Role of growth hormone, insulin-like growth factor-I, and insulin-

like growth factor binding proteins in the catabolic response to

injury and infection
Charles H. Lang and Robert A. Frost

The erosion of lean body mass resulting from protracted critical
illness remains a significant risk factor for increased morbidity
and mortality in this patient population. Previous studies have
documented the well known impairment in nitrogen balance
results from both an increase in muscle protein degradation as
well as a decreased rate of both myofibrillar and sacroplasmic
protein synthesis. This protein imbalance may be caused by an
increased presence or activity of various catabolic agents, such
as tumor necrosis factor-a, interleukin-1b, interleukin-6 or
glucocorticoids, or may be mediated via a decreased
concentration or responsiveness to various anabolic hormones,
such as growth hormone or insulin-like growth factor-I. This
review focuses on recent developments pertaining to the
importance of alterations in the growth hormone±insulin-like
growth factor-I axis as a mechanism for the observed defects in
muscle protein balance. Curr Opin Clin Nutr Metab Care 5:271±279.
# 2002 Lippincott Williams & Wilkins.
Department of Cellular and Molecular Physiology, and Surgery, Penn State College of
Medicine, Hershey, Pennsylvania, USA
Introduction
Gram-negative infection and traumatic injury are increas-
ingly common events. One hallmark of these stresses is
the negative nitrogen balance produced by the net
catabolism of protein originating primarily, but not
exclusively, from skeletal muscle, that cannot be solely
explained by reduced caloric intake. This net catabolism
of body protein stores is multifactorial, resulting from an
increase in protein degradation and a decrease in protein
synthesis (for recent reviews see [1 .,2 .]). The imbalance
in protein metabolism, when prolonged, leads to the
erosion of lean body mass (LBM) and the wasting
commonly observed in septic patients and other patients
with hypermetabolic illness. The loss of muscle protein is
probably of minor clinical importance when the stress is
self limiting. In response to protracted hypermetabolism,
however, the decrease in LBM is causally linked to an
increase in morbidity and mortality. Thus, maintaining
muscle protein stores is highly desirable and a more
complete understanding of the factors capable of regulat-
ing protein metabolism is of great clinical relevance.

Correspondence to Charles H. Lang PhD, Department of Cellular and Molecular Numerous factors are known to in¯uence muscle protein
Physiology (H166), Penn State College of Medicine, 500 University Drive, Hershey, balance, either positively or negatively. On the catabolic
PA 17033, USA
Tel: +1 717 531 5538; fax: +1 717 531 7667; e-mail: clang@psu.edu side of the protein balance equation, several lines of
evidence suggest that the stimulation of various cytokine
Current Opinion in Clinical Nutrition and Metabolic Care 2002, 5:271±279
networks, particularly those involving tumor necrosis
Abbreviations factor-a (TNFa), interleukin-1b and interleukin-6, plays
cAMP cyclic adenosine monophosphate a critical role in the observed muscle wasting. In
CIS cytokine-inducible SH-2
eIF eukaryotic initiation factor addition, the sustained elevation in glucocorticoids
IGF insulin-like growth factor produced by injury and infection adversely impacts on
IGFBP insulin-like growth factor binding protein
JAK Janus family of nonreceptor kinase both muscle protein synthesis and degradation. Con-
LBM lean body mass versely, injury also leads to either a reduction in the
MAP mitogen-activated protein
SOCS suppressers of cytokine signaling circulating concentration or a diminished responsiveness
STAT signal transducers and activators of transcription of tissues to several anabolic agents, including insulin-
TGF transforming growth factor
TNFa tumor necrosis factor-a like growth factor (IGF)-I and growth hormone. Hence,
attempts to improve muscle protein balance have
# 2002 Lippincott Williams & Wilkins spawned therapeutic strategies designed to either
1363-1950 decrease the presence of selected catabolic stimuli or
increase the amount or activity of anabolic mediators.
The purpose of this review is to highlight recent studies
related to trauma-induced changes in the growth
hormone±IGF axis and, where possible, relate them to
observed changes in skeletal muscle protein metabolism.
This review will not focus on injury and in¯ammation-
induced changes in in¯ammatory cytokines per se, except
as they pertain to changes in the growth hormone±IGF
system and muscle protein balance.
271
272 Anabolic and catabolic signals
Alterations in insulin-like growth factor-I
produced by critical illness
There is general agreement that traumatic injury and
in¯ammatory mediators, including trauma, bacterial and
viral infection, thermal injury, endotoxin, elevations in
in¯ammatory cytokines (TNFa, interleukin-1b and
interleukin-6) and glucocorticoid excess are all capable
of decreasing the circulating concentration of IGF-I [3].
Blood IGF-I can be acutely downregulated within several
hours after the insult and often remains suppressed for
many weeks in hypermetabolic patients. This decrease
appears most pronounced and sustained in severely
burned patients [4]. Because the majority of the blood-
borne IGF-I originates from the liver [5 . .], the reduction
in blood IGF-I noted in the above-mentioned catabolic
conditions appears to be caused primarily by the
concomitant decrease in hepatic synthesis and secretion
of IGF-I. The importance of the local production of IGF-
I in muscle, however, has been eloquently demonstrated
by Butler and LeRoith [5 . .] when the igf1 gene was
selectively deleted in the liver. These mice, which have
normal levels of IGF-I mRNA in skeletal muscle,
demonstrate normal postnatal growth despite a 75%
reduction in blood IGF-I, thus highlighting the impor-
tance of locally produced IGF-I in the accretion of LBM.
In this regard, all of the traumatic and in¯ammatory
insults described above also decrease the mRNA and
peptide content of IGF-I in skeletal muscle [3].
Previously, we demonstrated that the sepsis-induced
decrease in muscle IGF-I content is strongly correlated
with the reduction in the rate of muscle protein synthesis
[6]. A similar relationship has been observed after in-vivo
administration of endotoxin [7 . .]. Furthermore, data
from this later study also reveal that the endotoxin-
induced decrease in muscle IGF-I is correlated with a
reduction in the amount of the active eukaryotic
initiation factor (eIF) 4E .eIF4G complex (Fig. 1). This
complex, along with other factors, controls translation
initiation by regulating the binding of mRNA to the 43S
preinitiation complex [8 .]. Similarly, a relatively pro-
longed (24 h) intravenous infusion of TNFa, a cytokine
known to be upregulated in many traumatic conditions,
has also been shown to decrease mRNA translational
ef®ciency resulting from an impairment in translation
initiation associated with alterations in eIF4E availability
and IGF-I content in muscle [9 . .]. Collectively, these
data are consistent with the reported ability of IGF-I to
promote muscle protein synthesis in the isolated
perfused hindlimb by enhancing the formation of the
eIF4E .eIF4G complex [10].
Hepatic synthesis and hence the plasma concentration of
IGF-I is exquisitely sensitive to nutrient availability [11].
That is, protein or caloric reduction decreases hepatic
IGF-I mRNA and the circulating concentration of IGF-I,
Figure 1. Correlation between muscle insulin-like growth factor-I
mRNA content and the amount of eukaryotic initiation factor 4G
bound to eukaryotic initiation factor 4E in the same muscle
elF4G 1500
bound
with 1250
elF4E in r2 = 0.79
muscle 1000
(AU)
750
500
250
0
0.0 0.2 0.4 0.6 0.8 1.0 1.2
Muscle IGF-I mRNA content (AU/18S)
Equation for the line based on least squares linear analysis of data is
y = 928.2x + 74.8; r2 = 0.79; P 5 0.05. *, Controls; ~, endotoxin;
^sepsis; and &tumor necrosis factor-infused. Original data were
obtained from [7 . .,9 . .] and unpublished data, Lang, 2001. eIF,
eukaryotic initiation factor; IGF-I, insulin-like growth factor-I.
whereas refeeding increases the synthesis of IGF-I,
returning the blood concentration back toward normal.
Several studies, however, now indicate that the composi-
tion of the nutritional support may greatly impact the
recovery of IGF-I. For example, in a randomized,
double-blind clinical trial, provision of nutritional sup-
port containing a high ®sh oil (e.g. omega-3 fatty acids)
content to burn patients increased blood IGF-I concen-
trations to a greater extent than an isonitrogenous
supplement containing the same percentage of fat
without ®sh oil [4]. Although the mechanism of this
response was not elucidated, it presumably results at
least in part from a diminished production of arachidonic
acid-derived eicosanoids via the cyclooxygenase path-
way. Likewise, the amino acid composition of the
supplement might also be expected to in¯uence the
rate at which the blood IGF-I levels return to basal
levels. It is appreciated that provision of an isocaloric
diet low in total protein slows the recovery of IGF-I [12].
Recent data, however, suggest that dietary restriction of
a single essential amino acid might also be expected to
impair IGF-I recovery [13 .]. Finally, the route by which
nutritional support is delivered also in¯uences the IGF-I
system. In this regard, compared with animals adminis-
tered total parenteral nutrition, those provided with
isocaloric isonitrogenous nutritional support via the
enteral route have a faster recovery of their plasma
IGF-I levels after surgical trauma [14]. There was also a
more robust increase in the peptide and mRNA content
for IGF-I in liver and muscle in rats provided enteral
versus parenteral nutrition. Furthermore, administration
of endotoxin following surgical trauma (e.g. a `second-

hit') resulted in a smaller decrement in IGF-I in
enterally fed rats compared with parenterally fed
animals. The maintenance of higher IGF-I levels in
enterally fed rats is associated with lower rates of
myo®brillar degradation, as assessed by urinary 3-
methylhistidine excretion, and a reduction in the plasma
TNFa concentration.
Growth hormone resistance: possible
mechanism for the reduction in insulin-
like growth factor-I
Growth hormone is synthesized and secreted from the
anterior pituitary somatotrope. The synthesis of this
hormone is regulated through a complex neuroendocrine
control system involving stimulation by hypothalamic
growth hormone releasing hormone and inhibition by
somatostatin. In addition, both growth hormone releas-
ing hormone and somatostatin can be regulated by
numerous other neuroendocrine factors. (For a thorough
review of the neuroendocrine control of growth hormone
secretion the reader is referred to the review by Muller et
al. [15]). Collectively, these various modulators result in
the episodic and pulsatile secretion of growth hormone.
The effects of growth hormone are in turn mediated
either directly by binding to the growth hormone
receptor or indirectly via the enhanced synthesis of
IGF-I. In humans, during the early phase of trauma and
infection the circulating concentration of growth hor-
mone is markedly elevated because of the increased
frequency of growth hormone pulses. These pulses have
relatively high peak concentrations as well as elevated
interpulse levels of growth hormone [16 . .]. Because
growth hormone is the primary proximal mediator of
IGF-I synthesis in the liver and other peripheral tissues,
in humans it is paradoxical that the stress-induced
elevation in plasma growth hormone is associated with
a decrease in the circulating concentration of IGF-I. A
similar inverse relationship between growth hormone
and IGF-I has been reported in sheep injected with
endotoxin [17].
One possible explanation for the mismatch between
growth hormone and IGF-I in trauma and septic patients
might be the presence of growth hormone resistance.
This acquired resistance to the anabolic effects of growth
hormone has been conclusively demonstrated by studies
in which the injection of exogenous growth hormone
fails to increase the plasma IGF-I levels to the same
extent in septic patients as in controls [18]. Growth
hormone resistance has also been demonstrated in rats
injected with endotoxin [19], despite the marked
reduction of plasma growth hormone concentrations in
this species. Collectively, these data suggest that the
stress-induced increase in plasma growth hormone is not
a prerequisite for the observed growth hormone resis-
tance.
Catabolic response to injury and infection Lang and Frost 273
The biological responses produced by growth hormone
are initiated by binding of the hormone to its cell surface
receptors. An early study reported that endotoxin-
induced growth hormone resistance is associated with a
decrease in growth hormone receptor mRNA content and
growth hormone binding in liver extracts [19]. In studies
using lower doses of endotoxin [20] and in studies using
septic rats [21], however, growth hormone receptor
protein and growth hormone binding activity are not
signi®cantly decreased, suggesting that the reduction in
growth hormone receptor is also not essential for the
development of growth hormone resistance. Growth
hormone binding to its cognate receptor leads to receptor
homodimerization and the activation of a number of
intracellular signaling pathways. The lack of intrinsic
kinase activity necessitates that members of this receptor
superfamily recruit or activate cytoplasmic tyrosine
kinases to transduce the signal. The growth hormone
receptor is constitutively associated with members of the
Janus family of nonreceptor kinases (JAKs) that are
transphosphorylated and activated by growth hormone
binding [22 .]. In the only study to date, endotoxin has
been shown to decrease hepatic JAK2 phosphorylation
when normalized to the total amount of JAK2 [20]. Under
normal conditions, the phosphorylation of JAK2 leads to
the recruitment and activation of multiple signaling
pathways, including the signal transducers and activators
of transcription (STAT) protein family. In control
animals, injection of a maximally stimulating dose of
growth hormone increases STAT5 tyrosine phosphoryla-
tion many fold in whole liver homogenates; however, in
endotoxin-treated rats this growth hormone-induced
increase is markedly suppressed [20]. The relative
importance of STAT5 in mediating growth hormone-
induced stimulation of hepatic IGF-I synthesis has
recently been demonstrated using the STAT5b knockout
mouse [23 . .]. The deletion of STAT5b decreased the
basal plasma IGF-I concentration and the abundance of
IGF-I mRNA in liver. Additionally, while the adminis-
tration of growth hormone to hypophysectomized wild-
type mice increased hepatic IGF-I mRNA content,
STAT5b null mice were completely insensitive to
hormonal stimulation. Finally, the injection of endotoxin
into hypophysectomized rats also dramatically decreased
the growth hormone-induced accumulation of STAT5 in
isolated hepatic nuclei and their binding to a growth
hormone response element for the serine protease
inhibitor 2.1 [24 . .]. This response may be a direct effect
of endotoxin at the level of the liver because incubation of
isolated hepatocytes with TNFa, interleukin-1b or
interleukin-6 also inhibited growth hormone-induced
serine protease inhibitor 2.1 mRNA expression.
Recently, attention has focused on how cells regulate the
duration of their response to growth hormone and return
to the basal condition. One such mechanism involves the
274 Anabolic and catabolic signals
interaction of negative regulatory proteins directly with
components of the JAK±STAT signaling pathway. It is
now recognized that the suppressers of cytokine signal-
ing (SOCS) family of proteins function as an integral part
of a negative feedback loop inhibiting cytokine and
growth hormone signaling [25 .]. The potential physio-
logical role of one of these proteins, SOCS-2, on growth
has been emphasized by studies using SOCS-2 null mice
[26 .]. Compared with wild-type littermates, the SOCS-
2±/± mice were larger with an increase in bone length and
a proportionate enlargement of most visceral organs. In
addition, the IGF-I mRNA content in liver and several
other organs was increased in the transgenic mice.
Numerous lines of evidence clearly establish that SOCS
gene expression is STAT regulated (as reviewed in
[25 .]). The in-vivo administration of growth hormone
produces a prompt (1 h) but transient (3±6 h) increase in
CIS (cytokine-inducible SH-2 containing protein),
SOCS-2 and SOCS-3 mRNA content in liver [27 . .].
Using STAT5b knockout mice, it has been determined
that much of the increase in SOCS-2 and SOCS-3
mRNA is mediated via this particular signaling element
[28]. Intravenous injection of endotoxin into intact (e.g.
non-hypophysectomized) rats produces large increases in
the hepatic mRNA content for SOCS-3 and CIS, and a
much smaller increase in SOCS-2 mRNA [20,27 . .]. The
temporal progression of these endotoxin-induced
changes (e.g. 1±6 h) is consistent with the hepatic
growth hormone resistance previously described. More
prolonged elevations in SOCS-1 and SOCS-3, but not
SOCS-2 or CIS, have been observed in septic rats 18 h
after cecal ligation and puncture [29]. Additionally,
incubation of primary cultured rat hepatocytes with
either interleukin-1b or TNFa weakly increases SOCS-3
and CIS mRNA under basal conditions. Both cytokines,
however, are capable of interacting with growth hormone
in a synergistic manner to dramatically upregulate the
mRNA abundance for SOCS-3 and CIS, as well as
produce a more modest potentiation of SOCS-2 [27 . .].
The various SOCS family members appear to use several
different molecular mechanisms to negatively regulate
growth hormone signaling [25 .]. For example, SOCS-1
binds directly with active JAKs thereby blocking further
catalytic action, SOCS-3 binds to JAK-proximal sites on
growth hormone receptors and inhibits JAK activity, and
CIS binds to the growth hormone receptor and inhibits
STAT signaling. Additionally, both SOCS-2 and SOCS-
3 have been shown to bind to the IGF-I receptor and,
therefore, the possibility exists that this family of
proteins may also be capable of directly mediating some
of the anabolic actions of this hormone [30,31]. It is
noteworthy that, to date, all studies pertaining to the
effect of trauma and infection on growth hormone
resistance have focused on the effects of growth
hormone on IGF-I synthesis in the liver. Based on
previously described studies involving the importance of
locally produced IGF-I, however, it will be necessary to
determine whether skeletal muscle is also growth
hormone resistant and whether similar mechanisms are
operational in this tissue.
Investigation into the mechanisms by which cytokines
and catabolic hormones impair muscle growth hormone
action have been slowed by the lack of an appropriate in-
vitro model. Recently our laboratory [32 . .] and others
[33 .] have found that the C2C12 skeletal muscle cell
line is growth hormone responsive. Growth hormone
stimulates the phosphorylation of both STAT3 and
STAT5 as well as the expression of IGF-I mRNA
[32 . .,33 .]. Inhibition of JAK3, in this cell type, blocks
growth hormone-stimulated STAT3 phosphorylation
and the accumulation of IGF-I mRNA [33 .]. Cytokines
and hormones that are increased during catabolic
conditions may induce growth hormone resistance by
preventing STAT phosphorylation. In this regard, we
®nd that the synthetic glucocorticoid dexamethasone
blocks growth hormone-stimulated phosphorylation of
STAT5 and, to a lesser extent, phosphorylation of
STAT3 (Fig. 2). These events are glucocorticoid
receptor dependent because they are prevented by the
glucocorticoid receptor antagonist RU486.
Trauma and infection-induced alterations in
insulin-like growth factor binding proteins
IGF-I in the blood and various body ¯uid compartments
is bound noncovalently to one of several IGF binding
proteins (IGFBPs). The majority of the circulating IGF-I
is bound to IGFBP-3 and the acid-labile subunit to form
a ternary complex. Because of its large molecular weight,
this complex is restricted to the vascular compartment
and is believed to represent a storage reservoir for IGF-I.
In contrast, a relatively small amount of the total IGF-I
in the blood is carried by IGFBP-1. Because of the size
of this binary complex, IGFBP-1 represents a potential
chaperone for the translocation of IGF-I across the
capillary endothelial wall. Although the exact functions
of these binding proteins are not known, it is clear they
represent another mechanism by which IGF-I bioavail-
ability and bioactivity can be modulated [34 . .]. For
example, desIGF-I and LR3-IGF-I are both more potent
than native IGF-I at stimulating weight gain and
nitrogen retention in glucocorticoid-treated or food
restricted rats [35,36]. Because these IGF-I variants
have a reduced af®nity for the IGFBPs, these data imply
that the IGFBPs normally restrain the protein anabolic
effects of IGF-I. This conclusion is also supported by in-
vivo studies in mice where the overexpression of
IGFBP-3, acid-labile subunit, IGFBP-2 or IGFBP-1
impairs normal postnatal growth [36,37 .,38]. To date,
however, there are no studies that directly assess the
ability of IGFBPs to regulate muscle protein metabolism
 Catabolic response to injury and infection Lang and Frost 275

Figure 2. Growth hormone-inducible STAT3 and STAT5 phosphor- injury). Moreover, the stress-induced increase in IGFBP-
ylation is suppressed by dexamethasone
1 is not species speci®c. Elevated concentrations of
IGFBP-1 are known to impair the ability of IGF-I and
(a) serum to stimulate protein synthesis in myocytes [39]

GH + Dex + RU
and to decrease IGF-I-mediated glucose uptake in-vivo
[40]. Although an increase in hepatic IGFBP-1 mRNA

GH + Dex
Control abundance is observed in all of the above mentioned
conditions, these insults also clearly stimulate IGFBP-1

GH
synthesis in the kidney [41], and the relative importance
pSTAT5 of these two organs in determining the plasma concen-
tSTAT5 tration of the binding protein remains to be elucidated.
pSTAT3
Under normal conditions, variation in the plasma insulin
concentration produced by the availability of nutrients is
(b) an important regulator of IGFBP-1 synthesis. This
pSTAT-5 3000
mechanism, however, appears less important during
(AU) trauma and in¯ammation as evidenced by the lack of
2500 association between IGFBP-1 and the prevailing plasma
insulin concentration [3]. The physiological regulators
2000
that increase IGFBP-1 under stress conditions have not
1500 been fully elucidated and appear to vary depending on
the speci®c traumatic insult. For example, infusion of
1000
the interleukin-1 receptor antagonist completely pre-
500 vents the sepsis-induced increase in IGFBP-1 in blood
and liver [6] but does not signi®cantly ameliorate the
0 increased IGFBP-1 produced by endotoxin (Lang,
Control

GH

GH + Dex

GH + Dex + RU

unpublished observations, 2001). In contrast, inhibition

Cell extracts were isolated from C2C12 myocytes that had been
pretreated with either dexamethasone alone or RU486 and dexametha-
sone for 30 min and then stimulated with growth hormone for 10 min.
After SDS-PAGE and transfer to nitrocellulose, the resulting blots (a)
were probed for phosphorylated STAT5 (first blot), total STAT5 (second
blot), or phosphorylated STAT3 (third blot). The STAT5 data were
analyzed with NIH Image and are presented in (b). All data were
normalized for total STAT5. Values are means+SEM. Dex, dexametha-
sone; GH, growth hormone; RU, RU486; STAT, signal transducers and
activators of transcription.
of TNF action by pretreatment with a neutralizing
antibody partially prevents the endotoxin-induced in-
crease in IGFBP-1 [42], but TNF antagonists are largely
ineffective at preventing the increase in IGFBP-1
produced by thermal injury [43 . .]. Conversely, pretreat-
ing animals with the glucocorticoid receptor antagonist
RU486 blunts the burn-induced increase in IGFBP-1
[43 . .] but not the increase observed in response to
endotoxin [44]. Hence, at this time, the physiological
regulator of IGFBP-1 appears largely dependent on the
particular traumatic insult, which may be a re¯ection of
differences in the hormonal and cytokine milieu present
in these conditions.

At the cellular level it is known that TNFa, interleukin-

in the basal state or in catabolic conditions where the
blood concentrations of several of the binding proteins
are altered.
The preponderance of work related to IGFBPs has
focused on mechanisms producing trauma and in¯am-
mation-induced changes in the plasma concentration of
either IGFBP-1 or IGFBP-3. The plasma concentration
of IGFBP-1 is markedly elevated in many conditions
associated with the erosion of LBM, including sepsis,
endotoxemia, burn injury, in¯ammation, diabetes and
alcohol intoxication [3]. Elevation in IGFBP-1 levels can
occur rapidly (e.g. up to 2 h after endotoxin) and may be
relatively sustained (e.g. weeks after burn or traumatic
1b, intereukin-6, cyclic adenosine monophosphate
(cAMP) analogs and, to a lesser extent, oxidative stress
have the ability to directly stimulate IGFBP-1 synthesis
in a human hepatoma cell line (HepG2) [45,46 . .]. The
cytokine-induced increase in secretion is accompanied
by an increase in IGFBP-1 mRNA content. Additionally,
the interleukin-1b induced increase in IGFBP-1 expres-
sion appears to be regulated at the transcriptional level
because cytokine treatment did not signi®cantly alter
IGFBP-1 mRNA stability [45]. Studies have also been
performed addressing the signaling pathways involved in
cytokine stimulation of IGFBP-1 [46 . .]. Interleukin-1b
actively stimulates the mitogen-activated protein (MAP)
kinase pathway and inhibition of this pathway with the
276 Anabolic and catabolic signals
MEK-1 inhibitor PD98059 completely prevents the
interleukin-1-induced increase in IGFBP-1 mRNA and
production in HepG2 cells. IGFBP-1 synthesis is also
stimulated by cAMP; however, this increase is mediated
via protein kinase A (PKA), not by a stimulation of MAP
kinase [46 . .]. In this regard, in-vivo studies have
demonstrated that elevating catecholamines increases
the plasma concentration of IGFBP-1 in humans [47]
and the hepatic synthesis of IGFBP-1 in animals [48].
Collectively, these data suggest that there are multiple
mechanisms by which hepatic IGFBP-1 can be increased
during stress conditions. Additional studies should be
conducted to determine whether adrenergic stimulation
is a signi®cant physiological modulator of IGFBP-1
synthesis under in-vivo conditions.
Trauma and in¯ammation-induced changes in blood
IGFBP-3 concentrations are relatively more variable than
changes in IGFBP-1 [3]. Many acute insults fail to
consistently decrease plasma IGFBP-3 levels, which is
likely related to the relatively long half-life of the binding
protein in the circulation, whereas more chronic catabolic
conditions often, but not always, lead to a reduction in
IGFBP-3 [4,41,43 . .]. The decrease in blood IGFBP-3
may result from an increased clearance or a decreased rate
of synthesis. An increase in IGFBP-3 proteolysis has been
demonstrated in patients after thermal injury [4]. More-
over, the inclusion of omega-3 fatty acids in the
nutritional supplementation provided to these patients
appears to decrease the extent of IGFBP-3 proteolysis
[4]. Minimizing IGFBP-3 proteolysis may be of bene®t to
the patient because the IGFBP-3 proteolytic fragments
are known to bind IGF-I with less af®nity than the native
binding protein, resulting in a more rapid clearance of
IGF-I from the circulation. In addition, the burn-induced
decrease in blood IGFBP-3 also results from a decrease in
its synthesis, as evidenced by the marked reduction in the
IGFBP-3 mRNA content in liver within 24 h after injury
[41,43 . .]. This response contrasts with that observed in
rats made septic by cecal ligation and puncture when only
a very slight diminution of hepatic IGFBP-3 expression
occurred at the same time point [49]. It seems likely that
the burn-induced decrease in hepatic IGFBP-3 mRNA
results from a reduction in the growth hormone concen-
tration or the presence of growth hormone resistance [41],
and could not be prevented in rats pretreated with
antagonists to either TNFa or glucocorticoids [43 . .].
Finally, in contradistinction to the change in liver, it is
noteworthy that thermal injury increases IGFBP-3
mRNA content in kidney and skeletal muscle and that
this increase is at least partially glucocorticoid dependent
[43 . .]. These results indicate, at least for burn injury, that
plasma concentration of IGFBP-3 is not a reliable
indicator of IGFBP-3 mRNA expression in all tissues
and that tissue IGFBP-3 synthesis can be differentially
regulated.
Insulin-like growth factor-I treatment and
responsiveness
Trauma-induced increases in various IGFBPs as well as
the marked elevation in various stress hormones (e.g.
glucocorticoids and catecholamines) might be expected
to impair IGF-I action. For the most part, however, the
biological actions of IGF-I on protein metabolism appear
to be largely unaffected by traumatic injury. Early work
by Jurasinski and Vary [50] revealed that while the
ability of insulin to stimulate protein synthesis in the
isolated perfused hindlimb is decreased in septic rats,
muscle from these animals retains its normal responsive-
ness to the anabolic actions of IGF-I. Similar ®ndings
have been reported by other investigators for muscles
isolated from either septic or burn rats and incubated in-
vitro with IGF-I [51 .,52]. Hence, it is not totally
unexpected that chronic 5-day treatment of septic rats
with a complex of IGF-I and IGFBP-3, which function-
ally extends the IGF-I half-life, is able to return muscle
protein synthesis to basal control values by stimulating
translational ef®ciency [53]. The use of this IGF/IGFBP-
3 binary complex also improves protein balance in cancer
cachexia [54] and various aspects of host defense after
thermal injury [55].
Myostatin
Cytokines released during catabolic injury are known to
stimulate the synthesis of transforming growth factor
(TGF) family members, such as TGFb1. Recently,
myostatin, a highly conserved muscle-speci®c member
of the TGFb superfamily has been cloned. Genetic
studies show myostatin to be a negative regulator of
muscle mass. Hence, transgenic mice lacking the
myostatin (GDF-8) gene have a marked increase in
muscle mass, compared with wild-type animals [56 . .].
Conversely, the concentrations of myostatin in serum
and muscle are increased in AIDS patients with muscle
wasting, and levels are inversely proportional to LBM
[57]. Likewise, myostatin mRNA and protein are
increased in response to disuse atrophy [58]. Further-
more, myostatin mRNA is abundantly expressed in
gastrocnemius but not soleus. This observation is
particularly relevant because the decrease in muscle
protein synthesis and IGF-I observed in catabolic
conditions occurs predominantly in fast-twitch (e.g.
gastrocnemius) as opposed to slow-twitch (e.g. soleus)
muscles. Finally, addition of puri®ed myostatin to
C2C12 myocytes in culture signi®cantly impairs cell
proliferation and protein synthesis [59 . .]. Therefore,
while IGF-I is a positive regulator of muscle growth and
metabolism, myostatin appears to be a negative regulator
of muscle mass.
The results described above provide the scienti®c basis
for studies designed to determine whether different
catabolic insults known to adversely in¯uence muscle

protein balance would also increase myostatin expression
[60 . .]. Results from these studies indicate that myostatin
mRNA content is increased several fold in the predomi-
nately fast-twitch gastrocnemius and psoas muscles (but
not soleus), 24 h after 30% total body surface area burn
injury in adult rats. The burn-induced increase in
myostatin is associated with a concomitant reduction in
the protein content of the gastrocnemius muscle and a
reduction in IGF-I mRNA. In contrast, myostatin
remained unchanged in muscle either 4 or 24 h after
injection of endotoxin, and 24 h after induction of
hypermetabolic peritonitis. Both of these insults produce
muscle wasting that is comparable to or greater than that
observed after thermal injury. Additionally, both en-
dotoxemia and sepsis are associated with a reduction in
IGF-I mRNA content in gastrocnemius muscle. More-
over, none of these traumatic insults signi®cantly altered
the expression of IGF-II mRNA in skeletal muscle.
These data support a possible role for IGF-I as an
important mediator of muscle protein balance, but
suggest that changes in myostatin abundance are not a
generalized muscle response to traumatic injury and
infection.
The three catabolic insults used in the above-mentioned
study appear to elicit a glucocorticoid response that
differs in magnitude and duration. Burn injury results in
a rapid and sustained elevation in circulating corticoster-
one, whereas the injection of endotoxin increased
corticosterone levels to a comparable level at 4 h but
concentrations had returned to basal values by 24 h. In
contrast, the peritonitis model used showed only small
increases in plasma glucocorticoids at the time of
sacri®ce. Hence, a sustained large elevation in glucocor-
ticoids might be responsible for the burn-induced
increase in myostatin. This conclusion is supported by
data indicating that the injection of the potent synthetic
glucocorticoid dexamethasone also increases myostatin
mRNA [60 . .]. In a complementary study, the glucocor-
ticoid antagonist RU486 administered prior to burn
injury prevented both the increase in myostatin mRNA
and the reduction in muscle protein content. Addition-
ally, the 5'-regulatory region of the human myostatin
gene has been shown to contain a putative glucocorticoid
response element, and dexamethasone produces a dose-
dependent increase in both promoter transcriptional
activity and mRNA expression in C2C12 myoblasts
[61 .]. Collectively, these data indicate that sustained
elevations in circulating glucocorticoids are capable of
increasing myostatin and that an elevation in the
endogenous levels of this hormone is largely responsible
for the increased myostatin observed in response to
thermal injury. Finally, pretreatment of burned rats with
a TNF antagonist (e.g. TNFBP) was unable to prevent
the burn-induced increase in myostatin, indicating that
the response was TNF independent.
Catabolic response to injury and infection Lang and Frost 277
Conclusion
Many hormones, cytokines and growth factors impact on
muscle protein balance. Recent studies suggest that
IGF-I plays a central role in regulating both muscle
protein synthesis and degradation under both basal and
stress conditions. In addition, IGFBPs provide an
additional layer of complexity and regulation by altering
the stability, transport and bioactivity of IGF-I. Because
the six binding proteins have different binding af®nities
for IGF-I and respond in a different dose and time
dependency to various types of stress, the interplay
between these proteins in regulating IGF action at the
tissue level, especially muscle, is likely to be multi-
faceted. It is becoming increasingly evident that the
autocrine and paracrine effects of the various IGF
system components may be important regulators of
tissue and organ metabolism, and that the control of
these various elements may be regulated in a tissue-
speci®c manner that is not fully understood. Further-
more, the similarity of changes in the plasma concentra-
tions of IGF system components among different types
of catabolic injury suggests a common underlying
mechanism. A more thorough analysis of the stress-
induced changes in the IGF system within individual
tissues, however, reveals that changes in the plasma
concentration are not necessarily indicative of changes at
the tissue level and that the same tissue may respond
differently depending on the particular insult. Moreover,
while the classical nutritional and hormonal regulators of
the IGF system may be operational during catabolic
states, it is now clear that additional factors, such as the
cytokine milieu, play a prominent regulatory role in
response to trauma and in¯ammation. These results
suggest that there is much yet to be learned regarding
the complex regulation of the IGF system.
Acknowledgements
Work by the authors cited in this review was supported in part by grants
from the National Institutes of Health GM-38032 and HL-66443.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
. of special interest
.. of outstanding interest
1 Hasselgren PO. Catabolic response to stress and injury: implications for
. regulation. World J Surg 2000; 24:1452±1459.
An excellent review of the possible mechanisms mediating sepsis-induced
changes in muscle protein synthesis and degradation.
2 Ferrando AA. Effects of inactivity and hormonal mediators on skeletal muscle
. during recovery from trauma. Curr Opin Clin Nutr Metab Care 2000; 3:171±
175.
This is a concise review of the use of insulin and testosterone as anabolic agents in
the treatment of catabolic illness.
3 Frost RA, Lang CH. Growth factors in critical illness: regulation and
therapeutic aspects. Curr Opin Clin Nutr Metab Care 1998; 1:195±204.
278 Anabolic and catabolic signals
4 Abribat T, Nedelec B, Jobin N, Garrel DR. Decreased serum insulin-like
growth factor-I in burn patients: relationship with serum insulin-like growth
factor binding protein-3 proteolysis and the influence of lipid composition in
nutritional support. Crit Care Med 2000; 28:2366±2372.
5 Butler AA, LeRoith D. Control of growth by the somatropic axis: growth
. . hormone and the insulin-like growth factors have related and independent roles.
Ann Rev Physiol 2001; 63:141±164.
This is a well written review that examines the original somatomedin hypothesis
and how data from transgenic mice with a liver-specific deletion of the igf1 gene
have led to the revision of this hypothesis.
6 Lang CH, Fan J, Cooney R, Vary TC. IL-1 receptor antagonist attenuates
sepsis-induced alterations in the IGF system and protein synthesis. Am J
Physiol Endocrinol Metab 1996; 270:E430±E437.
7 Lang CH, Frost RA, Jefferson LS, et al. Endotoxin-induced decrease in muscle
. . protein synthesis is associated with changes in eIF2B, eIF4E and IGF-I. Am J
Physiol Endocrinol Metab 2000; 278:E1133-E1143.
This paper is the first to demonstrate a strong linear relationship between the
endotoxin-induced decrease in muscle protein synthesis, the decrease in peptide-
chain initiation, and the reduction in tissue IGF-I content. This paper also contains
a useful discussion related to the translational control of muscle protein synthesis
by various eIFs.
8 Shah OJ, Anthony JC, Kimball SR, Jefferson LS. 4E-BP1 and S6K1:
. translational integration sites for nutritional and hormonal information in muscle.
Am J Physiol Endocrinol Metab 2000; 279:E715±E729.
This is an excellent review covering the translational control of muscle protein
synthesis by fasting, insulin, amino acids, and glucocorticoid excess.
9 Lang CH, Frost RA, Nairn AC, et al. TNF impairs heart and skeletal muscle
.. protein synthesis by altering translation initiation. Am J Physiol Endocrinol Metab
2001; 282:E336±E347.
Although the addition of TNFa to myocytes in vitro has been demonstrated to
inhibit protein synthesis, several investigators have previously failed to demonstrate
such an effect under in-vivo conditions. Data in this paper indicate that a
continuous infusion of a nonlethal dose of TNFa for 24 h is indeed capable of
decreasing muscle protein synthesis (both myofibrillar and sacroplasmic),
translational efficiency, and the availability of eIF4E. The authors suggest that
the prolonged exposure of tissues to TNFa, which is not observed when the
cytokine is administered as a bolus injection, may be necessary for TNFa to impair
in-vivo muscle protein synthesis.
10 Vary TC, Jefferson LS, Kimball SR. Role of eIF4E in stimulation of protein
synthesis by IGF-I in perfused rat skeletal muscle. Am J Physiol Endocrinol
Metab 2000; 278:E58±E64.
11 Noguchi T. Protein nutrition and insulin-like growth factor system. Br J Nutr
2000; 84 (Suppl 2):S241±S244.
12 Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of insulin-
like growth factors. Endocr Rev 1994; 15:80±101.
13 Takenaka A, Oki N, Takahashi SI, Noguchi T. Dietary restriction of single
. essential amino acids reduces plasma insulin-like growth factor-I (IGF-I) but
does not affect plasma IGF-binding protein-1 in rats. J Nutr 2000; 130:2910±
2914.
This paper demonstrates that exclusion of a single essential amino acid (i.e. either
leucine, lysine, methionine, or threonine) from an otherwise nutritionally complete
diet reduces the plasma IGF-I concentration and body weight gain.
14 Wojnar MM, Fan J, Li YH, Lang CH. Endotoxin-induced changes in IGF-I
differ in rats provided enteral vs parenteral nutrition. Am J Physiol Endocrinol
Metab 1999; 276:E455±E464.
15 Muller EE, Locatelli V, Cocchi D. Neuroendocrine control of growth hormone
secretion. Physiol Rev 1999; 79:511±607.
16 Van den Berghe G. Novel insights into the neuroendocrinology of critical illness.
. . Eur J Endocrinol 2000; 143:1±13.
This review summarizes the original studies of Van den Berghe and colleagues
related to the neuroendocrinology of critical illness. It was originally assumed that
the elevation in growth hormone secretion observed during early injury was
sustained during the latter stages of critical illness. The author, however, presents
data invalidating this assumption and suggests that this newly recognized
difference may in part explain the increased mortality associated with growth
hormone treatment in critically ill patients; N Engl J Med 1999; 341:785-792.
17 Briard N, Dadoun F, Pommier G, et al. IGF-I/IGFBPs system response to
endotoxin challenge in sheep. J Endocrinol 2000; 164:361±369.
18 Dahn MS, Lange MP. Systemic and splanchnic metabolic response to
exogenous human growth hormone. Surgery 1998; 123:528±538.
19 Defalque D, Brandt N, Ketelslegers JM, Thissen JP. GH insensitivity induced
by endotoxin injection is associated with decreased liver GH receptors. Am J
Physiol Endocrinol Metab 1999; 276:E565±E572.
20 Mao Y, Ling PR, Fitzgibbons TP, et al. Endotoxin-induced inhibition of growth
hormone receptor signaling in rat liver in vivo. Endocrinology 1999;
140:5505±5515.
21 O'Leary MJ, Quinton N, Ferguson CN, et al. In rats with sepsis, the acute fall
in IGF-I is associated with an increase in circulating growth hormone-binding
protein levels. Int Care Med 2000; 26:1547±1552.
22 Zhu T, Goh ELK, Graichen R, et al. Signal transduction via the growth hormone
. receptor. Cell Signal 2001; 13:599±616.
This review provides an up-to-date summary of the pertinent signal transduction
pathways used by growth hormone in an attempt to provide a better understanding
of the various physiological functions of the hormone.
23
.. Davey HW, Xie T, McLachlan MJ, et al. STAT5b is required for GH-induced
liver Igf-I gene expression. Endocrinology 2001; 142:3836±3841.
This is the first paper to demonstrate in vivo that deletion of STAT5b is capable of
decreasing the basal content of IGF-I mRNA in intact mice as well as preventing
growth hormone from increasing IGF-I mRNA content in livers from hypophy-
sectomized mice.
24 Bergad PL, Schwarzenberg SJ, Humbert JT, et al. Inhibition of growth hormone
. . action in models of inflammation. Am J Physiol Cell Physiol 2000; 279:C1906±
C1917.
Using hypophysectomized rats, the authors demonstrate that pretreatment with
endotoxin decreases the activation of STAT5 and STAT3, and their subsequent
binding to appropriate nuclear response elements. Complementary in-vitro studies
further indicate that TNF, IL-1 and IL-6 treatment of isolated hepatocytes is
capable of inhibiting growth hormone-induced increases in Spi 2.1 mRNA
expression and reporter activity.
25 Greenhalgh CJ, Hilton DJ. Negative regulators of cytokine signaling. J Leukoc
. Biol 2001; 70:348±356.
A concise, well-written review of the expanding field of SOCS proteins. Studies
utilizing SOCS knockout mice are summarized in an attempt to determine the
physiological role for these potential regulators.
26 Metcalf D, Greenhalgh CJ, Viney E, et al. Gigantism in mice lacking suppressor
. of cytokine signalling-2. Nature 2000; 405:1069±1073.
The first demonstration that deletion of the SOCS-2 gene leads to increased
postnatal growth of mice, which is associated with an increased expression of
IGF-I mRNA in liver and other organs.
27 Colson A, Le Cam A, Maiter D, et al. Potentiation of growth hormone-induced
. . liver suppressors of cytokine signaling messenger ribonucleic acid by
cytokines. Endocrinology 2000; 141:3687±3695.
Using the liver from intact rats, this paper confirms the ability of endotoxin to
increase hepatic SOCS-3 and CIS mRNA content under in-vivo conditions.
Additionally, data are presented that nicely demonstrate that in cultured
hepatocytes interleukin-1b and TNFa, but not inerleukin-6, are capable of
interacting synergistically with growth hormone to potentiate the increase in
SOCS-3, CIS and, to a lesser extent, SOCS-2 mRNA expression.
28 Davey HW, McLachlan MJ, Wilkins RJ, et al. STAT5b mediates the GH-
induced expression of SOCS-2 and SOCS-3 mRNA in the liver. Mol Cell
Endocrinol 1999; 158:111±116.
29 Johnson TS, O'Leary M, Justice SK, et al. Differential expression of
suppressors of cytokine signalling genes in response to nutrition and growth
hormone in the septic rat. J Endocrinol 2001; 169:409±415.
30 Dey BR, Spence SL, Nissley P, Furlanetto RW. Interaction of human
suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-
I receptor. J Biol Chem 1998; 273:24095±24101.
31 Dey BR, Furlanetto RW, Nissley P. Suppressor of cytokine signalling
(SOCS)-3 protein interacts with the insulin-like growth factor-I receptor.
Biochem Biophys Res Commun 2000; 278:38±43.
32 Sadowski CL, Wheeler TT, Wang LH, Sadowski HB. GH regulation of IGF-I
. . and suppressor of cytokine signaling gene expression in C2C12 skeletal
muscle cells. Endocrinology 2001; 142:3890±3900.
These studies convincingly demonstrate that growth hormone can increase IGF-I
gene expression in skeletal muscle cells in culture, and that this increase is
associated with increased tyrosine phosphorylation of the growth hormone
receptor, JAK2 and STAT5a and 5b. Additionally, growth hormone increased
mRNA expression of SOCS-2 in this cell type.
33 Frost RA, Nystrom GJ, Lang CH. Regulation of IGF-I mRNA and signal
. transducers and activators of transcription-3 and -5 (Stat-3 and -5) by GH in
C2C12 myoblasts. Endocrinology 2002; 143:492±503.
Data contained within demonstrate that JAK2 and JAK3 and their downstream
targets, STAT3 and STAT5, may play an important role in the expression of IGF-I
mRNA in response to growth hormone.

34 Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with
. . IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab 2000;
278:E967±E976.
This review focuses on data pertaining to the structure-function relationship for
IGF binding to various IGFBPs and summarizes natural modifications in IGFBPs
that influence IGF binding. Additional sections of the review are devoted to
describing studies demonstrating that IGFBPs can either inhibit or stimulate IGF
activity. Finally, the last section of the review illustrates IGF receptor-independent
actions of selected IGFBPs.
35 Tomas FM. Insulin-like growth factor-I (IGF-I) analogue, LR(3)IGF-I,
ameliorates the loss of body weight but not the skeletal muscle during food
restriction. Growth Horm IGF Res 2001; 11:92±103.
36 Tomas FM, Knowles SE, Owens PC, et al. Insulin-like growth factor-I (IGF-I)
and especially IGF-I variants are anabolic dexamethasone-treated rats.
Biochem J 1992; 282:91±97.
37 Hoeflich A, Nedbal S, Blum WF, et al. Growth inhibition in giant growth hormone
. transgenic mice by overexpression of insulin-like growth factor binding protein-
2. Endocrinology 2001; 142:1889±1898.
The eloquent studies in this paper indicate that overexpression of IGFBP-2 inhibits
normal age-related growth as well as the increased growth produced by
overexpression of growth hormone. In the transgenic mice, IGFBP-2 was
overexpressed in a number of tissues, including skeletal muscle, and the ability
of this binding protein to impair growth was due at least in part to its effect on
carcase weight. These data suggest an inhibitory effect of IGFBP-2 on muscle
protein balance under in-vivo conditions.
38 Silha JA, Gui Y, Modric T, et al. Overexpression of the acid-labile subunit of
the IGF ternary complex in transgenic mice. Endocrinology 2001; 142:4305±
4313.
39 Frost RA, Lang CH. Differential effects of insulin-like growth factor I (IGF-I)
and IGF-binding protein-1 on protein metabolism in human skeletal muscle
cells. Endocrinology 1999; 140:3962±3970.
40 Rajkumar K, Krsek M, Dheen ST, Murphy LJ. Impaired glucose homeostasis
in insulin-like growth factor binding protein-1 transgenic mice. J Clin Invest
1996; 98:1818±1825.
41 Lang CH, Liu X, Nystrom GJ, Frost RA. Acute response of IGF-I and IGF
binding proteins induced by thermal injury. Am J Physiol Endocrinol Metab
2000; 278:E1087±E1096.
42 Fan J, Char D, Bagby GJ, et al. Regulation of insulin-like growth factor-I (IGF-
I) and IGF-binding proteins by tumor necrosis factor. Am J Physiol Regul
Integr Comp Physiol 1995; 269:R1204±R1212.
43 Lang CH, Nystrom GJ, Frost RA. Burn-induced changes in IGF-I and IGF
. . binding proteins are partially glucocorticoid-dependent. Am J Physiol Regul
Integr Comp Physiol 2001; 282:R207±R215.
This paper characterizes the changes in IGF-I and various IGFBPs in blood and
selected tissues in response to thermal injury. The data presented suggest that the
burn-induced decrease in plasma IGF-I is largely dependent on the concomitant
increase in glucocorticoids. In contrast, the increase in IGFBP-1 in blood, liver and
kidney were only partially prevented by the glucocorticoid antagonist RU486. The
burn-induced decrease in IGFBP-3 in blood and liver were glucocorticoid
independent. Finally, there was little evidence that the overproduction of TNF
was a mediator for any of the burn-induced changes in either IGF-I or IGFBPs.
44 Li YH, Fan J, Lang CH. Differential role of glucocorticoids in mediating
endotoxin-induced changes in IGF-I and IGFBP-1. Am J Physiol Regul Integr
Comp Physiol 1997; 272:R1990±R1997.
45 Lang CH, Nystrom GJ, Frost RA. Regulation of IGF binding protein-1 in
HepG2 cells by cytokines and reactive oxygen species. Am J Physiol
Gastrointest Liver Physiol 1999; 276:G719±G727.
46 Frost RA, Nystrom GJ, Lang CH. Stimulation of insulin-like growth factor
. . binding protein-1 synthesis by interleukin-1b: requirement of the mitogen-
activated protein kinase pathway. Endocrinology 2000; 141:3156±3164.
Data contained herein indicate that at least one cytokine, interleukin-1b, stimulates
IGFBP-1 synthesis and secretion via activation of the MAP kinase signaling
pathway. Additionally, cAMP analogs were also demonstrated to increase IGFBP-
1, not via a MAP kinase pathway but, instead, via activation of PKA.
47 Fernqvist-Forbes E, Hilding A, Ekberg K, Brismar K. Influence of circulating
epinephrine and norepinephrine on insulin-like growth factor binding protein-1
in humans. J Clin Endocrinol Metab 1997; 82:2677±2680.
Catabolic response to injury and infection Lang and Frost 279
48 Hooper SB, Bocking AD, White SE, et al. Catecholamines stimulate the
synthesis and release of insulin-like growth factor binding protein-1 (IGFBP-
1) by fetal sheep liver in vivo. Endocrinology 1994; 134:1104±1112.
49 Rodriquez-Arnao J, Yarwood G, Ferguson C, et al. Reduction in circulating
IGF-I and hepatic IGF-I mRNA levels after caecal ligation and puncture are
associated with differential regulation of hepatic IGF-binding proteins-1, -2,
and -3 mRNA levels. J Endocrinol 1996; 151:287±292.
50 Jurasinski CV, Vary TC. Insulin-like growth factor-I accelerates protein
synthesis in skeletal muscle during sepsis. Am J Physiol Endocrinol Metab
1995; 269;E977±E981.
51 Fang CH, Li BG, Sun X, Hasselgren PO. Insulin-like growth factor I reduces
. ubiquitin and ubiquitin-conjugating enzyme gene expression but does not inhibit
muscle proteolysis in septic rats. Endocrinology 2000; 141:2743±2751.
This study illustrates that IGF-I is able to stimulate muscle protein synthesis but not
inhibit muscle protein degradation in septic rats.
52 Fang CH, Li BG, Wang JJ, et al. Treatment of rats with insulin-like growth
factor I inhibits the catabolic response in skeletal muscle following burn injury.
Am J Physiol Regul Intregr Comp Physiol 1998; 275:R1091-R1098.
53 Svanberg E, Frost RA, Lang CH, et al. IGF-I/IGFBP-3 binary complex
modulates sepsis-induced inhibition of protein synthesis in skeletal muscle.
Am J Physiol Endocrinol Metabol 2000; 279:E1145±E1158.
54 Wang W, Iresjo BM, Karlsson L, Svanberg E. Provision of rhIGF-I/IGFBP-3
complex attenuated development of cancer cachexia in an experimental tumor
model. Clin Nutr 2000; 19:127±132.
55 Jeschke MG, Herndon DN, Barrow RE. Insulin-like growth factor I in
combination with insulin-like growth factor binding protein 3 affects the
hepatic acute phase response and hepatic morphology in thermally injured
rats. Ann Surg 2000; 231:408±416.
56 Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth.
. . Proc Natl Acad Sci USA 2001; 98:9306±9311.
This paper describes follistatin as an endogenous agent that blocks signaling
through the myostatin pathway and therefore suggests possible molecular
mechanisms that may be responsible for changes in muscle growth. This paper
also contains a thorough discussion of early seminal work by this laboratory related
to myostatin.
57 Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, et al. Organization of the
human myostatin gene and expression in healthy men and HIV-infected men
with muscle wasting. Proc Natl Acad Sci USA 1998; 95:14938±14943.
58 Wehling M, Cai B, Tidball JG. Modulation of myostatin expression during
modified muscle use. FASEB J 2000; 14:103±110.
59 Taylor WE, Bhasin S, Artaza J, et al. Myostatin inhibits cell proliferation and
. . protein synthesis in C C
2 12 cells. Am J Physiol Endocrinol Metab 2001;
280:E221±E228.
This paper describes the synthesis and purification of human recombinant
myostatin using CHO cells. Addition of this purified protein to myocytes dose
dependently inhibited cell proliferation, DNA synthesis, and protein synthesis. It is
noteworthy, that myostatin did not increase protein degradation or apoptosis in
myocytes.
60 Lang CH, Silvis C, Nystrom G, Frost RA. Regulation of myostatin by
. . glucocorticoids after thermal injury. FASEB J 2001; 15:1807±1809.
This paper presents data showing that an increase in muscle myostatin occurs in
response to thermal injury and excess glucocorticoids. Specifically, the burn-
induced increase in myostatin mRNA appears to be glucocorticoid dependent but
TNF independent based on inhibitor studies. Finally, because myostatin was not
increased in response to the injection of endotoxin or recombinant human TNFa or
the induction of peritonitis, all insults which impair muscle protein balance, up-
regulation of this TGFb family member does not appear to be an essential mediator
for the trauma-induced muscle wasting observed in adult animals.
61 Ma K, Mallidis C, Artaza J, et al. Characterization of 5'-regulatory region of
. human myostatin gene: regulation by dexamethasone in vitro. Am J Physiol
Endocrinol Metab 2001; 281:E1128±E1136.
This paper demonstrates for the first time that the human myostatin gene contains
the promoter sequence for several muscle growth response elements including
response elements for glucocorticoids, androgen, thyroid hormone, myogenic
differentiation factor 1, myocyte enhancer factor 2, peroxisome proliferator-
activated receptor, and nuclear factor-kB. Moreover, dexamethasone was able to
dose dependently increase transcriptional activity of the full-length myostatin
promoter in C2C12 myotubes.