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1 Department of Surgery, University of Cincinnati, Cincinnati 45267-0558; and 2 Shriners Hospitals for Children, Cincinnati, Ohio 45229-3095
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Sepsis-induced muscle cachexia is
associated with increased expression of several genes in the
ubiquitin-proteasome proteolytic pathway, but little is known about the
activation of transcription factors in skeletal muscle during sepsis.
We tested the hypothesis that sepsis upregulates the expression and
activity of the transcription factors CCAAT/enhancer binding protein
(C/EBP)-
and -
in skeletal muscle. Sepsis was induced in
rats by cecal ligation and puncture, and control rats were sham
operated. C/EBP- and - DNA-binding activity was determined by
electrophoretic mobility shift assay and supershift analysis. In
addition, C/EBP- and - nuclear protein levels were determined by
Western blot analysis. Sepsis resulted in increased DNA-binding
activity of C/EBP, and supershift analysis suggested that this
reflected activation of the - and -isoforms of C/EBP.
Concomitantly, C/EBP- and - protein levels were increased in the
nuclear fraction of skeletal muscle. In additional experiments, we
tested the role of glucocorticoids in sepsis-induced activation of
C/EBP- and - by treating rats with the glucocorticoid receptor antagonist RU-38486. This treatment inhibited the
sepsis-induced activation of C/EBP- and -, suggesting that
glucocorticoids participate in the upregulation of C/EBP in skeletal
muscle during sepsis. The present results suggest that C/EBP- and
- are activated in skeletal muscle during sepsis and that this
response is, at least in part, regulated by glucocorticoids.
transcription factors; cachexia; proteolysis; ubiquitin; proteasome; CCAAT/enhancer binding protein; deoxyribonucleic acid
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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MUSCLE CACHEXIA during sepsis and various other catabolic conditions, including cancer, burn injury, starvation, and uremia, mainly reflects increased ubiquitin-proteasome-dependent protein degradation (10). Muscle wasting in these conditions is associated with increased expression of several genes in the ubiquitin-proteasome proteolytic pathway (25, 26). In addition, there is evidence that mRNA levels for calpains are increased in skeletal muscle during sepsis, possibly reflecting the role of calcium-calpain-dependent release of myofilaments from the sarcomere before ubiquitination and degradation by the 26S proteasome (30).
Despite the fact that the expression of several genes that are involved
in the regulation of protein breakdown is increased in cachectic
muscle, little is known about the activation of transcription factors
in skeletal muscle. Sequence analysis of genes that are upregulated in
septic muscle, such as the genes for calpains and members of the
ubiquitin-proteasome pathway (12, 13, 15, 22, 23, 31),
demonstrated that the promoter regions of several of these genes
contain binding sites for transcription factors commonly associated
with inflammation, including nuclear factor-
B (NF-B), activating
protein-1 (AP-1), and CCAAT/enhancer binding protein (C/EBP) (Fig.
1). In a recent study we found that
sepsis in rats influenced the activity of AP-1 and NF-B in skeletal muscle (17). In contrast, the regulation of C/EBP in
skeletal muscle during sepsis is poorly understood.
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The C/EBP family of transcription factors consists of at least
six isoforms: C/EBP-
, -, -
, -, and -
and
C/EBP-homologous protein-10 (CHOP-10) (1, 14, 19).
The different isoforms form homo- or heterodimers at a leucine zipper
region before binding to DNA. The composition of the dimers and
abundance of the isoforms vary between different tissues and
conditions. Among the C/EBP family members, there is evidence that
C/EBP- and - are particularly important for the inflammatory
response (19).
The purpose of the present study was to test the hypothesis that sepsis
upregulates the expression and activity of C/EBP- and - in
skeletal muscle. Because in other studies we found evidence that
glucocorticoids regulate sepsis-induced muscle cachexia (8, 9,
24), we also examined the potential role of glucocorticoids in
C/EBP activation in septic muscle. This was done by treating rats with
the glucocorticoid receptor antagonist RU-38486 (18). Results reported here provide evidence that sepsis upregulates the
expression and activity of C/EBP- and - in skeletal muscle and
that this response to sepsis is at least in part regulated by glucocorticoids.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals.
Sepsis was induced in male Sprague-Dawley rats (40-60 g) by cecal
ligation and puncture (CLP) as described previously (8, 24,
25). Control rats underwent sham operation, i.e., laparotomy and
manipulation but no ligation or puncture of the cecum. All rats were
resuscitated with 100 ml/kg body wt of saline administered subcutaneously on the back at the time of surgery. The rats had free
access to drinking water, but food was withheld after surgery to avoid
any influence on metabolic changes caused by different food intake
between the two groups of rats. At different time points up to 16 h after CLP or sham operation, the extensor digitorum longus (EDL) and
soleus muscles were harvested and immediately frozen at 
70° for
subsequent study. In previous reports from this laboratory,
energy-ubiquitin-dependent protein breakdown and gene expression of
several components of the ubiquitin-proteasome proteolytic pathway
(24, 25, 27), as well as calpains (30), were
increased in muscle after induction of sepsis in rats by CLP.
Preparation of nuclear protein. Nuclei were isolated from EDL and soleus muscles of sham-operated and septic rats as described previously (5, 17) with the addition of 2 µM phenylmethylsulfonyl fluoride, protease inhibitor cocktail (Sigma Chemical, St. Louis, MO; P8340), and phosphatase inhibitor cocktail I (Sigma, P2850) to all buffers. To increase the amount of nuclear protein, muscles from five rats were pooled for each electrophoretic mobility shift assay (EMSA). The nuclear preparations were examined under a light microscope, and only preparations containing even, round nuclei were used for further analysis. The nuclear proteins were extracted from the nuclei into buffer containing 75 mM HEPES (pH 7.5), 60 mM KCl, 0.42 M NaCl, 0.1 mM EDTA, 0.1 mM EGTA, 40% glycerol, 0.5 mM dithiothreitol (DTT), 0.5 mM spermidine, and 0.5 mM spermine on ice for 30 min. The samples were centrifuged at 16,000 g for 20 min, and the supernatants were saved as the nuclear extracts. A Bio-Rad Bradford protein assay kit was used to determine protein concentrations in the nuclear extracts (Bio-Rad Laboratories, Hercules, CA).
EMSA.
Oligonucleotide encoding the sequence for C/EBP binding (5'-TGC AGA TTG
CGC AAT CTG CA) (Santa Cruz Biotechnology, Santa Cruz, CA) was end
labeled with [-32P]ATP using T4 polynucleotide kinase
(Amersham Pharmacia Biotech, Piscataway, NJ). End-labeled probe was
purified from unincorporated [-32P]ATP using a
purification column (Bio-Rad Laboratories) and recovered in Tris-EDTA
buffer, pH 7.4. Nuclear protein (20 µg) was incubated in buffer
containing 12% glycerol (vol/vol), 12 mM HEPES, pH 7.9, 4 mM
Tris · HCl, pH 7.9, 1 mM EDTA, 1 mM DTT, 25 mM KCl, 5 mM MgCl2, and 0.04 µg/µl poly(dI.dC) (Boehringer Mannheim,
Indianapolis, IN). Labeled probe was added, and the samples were
incubated for 30 min on ice. Where indicated in RESULTS, an
excess (15×) of unlabeled consensus or mutant oligonucleotide (5'-TCG
AGA GAC TAG TCT CTG CA; nucleotide substitutions
underlined; Santa Cruz Biotechnology) was added to test the
specificity of the EMSA. For supershift reactions, 1 µl of rabbit
polyclonal or mouse monoclonal antibody to C/EBP- or rabbit
polyclonal antibody to C/EBP- (Santa Cruz Biotechnology) was added
30 min after addition of the radiolabeled probe with an additional 15 min of binding time at room temperature. Samples were subjected to
electrophoretic separation on a nondenaturing 5% polyacrylamide gel at
100 V in 0.5 × TBE buffer (1 × TBE = 89 mM
Tris-borate, 2 mM EDTA, pH 8.3). Gels were dried and analyzed by
exposure to PhosphorImage screens (Molecular Dynamics, Sunnyvale, CA).
Western blot analysis.
Nuclear proteins (50 µg) were separated electrophoretically on an
8-16% Tris-glycine gel (Novex, San Diego, CA). The proteins were
transferred to nitrocellulose membrane, and Western blot analysis was
performed using a polyclonal antibody to C/EBP- or C/EBP- (Santa
Cruz Biotechnology).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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C/EBP DNA-binding activity in EDL muscle was increased 4 h
after induction of sepsis by CLP and remained increased throughout the
duration of the experiment (Fig. 2,
left). At earlier time points (1 and 2 h), there was no
difference in C/EBP DNA-binding activity between septic and
sham-operated rats (data not shown). The C/EBP binding activity in
muscles from control rats was higher at 16 h than at earlier time
points, most likely reflecting the fact that these rats were subjected
to trauma (laparotomy) and fasting. The relative difference in C/EBP
DNA-binding activity between sham-operated and septic rats was most
pronounced at 4-8 h. When an excess of unlabeled wild-type C/EBP
oligonucleotide was added to the reaction, the C/EBP band on the EMSA
was obliterated, whereas a mutant C/EBP oligonucleotide did not affect
the C/EBP band. This result confirms the specificity of the EMSA.
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In previous studies we found that the catabolic response to sepsis in rats was more pronounced in the white fast-twitch EDL than in the red slow-twitch soleus muscle (11, 27). To examine whether C/EBP binding activity was differentially regulated in different types of skeletal muscle, we next determined the influence of sepsis on C/EBP activity in soleus muscle. Results from this experiment showed that C/EBP DNA-binding activity was upregulated in soleus muscle at the same time points as in the EDL muscle (Fig. 2, right).
To test whether the C/EBP- and - isoforms were involved in the
sepsis-induced activation of C/EBP, supershift analysis was performed.
When an antibody against C/EBP- was used, supershift analysis
indicated that this isoform was at least in part responsible for the
basal C/EBP binding activity in EDL muscles (Fig.
3A). Sepsis resulted in
upregulation of C/EBP- binding activity noted at 4 h and
persisting throughout the septic course. Sham operation as well
resulted in increased C/EBP- activity. Supershift analysis showed
that C/EBP- DNA-binding activity was low under basal conditions and
was upregulated in EDL muscles during sepsis (Fig. 3A).
Because of the low basal C/EBP- activity, the relative difference
between muscles from sham-operated and septic rats was more pronounced for C/EBP- than for C/EBP-.
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Supershift analysis of the EMSA from soleus muscle showed a similar
pattern as seen in the EDL muscle. Thus there was evidence of C/EBP-
DNA-binding activity under basal conditions and upregulation of both
C/EBP- and - during sepsis (Fig. 3B).
An additional way to examine the involvement of the different isoforms
in the activation of C/EBP is to determine the expression of C/EBP-
and - proteins. Results from experiments in which Western blot
analysis was performed on nuclear proteins were consistent with the
supershift analysis, i.e., C/EBP- and - protein levels were
increased in both EDL and soleus muscles from septic rats (Fig.
4).
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Taken together, the results reported so far suggest that sepsis
upregulates the DNA-binding activity of C/EBP in skeletal muscle and
that this response at least in part reflects C/EBP- and -
activation. We next performed experiments to test the role of
glucocorticoids in the sepsis-induced activation of C/EBP in muscle.
This was important because we previously found evidence that
glucocorticoids regulate protein breakdown and the gene expression of
ubiquitin in skeletal muscle during sepsis (8, 24).
Because activation of C/EBP by sepsis was similar in EDL and soleus
muscle, only one muscle (EDL) was studied in this experiment. When rats were treated with the glucocorticoid receptor antagonist RU-38486, the
sepsis-induced activation of C/EBP was blunted (Fig.
5). Supershift analysis indicated that
RU-38486 reduced the activation of both C/EBP- and -. In this
experiment, a monoclonal antibody to C/EBP- was used that probably
explains why the supershifted band had a different position than in the
experiment depicted in Fig. 3, in which a polyclonal antibody to
C/EBP- was used. Western blot analysis suggested that RU-38486
reduced nuclear levels of both C/EBP- and - (Fig. 5,
bottom), although this effect of RU-38486 was less
pronounced than the effect on C/EBP DNA-binding activity determined by
EMSA.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, sepsis induced by CLP in rats resulted in
increased C/EBP DNA-binding activity in skeletal muscle determined by
EMSA. Supershift analysis as well as determination of protein levels by
Western blotting suggested that the - and -isoforms of C/EBP were
involved in this response to sepsis. The sepsis-induced activation of
C/EBP was reduced by the glucocorticoid receptor antagonist RU-38486,
suggesting that glucocorticoids were at least in part responsible for
the C/EBP activation in septic muscle. To our knowledge, this is the
first report of upregulated C/EBP activity in skeletal muscle during
sepsis (or in any condition associated with muscle catabolism). The
results are important because they contribute to the understanding of
the molecular regulation of sepsis-induced muscle cachexia and suggest
that transcription factor(s) involved in the inflammatory response in
other tissues may be activated in skeletal muscle as well.
Increased levels of the C/EBP- and - proteins as noted here were
reported in liver and intestinal mucosa of endotoxemic mice in previous
studies by Papaconstantinou and co-workers (2, 3). It
should be noted that the abundance of the proteins is not the only
factor accounting for their activity. Mitogen-activated protein
kinase (MAPK)-dependent phosphorylation of C/EBP-
(28) and probably of C/EBP- as well (21)
is an additional mechanism accounting for upregulation of C/EBP
DNA-binding activity. This may explain why in the present study
the inhibition by RU-38486 of C/EBP- and - DNA-binding activity
was more pronounced than the reduction of C/EBP- and - protein
levels. It is possible that the glucocorticoid receptor antagonist
inhibited C/EBP DNA-binding activity both by reducing the amounts of
the C/EBP- and -isoforms and by inhibiting signaling pathway(s).
In several previous reports, three different isoforms of C/EBP- were
detected by Western blot analysis (2, 3, 6, 7). The sizes
of the different isoforms varied somewhat between different tissues and
cell types, but the largest C/EBP- isoform was reported to be ~36
kDa, similar to the size found in the present study. A recent report
provided evidence that the smaller C/EBP- isoforms may be products
of C/EBP- degradation generated during preparation of tissues
(4). Because of this, and because only minimal amounts of
smaller C/EBP- isoforms (30 and 20 kDa) were noticed in the present
experiments, only changes in the larger C/EBP- isoform were reported here.
We tested the potential role of glucocorticoids in sepsis-induced C/EBP activation by treating rats with the glucocorticoid receptor antagonist RU-38486. In previous reports from this laboratory, RU-38486 prevented the increase in ubiquitin-proteasome-dependent proteolysis as well as the upregulation of the gene expression of ubiquitin in skeletal muscle during sepsis (8, 24). Thus the effect of RU-38486 on C/EBP activation paralleled the effects on proteolysis and ubiquitin gene expression, suggesting that C/EBP may be involved in the regulation of sepsis-induced muscle cachexia. It should be noted, however, that the present finding of a similar upregulation of C/EBP in the white, fast-twitch EDL and the red, slow-twitch soleus muscle differed from the more pronounced effect of sepsis on ubiquitin-proteasome-dependent proteolysis in white, fast-twitch muscle (11, 27). This observation is consistent with the concept that C/EBP regulates genes that are involved in sepsis-induced metabolic changes other than, or in addition to, ubiquitin-dependent proteolysis and that may occur in different types of skeletal muscle.
Although the present experiments focused on the influence of sepsis on
C/EBP activation, it is likely that other transcription factors are
also activated in skeletal muscle in this condition. In fact, we
recently reported that AP-1 DNA-binding activity was increased in
muscle of septic rats (17). In the same study, NF-B
activity was upregulated early in sepsis but was subsequently downregulated. Taken together with the present results, the
observations suggest that sepsis regulates the expression and activity
in skeletal muscle of multiple transcription factors commonly involved
in the inflammatory response. An important question, of course, is which genes in skeletal muscle are regulated by C/EBP and the other
"inflammatory" transcription factors and which of these genes (if
any) are involved in the development of muscle cachexia during sepsis.
There is evidence that genes that are activated during inflammation are
often regulated by multiple transcription factors and that the
transcription factors interact with each other during inflammation. For
example, NF-B and C/EBP binding sites are frequently found in close
proximity to each other, and the two transcription factors can interact
physically and functionally (16). Such an interaction has
been found to be important for the regulation of the genes for several
cytokines and acute-phase proteins (29). When we analyzed
the promoter regions of several genes in the ubiquitin-proteasome
proteolytic pathway using the MatInspector V2.2 program
(20) (see Fig. 1), the results revealed that the promoter
of the rat ubiquitin gene has binding sites for C/EBP and NF-B
within 64 base pairs of each other, the proteasome C3 subunit gene
promoter has NF-B and C/EBP binding sites within 17 base pairs of
each other, and the ubiquitin-conjugating enzyme E214k gene
promoter has NF-B and C/EBP binding sites within 21 base pairs of
each other. These observations provide further (albeit circumstantial)
evidence that C/EBP (and NF-B) may be involved in the regulation of
genes that are activated in cachectic muscle. Further studies are
needed to test the role of C/EBP (and other transcription factors) in
the regulation of specific genes in cachectic muscle. Although the
present study and a recent study from our laboratory (17)
only provide indirect evidence that C/EBP, NF-B, and AP-1 may be
involved in sepsis-induced muscle cachexia, the observations are
important because they provide the first evidence that these
transcription factors are activated in skeletal muscle in vivo during sepsis.
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ACKNOWLEDGEMENTS |
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The study was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-37908 and by a grant from the Shriners of North America, Tampa, FL.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P.-O. Hasselgren, Dept. of Surgery, Univ. of Cincinnati, 231 Albert Sabin Way, Mail Location 0558, Cincinnati, OH 45267-0558 (E-mail: hasselp{at}uc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00512.2001
Received 23 August 2001; accepted in final form 5 October 2001.
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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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 D. L. Allen, E. R. Bandstra, B. C. Harrison, S. Thorng, L. S. Stodieck, P. J. Kostenuik, S. Morony, D. L. Lacey, T. G. Hammond, L. L. Leinwand, et al. Effects of spaceflight on murine skeletal muscle gene expression J Appl Physiol, February 1, 2009; 106(2): 582 - 595. [Abstract] [Full Text] [PDF]
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K. Ma, C. Mallidis, S. Bhasin, V. Mahabadi, J. Artaza, N. Gonzalez-Cadavid, J. Arias, and B. Salehian Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E363 - E371. [Abstract] [Full Text] [PDF]
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