present in a bina-
ry complex with 1 of the 6 IGFBP, IGFBP-1 to IGFBP-6.
Only a small percentage (i.e., 5%) of blood IGF-I is present
in the free, biologically active form (Conover et al., 1990;
Rajaram et al., 1997; Boisclair et al., 2001).
There are 3 types of receptors to which IGF-I may
bind: type 1 IGF receptors (IGF-IR), type 2 IGF or
 Growth hormone regulation of muscle growth
Figure 2. Insulin-like growth factor-I signaling pathways in bovine
muscle cells. Both the PI3K/AKT and MEK/ERK pathways are involved in
the stimulatory effects of IGF-I on cell proliferation and protein synthesis
in bovine skeletal muscle cells. The PI3K/AKT pathway also mediates the
inhibitory effect of IGF-I on protein degradation through the transcription
factor FOXO3A. Solid lines indicate direct links while dashed lines depict
indirect connections. Adapted from Ge et al. (2013). IGF-IR, IGF-I receptor;
mTOR, mammalian target of rapamycin; PI3K, phosphoinositide-3-kinase;
AKT, protein kinase B; MEK, mitogen-activated protein kinase kinase; ERK,
extracellular signal-regulated kinase; FOXO3A, forkhead box protein O3;
p70S6K, 70 kDa ribosomal protein S6 kinase 1.
mannose-6 phosphate receptors, and insulin receptors.
Insulin-like growth factor-I binds to the IGF-IR with
much greater affinity than to the other 2 types of recep-
tors (Stewart and Rotwein, 1996; Denley et al., 2005).
The IGF-IR is a transmembrane glycoprotein consist-
ing of 2 alpha subunits, which contain binding sites
for IGF-I, and 2 beta subunits, which possess intrinsic
tyrosine kinase activity (Jacobs et al., 1983; Ullrich
et al., 1986). Binding to the IGF-IR, IGF-I activates
multiple signaling pathways, of which the MEK/ERK
(mitogen-activated protein kinase kinase–extracellular
signal-regulated kinase) pathway and the PI3K/AKT
(phosphoinositide-3-kinase–protein kinase B) pathway
mediate most of the action of IGF-I on cell growth and
metabolism (Adams and McCue, 1998; Menetrey et
al., 2000; Fernandez et al., 2002; Sato et al., 2003). In
bovine muscle cells (Fig. 2), both the MEK/ERK and
PI3K/AKT pathways are involved in the stimulatory
effect of IGF-I on cell proliferation and protein syn-
thesis (Ge et al., 2013). The inhibitory effect of IGF-I
on protein degradation in bovine muscle cells appears
to be solely mediated by the PI3K/AKT pathway (Ge
et al., 2013). The role of these pathways in skeletal
23
Figure 3. Molecular basis of the GH-IGF-I link. Growth hormone
stimulates IGF-I gene transcription in liver by both direct and indirect mecha-
nisms. In the direct mechanism, GH action activates Janus kinase 2 (JAK2),
which phosphorylates the growth hormone receptor (GHR), itself, and the
transcription factor signal transducer and activator of transcription 5 (STAT5).
Phosphorylated STAT5 forms homodimers, which enter the nucleus and bind
to multiple intronic and 5′ distal STAT5 binding sites in the IGF-I gene. Note
that the IGF-I promoter does not contain a STAT5 binding site. In the indi-
rect mechanism, GH directly stimulates the transcription of the hepatocyte
nuclear factor 3γ (HNF-3γ) gene through STAT5, and HNF-3γ in turn binds
to the IGF-I promoter and stimulates its transcription. See online version for
figure in color.
muscle hypertrophy will be discussed in more detail in
a subsequent section.
MOLECULAR BASIS OF THE GH-IGF-I LINK
Although IGF-I was linked to GH more than a half
century ago as the “sulfation factor” to mediate the
growth-stimulatory effect of GH (Salmon and Daughaday,
1957), the molecular basis of this link was not clear until
recently. The effort to dissect the molecular relationship
between GH and IGF-I was hampered by the lack of GH-
responsive, IGF-I-expressing cell lines and the complex-
ity of the relationship. It is now known that GH stimulates
IGF-I production from the liver by stimulating IGF-I gene
transcription primarily through the JAK2-STAT5 signal-
ing pathway (Fig. 3). The GH-activated STAT5 enhances
IGF-I gene transcription through multiple STAT5 binding
sites located in introns or 5′ flanking regions distant from
the transcription start site (Woelfle et al., 2003; Wang and
Jiang, 2005; Chia et al., 2006; Eleswarapu et al., 2008;
Laz et al., 2009; Rotwein, 2012). In addition to direct
action, GH-activated STAT5 indirectly stimulates IGF-I
gene transcription through the transcription factor HNF-
3γ (Eleswarapu et al., 2009). Growth hormone-activated
STAT5 directly induces HNF-3γ expression in the liver
by binding to the HNF-3γ promoter, and the increased
HNF-3γ enhances IGF-I gene transcription by binding
to the IGF-I promoter (Eleswarapu et al., 2009). Because
24 Jiang and Ge
HNF-3γ is a liver-enriched transcription factor, it may
be one of the reasons why IGF-I is expressed at a much
greater level in liver than in other tissues.
BASIC MECHANISM OF POSTNATAL
SKELETAL MUSCLE GROWTH
Skeletal muscle is composed of multinucleated cells
called myofibers. Each myofiber is formed from fusion
of mononuclear cells called myoblasts. Because the total
number of myofibers is determined prenatally for most
species, skeletal muscle growth in postnatal animals re-
sults primarily from myofiber hypertrophy (Oksbjerg et al.,
2004). Postnatal myofiber hypertrophy is the result of in-
creased protein mass and increased number of nuclei (Dha-
wan and Rando, 2005; Bi and Kuang, 2012). Increased
protein mass comes from increased protein synthesis or
reduced protein degradation. New nuclei are provided by
satellite cells (Fig. 4), which are myogenic precursor cells
in adult skeletal muscle and are originally derived from
the central dermomyotome during embryonic develop-
ment (Gros et al., 2005). These cells, characterized by the
expression of Pax7 (paired box 7; Cornelison and Wold,
1997), are normally quiescent in postnatal skeletal muscle.
However, in response to muscle injury or other ill-defined
environmental stimuli (Dhawan and Rando, 2005; Bi and
Kuang, 2012), satellite cells are activated to proliferate,
differentiate as myoblasts, and fuse with each other to
generate new myofibers or fuse with existing myofibers
to provide additional DNA that increases the capacity of
myofibers to synthesize protein during hypertrophy (Fig.
4). Recent work indicates that muscle hypertrophy in adult
animals could occur without the activation of satellite cells
(Blaauw et al., 2009; McCarthy et al., 2011). This is per-
haps because other cell types, such as pericytes, could also
provide nuclei for postnatal skeletal muscle growth (Del-
lavalle et al., 2011). Formation of myofibers from satel-
lite cells in postnatal animals appears to be controlled by
the same set of myogenic regulatory factors (MRF; myo-
genic factor 5 [Myf5], myogenic differentiation 1 [MyoD],
myogenin [MyoG]), and MRF4 that control embryonic
myogenesis. The factors Myf5 and MyoD determine the
myogenic lineage of satellite cells, whereas MyoG and
MRF4 drive the terminal differentiation of satellite cells
into myofibers (Bentzinger et al., 2012).
The protein content in a myofiber is determined by
the balance between protein synthesis and protein deg-
radation. The PI3K/AKT pathway is the most important
pathway regulating protein synthesis in skeletal muscle
(Guttridge, 2004; Bodine, 2006). Signaling from this
pathway stimulates protein synthesis by phosphorylating
the mammalian target of rapamycin (mTOR; Bodine et
al., 2001; Bodine, 2006; Sandri, 2008). Upon phosphor-
ylation, mTOR enhances protein synthesis by activating
Figure 4. Contribution of satellite cells to postnatal skeletal muscle
growth. In response to undefined environmental cues, quiescent satellite cells,
which express the transcription factor Pax7 (Pax7+), are activated to prolifer-
ate as myoblasts. Myoblasts express the myogenic regulatory factors Myf5
and MyoD in addition to Pax7. At a certain stage, myoblasts exit the cell
cycle and differentiate into myocytes, which fuse with each other to form new
myotubes or with existing myotubes to form larger myotubes. The myogenic
regulatory factors myogenin (MyoG) and MRF4 play an important role in the
terminal differentiation of myoblasts. New myotubes mature into functional
myofibers through hypertrophy. Pax7, paired box 7; Myf5, myogenic factor
5; MyoD, myogenic differentiation 1; MRF4, myogenic regulatory factor 4.
p70S6K, a translation stimulator, and inhibiting 4EBP1,
a translation repressor (Glass, 2010). Phosphorylated
mTOR also stimulates translation by inhibiting the gly-
cogen synthase kinase 3 β (GSK3β), which inhibits the
translation initiation factor eukaryotic initiation factor
2B (eIF-2B; Bodine, 2006; Glass, 2010). The PI3K/
AKT pathway also controls protein degradation in skel-
etal muscle by phosphorylating the forkhead box protein
(FOXO) transcription factors, FOXO1 and FOXO3A.
These transcription factors activate the expression of
muscle atrophy-related genes known as atrogenes, in-
cluding atrogen-1 (also known as muscle atrophy F-box
(MAFbx) and muscle RING finger protein 1 (MuRF1)
in the nucleus (Sandri et al., 2004; Glass, 2010). How-
ever, when phosphorylated by AKT, FOXO1 and
FOXO3A cannot translocate to the nucleus to activate
the expression of these atrogenes. Atrogen-1 and MuRF1
encode ubiquitin ligases, which target myofibrillar pro-
teins for degradation through the ubiquitin-proteasome
system (Sandri et al., 2004; Sandri, 2008). The tran-
scription factor FOXO3A also controls the expression
of autophagy-related genes, such as BCL2/adenovirus
E1B 19 kDa interacting protein 3 (BNIP3), which can
mediate protein degradation through the autophagic-
lysosomal system (Mammucari et al., 2007).
MECHANISM OF GH STIMULATION
OF SKELETAL MUSCLE GROWTH:
LESSONS FROM KNOCKOUT MICE
Early studies on how GH stimulates somatic growth
focused on the effect of GH on bone growth (Daugha-
day, 2000). These studies led to the landmark discovery
that a GH-dependent serum factor mediates GH stimu-
lation of bone growth (Salmon and Daughaday, 1957).
 Growth hormone regulation of muscle growth
The serum factor was later identified to be IGF-I from
the liver (Daughaday, 2000). These discoveries led to
the hypothesis that GH stimulate somatic growth via
circulating IGF-I secreted from the liver, that is, the so-
matomedin hypothesis (Daughaday et al., 1972). Sub-
sequently, research with rodents in the 1980s found that
IGF-I was expressed in many tissues besides liver and
that IGF-I expression in many extrahepatic tissues was
also regulated by GH (D’Ercole et al., 1980; Roberts et
al., 1987; Lowe et al., 1988). These findings led to a
modification to the original somatomedin hypothesis to
emphasize the role of locally produced IGF-I (i.e., para-
crine or autocrine IGF-I) in addition to liver-derived cir-
culating IGF-I (i.e., endocrine IGF-I) in mediating the
effect of GH (Nilsson et al., 1986; Isaksson et al., 1987).
Recent research using tissue-specific gene deletion
approaches has indicated considerable more complexity
of the functional relationship between GH and IGF-I. In
2 studies published in 1999, liver-specific deletion of the
IGF-I gene through the Cre-loxP system in mice caused a
75% reduction in circulating IGF-I concentration but no
significant changes in body or organ weight (Sjogren et
al., 1999; Yakar et al., 1999). These data led LeRoith and
colleagues to propose that the effect of GH on growth is
mediated solely by locally produced IGF-I (LeRoith et
al., 2001). This view proved to be hasty by subsequent
knockout mouse studies. Reintroduction of the IGF-I
gene to the liver of mice on an IGF-I null background
caused a 30% increase in body weight (Stratikopoulos et
al., 2008). Similarly, overexpression of rat IGF-I in the
liver of IGF-I knockout mice caused a 2.5-fold increase
in serum IGF-I concentration and restored normal body
growth (Wu et al., 2009). These data demonstrated that
circulating IGF-I from liver can undisputedly contribute
to somatic growth. Double knockout of the IGF-I gene
and the acid-labile subunit gene in the liver resulted in
an 85% reduction in circulating IGF-I concentration ac-
companied by a 30% reduction in body weight (Yakar
et al., 2002). Considering all these data from different
knockout mouse models and the technical limitations of
generating tissue-specific knockouts (e.g., incomplete or
inconsistent deletion of the gene), we believe that liver-
derived circulating IGF-I mediates at least part of the
effect of GH on tissue growth. Locally produced IGF-I
and IGF-I-independent mechanism are the other possi-
ble mechanisms by which GH stimulates tissue growth.
MECHANISM OF GH STIMULATION
OF SKELETAL MUSCLE IN CATTLE:
ROLE OF LOCAL IGF-I
Studies in cattle and other domestic animals have
indicated that GH stimulates postnatal muscle growth in
these animals by increasing the size, not by increasing
25
Figure 5. Ribonuclease protection assays of the growth hormone recep-
tor (GHR) and IGF-I mRNA in bovine tissues. In panel A, all RNA except
mammary RNA was pooled from 2 bulls. Mammary RNA was pooled from
2 nonlactating and nonpregnant cows. In panel B, liver and LM were from
4 steers. Yeast (Y) RNA served as a negative control. The GHR and IGF-I
probes used in these assays detected all known bovine GHR and IGF-I mRNA
variants and were described in detail in a previous study (Wang et al., 2003b).
The glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA served as
a loading control.
the number of myofibers (Ono et al., 1996; Etherton and
Bauman, 1998; Vann et al., 1998, 2001). Growth hor-
mone has no effect on the proliferation or differentiation
of bovine satellite cells in vitro (Ge et al., 2012). Growth
hormone stimulates protein synthesis without affecting
protein degradation in bovine myotubes in vitro (Ge et
al., 2012). Therefore, stimulating protein synthesis ap-
pears to be one of the mechanisms by which GH stimu-
lates myofiber hypertrophy in cattle.
What is the role of IGF-I in GH stimulation of skel-
etal muscle hypertrophy in cattle? Whereas we may never
know definitively whether liver-derived circulating IGF-I
contributes to GH stimulation of skeletal muscle growth
in cattle (because we cannot make liver-specific knock-
out cattle, at least not now), multiple lines of evidence
argue against a role of skeletal muscle-derived IGF-I in
GH-stimulated muscle hypertrophy in cattle. The first line
of evidence is that skeletal muscle expresses little IGF-
I compared with other tissues in cattle (Fig. 5). Skeletal
muscle IGF-I mRNA expression in some cattle is so low
that it is not detectable by ribonuclease protection as-
say (Moloney et al., 1998), whose sensitivity is between
northern blotting and reverse transcription (RT)-PCR.
Using RT-PCR, Pfaffl and colleagues (2002) estimated
that the abundance of skeletal muscle IGF-I mRNA is
only 3 to 5% that of liver IGF-I mRNA in growing cattle.
The second line of evidence against a role of skel-
etal muscle-derived IGF-I in GH stimulation of skeletal
muscle hypertrophy in cattle is that GH does not appear
to regulate IGF-I gene expression in skeletal muscle of
cattle. Growth hormone treatment of cattle had no effect
on skeletal muscle IGF-I mRNA expression while mark-
edly increasing liver IGF-I mRNA expression and serum
IGF-I concentration (Ge et al., 2012). The same study
also demonstrated that GH had no effect on IGF-I mRNA
26
Table 1. Differential effects of GH and IGF-I on bovine
muscle cells
Myoblast My.oblast Protein Protein
proliferation fusion synthesis degradation
GH –1 – ↑2
IGF-I ↑↑3 – ↑↑
1Indicates no effect.
2Indicates a moderate stimulatory effect.
3Indicates a strong stimulatory effect.
4Indicates a strong inhibitory effect.
expression in bovine myoblasts or myotubes in culture
(Ge et al., 2012). That GH does not regulate skeletal
muscle IGF-I mRNA expression in cattle was also indi-
cated by earlier observation that skeletal muscle IGF-I
mRNA abundance was not correlated with serum GH
concentrations or growth rate in cattle (Hannon et al.,
1991). Skeletal muscle of cattle appears to express abun-
dant GHR mRNA (Fig. 5). It is intriguing why action
of GH on the GHR in skeletal muscle does not lead to
increased IGF-I gene transcription.
The third line of evidence against a role of skeletal
muscle-derived IGF-I in GH stimulation of skeletal mus-
cle hypertrophy in cattle is that direct actions of GH and
IGF-I on bovine muscle cells produce largely different
effects (Ge et al., 2012, 2013). Added to the cultures of
bovine myoblasts or myotubes, IGF-I caused marked in-
creases in cell proliferation and protein synthesis and a
marked reduction in protein degradation whereas the only
change caused by GH was a modest increase in protein
synthesis (Table 1). These differences indicate that the di-
rect effect of GH on protein synthesis in bovine muscle
cells is unlikely mediated by paracrine or autocrine IGF-I.
It should be noted that rodents seem to be the only spe-
cies where IGF-I expression in skeletal muscle has been
shown to be regulated by GH. Growth hormone adminis-
tration does not stimulate IGF-I gene expression in skel-
etal muscle in sheep (Pell et al., 1993), pigs (Grant et al.,
1991; Coleman et al., 1994; Brameld et al., 1996; Dunaiski
et al., 1999), or humans (Jorgensen et al., 2006). Therefore,
whether locally produced IGF-I mediates GH-stimulated
growth of skeletal muscle may depend on species.
SUMMARY AND CONCLUSIONS
Contrary to what is implied by recent liver-specific
IGF-I knockout mouse studies, skeletal muscle-derived
IGF-I does not seem to play a role in the growth-stim-
ulatory effect of GH on skeletal muscle in cattle. Cell
culture-based evidence indicates that GH stimulates skel-
etal muscle hypertrophy in cattle in part through GHR-
mediated, IGF-I-independent stimulation of protein
synthesis. In cattle and many other species, liver IGF-I
gene expression and serum IGF-I concentration are in
Jiang and Ge
general correlated with growth rates and nutritional status.
Therefore, liver-derived circulating IGF-I should still be
considered as a potential mediator of GH stimulation of
skeletal muscle growth in cattle and other animals. De-
– spite the fact that recombinant GH has been used to im-
↓↓4
prove milk production and lean tissue growth for decades,
a better understanding of the underlying mechanisms may
help promote more rational and more effective use of GH
in animal industry. Because GH is a major regulator of
growth and metabolism, a better understanding of the
mechanism of its action could also unveil novel targets for
genetic selection of breeds with superior production traits.
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