1 Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta T6G 2P5; and 2 Department of Physiology and Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy, Quebec, Canada G1V 4G2
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ABSTRACT |
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Proinflammatory cytokines are important factors in the
regulation of diverse aspects of skeletal muscle function; however, the
muscle cytokine receptors mediating these functions are
uncharacterized. Binding kinetics (dissociation constant = 39 ± 4.7 × 109 M, maximal binding = 3.5 ± 0.23 × 10
12 mol/mg membrane protein) of muscle
tumor necrosis factor (TNF) receptors were obtained. Skeletal muscle
was found to express mRNAs encoding interleukin-1 type I and II
receptors, interleukin-6 receptor (IL-6R), and interferon-
receptor
by RT-PCR, but these receptors were below limits of detection of
ligand-binding assay (
1 fmol binding sites/mg protein). Twenty-four
hours after intraperitoneal administration of endotoxin to rats, TNF
receptor type II (TNFRII) and IL-6R mRNA were increased in skeletal
muscle (P < 0.05). In cultured L6 cells, the
expression of mRNA encoding TNFRII and IL-6R receptors was induced by
TNF-
, and all six cytokine receptor mRNA were induced by a mixture
of TNF-
, IFN-
, and endotoxin (P < 0.05). This
suggests that the low level of cytokine receptor expression is
complemented by a capacity for receptor induction, providing a clear
mechanism for amplification of cytokine responses at the muscle level.
tumor necrosis factor-
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INTRODUCTION |
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INJECTION OF
BACTERIA or their endotoxin [lipopolysaccharide (LPS)] in
animals results in metabolic alterations in skeletal muscle, including
enhanced protein breakdown, decreased protein synthesis
(18), decreased fatty acid uptake and oxidation
(30), insulin resistance (24), and increased
expression of inducible nitric oxide synthase (iNOS; see Ref. 24). It
has been proposed that these metabolic alterations are mediated mainly
by four proinflammatory cytokines [interleukin-1 (IL-1), interleukin-6
(IL-6), tumor necrosis factor- (TNF-
), and interferon-
(IFN-
); see Refs. 2, 18, 30], at least in vivo.
Cytokines belong to a family of small proteins mainly produced by
activated macrophages and monocytes after infection (13, 16). Injection of the proinflammatory cytokines in animals
can reproduce many manifestations seen in infection (18,
30), and specific anti-cytokine treatment can prevent or
attenuate part of the pathological process (25).
Furthermore, these cytokines have various direct actions on skeletal
muscle cell lines, including 1) stimulation of the synthesis
of nitric oxide through induction of iNOS by TNF-, IFN-
, and IL-1
(2, 41), 2) induction of insulin
resistance by TNF-
and IFN-
(2), and 3)
suppression of protein synthesis by TNF-
(14).
The work cited above suggests the presence of cytokine production and
cytokine response in skeletal muscle. As proteins, cytokines exert
their biological effects via binding to specific membrane receptors.
There are two distinct cell surface binding sites for TNF-, a type I
receptor (p55-60 kDa) and a type II receptor (p75-80 kDa),
which differ in their intracellular domains and thus mediate distinct
cellular responses (20). IL-1 has two unique receptors; the type I receptor (IL-1RI) transduces a signal, whereas the type II
receptor (IL-1RII) binds IL-1 but does not transduce a signal. The
IL-1RII acts as a sink for IL-1 and has been termed a "decoy"
receptor (10). There is only one receptor form each for
IL-6 and IFN-
(16, 19). This information
comes from other cell types, and skeletal muscle cytokine receptors
have been barely studied to date. There is one report of specific
binding of TNF-
to myotubes (5), and another more
recent study established the presence of mRNAs of TNF type I receptor
(TNFRI) and TNF type II receptor (TNFRII) in skeletal muscle
(21).
The first objective of our study was to establish the presence of
receptors or receptor mRNA for the four proinflammatory cytokines
thought to modulate muscle metabolism by radioligand binding assay and
RT-PCR. Because binding assays require large amounts of muscle
membrane, this experiment was first conducted on porcine sarcolemma.
Commercially available 125I-labeled cytokines are either
human or murine types; however, there is sufficient homology between
gene sequences or amino acid sequences of human/mouse and porcine
cytokines/cytokine receptors for binding to take place (9,
26, 33, 41). The binding results
from porcine sarcolemma were confirmed by using murine sarcolemma. Our
initial results demonstrated the presence of specific binding sites for
TNF- on sarcolemma by radioligand binding assay. By contrast,
specific binding of IL-1, IL-6, and IFN-
was below the limits of
detection of this assay (~1 fmol receptor/mg membrane protein);
however, receptor mRNAs could be detected by RT-PCR.
Endotoxin and cytokines are known to modulate tissue and cell cytokine
receptors in vivo and in vitro, and both downregulation and
upregulation have been noted, depending on the specific cell type
(22, 34, 38). We hypothesized
that, as shown for other cell types, a low basal level of cytokine
receptors on muscle cells might be complemented by a capacity for
receptor upregulation. It is also known that synergy among cytokines is
essential for specific biological responses. For example, stimulation
of iNOS requires an interaction between IFN- and TNF-
or IL-1
(2, 41), and further combination of cytokines
with endotoxin enhanced the induction (2). To determine
whether cytokine receptor gene expression on skeletal muscle is
modulated, we employed the following two approaches: 1)
cytokine stimulation of cultured muscle cells using a cell line (L6)
that was derived from neonatal rat thigh muscle and retains many
morphological, biochemical, and metabolic characteristics of skeletal
muscle (42), and 2) endotoxin injection in
laboratory rats to stimulate cytokine production in vivo.
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MATERIALS AND METHODS |
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Reagents.
Recombinant cytokines (murine IL-1, human IL-6, TNF-
, and
IFN-
) were obtained from Peprotech (Peprotech, Rocky Hill, NJ). Murine TNF-
(ED50: 0.02-0.05 ng/ml) and rat IFN-
(4 × 103 U/µg) were purchased from R&D Systems.
I125-labeled cytokines (murine IL-1
, human IL-6,
TNF-
, and IFN-
) were purchased from Du Pont-New England Nuclear
(Boston, MA). Endotoxin (LPS: Escherichia coli O55:B5),
aprotinin, leupeptin, pepstatin A, phenylmethylsulfonyl fluoride, wheat
germ agglutinin, and BSA (fraction V) were purchased from Sigma (St.
Louis, MO). Iscove's modified Dulbecco's medium, MEM (Eagle's), FBS,
penicillin, streptomycin, Taq polymerase, TRIzol reagent,
restriction endonucleases, and the random-primer-labeling kit were
purchased from GIBCO (Grand Island, NY). Expend-RT was from Boehringer
Mannheim (Laval, Quebec). [32P]dATP was a product of
Amersham (Oakville, Ontario).
Experimental animals. Studies were carried out in accordance with the guidelines of the Canadian Council on Animal Care. Sprague-Dawley rats, mice, and domestic pigs were obtained from breeding colonies maintained at the University of Alberta. Male animals were used for skeletal muscle membrane isolation and purification. Rats were housed in individual wire mesh cages in a temperature (24°C)- and humidity (80%)-controlled room. Animals were on a 12:12-h light-dark cycle and were fed laboratory chow (Continental Grain, Chicago, IL) containing 24% crude protein. Total RNA samples obtained from both male and female rats were used in early pilot experiments with RT-PCR; no differences due to sex were detected. For the endotoxin experiment, eight female rats (~4 mo old, weight range 366 ± 13 g) were injected intraperitoneally with endotoxin (400 µg/kg wt) or an equal volume of sterile saline (n = 4/group). Twenty-four hours after endotoxin injection, rats were killed by CO2 asphyxiation, and epitrochlearis muscles (mixed fiber type) were dissected. Muscle tissue for membrane preparation was collected from healthy mice and pigs after humane killing.
Cell culture.
The murine fibroblast tumor cell line L929 and epithelial tumor cell
line NOB-1 were provided by Dr. L. Guilbert (University of Alberta,
Edmonton, Canada) and were cultured in DMEM supplemented with 10% FBS.
The murine OKT 4 cell line (CRL-8002) and human HeLa 229 cell line
(CCL-2.1) were purchased from American Type Culture Collection
(Rockville, MD). OKT 4 cells and HeLa cells were cultured in Iscove's
modified Dulbecco's medium plus 20% FBS and Eagle's MEM with 10%
FBS, respectively. L6 skeletal muscle cells were used as a purified
myogenic cell culture. Cells were grown and maintained in monolayer
culture in -MEM containing 2% (vol/vol) FBS in an atmosphere of 5%
CO2 at 37°C. L6 myoblasts were plated in 10-cm dishes at
20,000 cells/ml and were used after complete differentiation to
myotubes (7 days postplating). L6 myotubes were then incubated with or
without 1) murine TNF-
(10 ng/ml) or 2) murine
TNF-
(10 ng/ml) + rat IFN-
(50 ng/ml) + endotoxin (10 µg/ml) for 24 h before the RNA isolation. All of the above
culture media contained 1% (vol/vol) antibiotic/antimycotic solution
(10,000 U/ml penicillin, 10,000 µg/ml streptomycin, and 25 µg/ml
amphotericin B).
Membrane Preparation
Group I.
Plasma membranes from skeletal muscle were isolated using a procedure
reported by Ohlendieck et al. (31) as in our previous work
with muscle insulin and insulin-like growth factor I receptors (28). The procedure is based on subcellular fractionation
by differential centrifugation, density gradient centrifugation, and
wheat germ agglutination. The isolated plasma membrane is essentially
devoid of sarcoplasmic reticulum and T tubular markers (31). Membrane after the density-gradient-centrifugation
step was suspended in PBS buffer and stored at 70°C for further analysis.
Group II.
Plasma membranes were from cell lines described by Bird et al.
(6). Cells (~108) were centrifuged at 500 g for 5 min, and the pellet was resuspended in 5 ml
hypotonic buffer, disrupted in Dounce glass-glass homogenate made up to
35 ml with 0.25 M sucrose containing 5 mM Tris · HCl and 1 mM
MgCl2, and centrifuged at 150,000 g for 30 min.
The pellet was resuspended in PBS and stored at 70°C. Membrane
protein was determined after solubilization with 1 N NaOH by the method
of Bradford, using BSA (fraction V; Sigma) as standard.
Radioligand Binding Assay
As described previously (6, 28), 50 µl of porcine or murine membrane suspension (2 µg protein/µl, after density-gradient centrifugation) were incubated with individual I125-labeled cytokines (murine IL-1RT-PCR
Total RNA was extracted by the guanidinium isothiocyanate/phenol/chloroform method with TRIzol Reagent based on the method developed by Chomczynski and Sacchi (8). RNAs for PCR were harvested from differentiated rat muscle tissue, as well as from the cultured rat muscle cell line (L6). Primers were based on published sequences in the literature or according their mRNA sequences submitted to the National Gene Bank with the assistance of computer programs [Genejockey II from Biosoft (Ferguson, MO) and Amplify1.2]. The primer sequences are listed in Table 1 and are specific for rat genes.
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For qualitative PCR assay, total RNA (1 µg) was reverse transcribed
into cDNA in the presence of 50 units Expand-RT, 1 mM dNTP, 1 U/µl
RNase inhibitor, 0.5 µM sequence-specific antisense primer, 10 mM
dithiothreitol, and 1× Expand RT buffer (first strand) in a total
volume of 20 µl by the procedure recommended by the manufacturer. The
PCR reaction system contained 5 µl ×10 PCR buffer, an aliquot of RT
(5-10 µl) product, 1.5 µl of 50 mM MgCl2, 1 µl of 10 mM dNTP mixture, 1.25 units Taq DNA polymerase, and 2 µl each of 10 µM sense and antisense primers in a total volume of 50 µl. Amplification was carried out as follows: for IL-1RI, IL-6 type II receptor, IL-6 receptor (IL-6R), IFN- receptor (IFNR), TNFRI, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH): 1 × 3 min at 94°C, 1 min at 60°C, and 3 min at 72°C; 45 × 30 s at 94°C, 30 s at 55°C, and 45 s at 72°C; and
1 × 7 min at 72°C. For IL-1RII and TNFRII, the "Hot-start"
protocol provided by GIBCO-BRL was employed (1 × 3 min at 94°C)
before addition of Taq polymerase, followed by addition of
enzyme at 80°C, then 35 × 45 s at 94°C, 30 s at
60°C, and 1.5 min at 72°C and 1 × 10 min at 72°C. A portion (20 µl) of RT-PCR product was electrophoresed in 1% agarose gel in
Tris-borate-EDTA (TBE) buffer. The gel was stained with
ethidium bromide and photographed with Gel-Doc 1000 (Bio-Rad).
Restriction Enzyme Digestion of PCR Products
The PCR products were purified with the Geneclean Kit (Bio 101) from agarose gels. Restriction enzymes (5-10 units) and buffers adequate to optimize the reactive condition for each restriction enzyme were added to the purified PCR product. The volume was adjusted to 20 µl with DNase-free water. These reaction mixtures were incubated at 37°C for 2 h and electrophoresed in 1% agarose gel in TBE buffer. The gel was stained and photographed as described above.Semiquantitative RT-PCR Assay
To examine the possibility of semiquantitative analysis using RT-PCR, the samples with different amounts of total RNA (0.1-0.5 µg) were assayed for cytokine receptor mRNA by RT-PCR. The RT-PCR condition was as described above, except that the cycle number was reduced (24 for IL-1RI, 26 for IL-1RII, 24 for IL-6R, 22 for TNFRI and IFNR, and 28 for TNFRII) so that PCR reaction was conducted in the exponential phase. All of the PCR reactions were repeated in triplicate. The amplified products were detected by Southern blotting. After 1% agarose gel electrophoresis, the PCR product was transferred to nitrocellulose membranes and hybridized overnight with a random-primer 32P-labeled specific cDNA probe, which was generated by PCR reaction and purified with the Geneclean kit from agarose gel. The hybridized filters were then washed, exposed to Fuji Phosphoimage plates, and analyzed using a Fuji Bioimaging analyzer BAS1800. A similar semiquantitative method has been used previously to test mRNA abundance of IL-6 and IL-6R in rat hypothalamus (15).Data Analysis
Dissociation constant (Kd) and maximal binding (Bmax) values were calculated from binding data using the GraphPad program (GraphPad Software). The results of each treatment are presented as means ± SE. Differences were analyzed statistically by the unpaired Student's t-test for comparisons between groups. ![]() |
RESULTS |
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Evidence for the Presence of TNF- Receptors in
Sarcolemma
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Evidence for the Presence of IL-1,
IL-6, and IFN- Receptors
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The ligand binding assays suggest that skeletal muscle either does not
express receptors for IL-1, IL-6, and IFN- or expresses very low
levels of these receptors. To explore the latter possibility, we
employed RT-PCR to amplify cytokine receptor mRNAs and also to
determine whether receptor mRNA expression in skeletal muscle was
subject to upregulation by cytokines, as has been shown in other cell
types expressing low levels of receptor. Four transcripts of expected
size were identified by RT-PCR in RNA from mature rat skeletal muscle
[IL-1RI, IL-1RII, IL-6R, and IFNR (Fig.
3A)]. The PCR products were
further confirmed by digestion using appropriate restriction enzymes,
and digested products of the predicted lengths appeared (Fig.
3A). Cultured muscle cells are free of other cell types, and
this source of RNA was used to determine that cytokine receptors are
expressed by muscle cells per se. L6 cells expressed mRNA
encoding both IL-1 receptor isoforms as well as IL-6R and IFNR (Fig.
3B).
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Validity of Semiquantitative RT-PCR
To evaluate the ability of this method to measure the relative abundance of receptor mRNA, a group of concentration curves was generated for each of the cytokine receptor genes that we measured under the RT-PCR conditions defined in MATERIALS AND METHODS. GAPDH gene was used as an internal control, and its level was evaluated in the same RNA samples as described (2). Data for IL-1RI and GAPDH are shown in Fig. 4. The intensity of the bands was related linearly with the initial RNA concentration in the range of 0.1-0.4/0.5 µg. A concentration within the linear range (0.25 µg) was chosen for further analysis.
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Regulation of Muscle Cytokine Receptors in Endotoxemia and the Role
of TNF-
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Regulation of Cytokine Receptors by Cytokines and Endotoxin Treatment in L6 Cells
It has been established that synergy among cytokines exists for specific biological responses. For example, stimulation of iNOS activity in skeletal muscle requires an interaction between IFN-
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DISCUSSION |
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We have identified the presence of specific binding sites and/or
mRNAs encoding receptors for four proinflammatory cytokines in skeletal
muscle tissue and L6 cells. Specific modulation of cytokine mRNA
expression was observed after stimulation of muscle by cytokines.
TNF- had been previously reported to bind to myotubes (5). Our ligand-binding studies show that
125I-TNF-
bound specifically to highly purified muscle
plasma membrane, suggesting that differentiated skeletal muscle and
transformed muscle cell types in culture express cytokine receptors.
mRNAs for two types of TNF-
receptors had been reported in skeletal muscle (21). We confirmed this result by RT-PCR in both
muscle cell lines and differentiated muscle tissue. The
Kd value for muscle TNF receptors falls in the
range of the Kd values for L929 cell TNF
receptors and showed characteristics of one-site binding, as has been
shown for other cell types (39).
Specific TNF--binding sites on sarcolemma (3.5 ± 0.23 × 10
12 mol/mg membrane protein) are ~10-fold less
abundant than those that bind insulin (Bmax = 1-5 × 10
11 mol binding sites/mg sarcolemma
protein; see Ref. 28). RT-PCR revealed the presence of mRNAs encoding
four other proinflammatory cytokine receptors (IL-1RI, IL-1RII, IL-6R,
and IFNR) in skeletal muscle; however, the levels of these receptors
were below the limits of detection of the radioligand-binding assay.
Cytokines are thought to be capable of activating a signal transduction pathway, even at very low receptor levels (10). IL-1
signal transduction has been observed in cells expressing <10 type I receptors per cell. The physiological contribution of individual cytokines may not be proportional to the density of their membrane receptors, so the significance of the discrepancy between the densities
of specific binding sites for TNF-
(3.5 ± 0.23 × 10
12 mol/mg membrane protein) and the other cytokines
(<1 × 10
12 mol/mg membrane protein) remains unclear.
The relative abundance of TNF- receptors on sarcolemma suggests that
TNF-
might play a primary direct role in regulating muscle function.
Most or all of the injurious sequelae of septic shock syndrome are
attributable to the effects of TNF-
and the cytokine cascade
triggered by TNF-
(13, 37). TNF-
appears early in the plasma after infection (13,
37), and early blockade of TNF-
inhibited the
production of IL-1 and IL-6 (13, 37). At the
same time, IFN-
, but not TNF-
, was essential to formulate a
functional cytokine cocktail inducing iNOS from skeletal muscle cells
(41). IL-6, not TNF-
, was found to shorten the
half-life of long-lived proteins in C2C12
myotubes (11). These results point to a high degree of
complexity in cytokine responses by skeletal muscle.
Our studies showed that mRNA levels for TNFRII (p75) and IL-6R were
increased in skeletal muscle samples from endotoxic animals. TNF- is
able to regulate its own receptors as well as other cytokine receptors,
and the regulation pattern is cell type specific (22, 34, 38). Our work showed that TNF-
by
itself was capable of upregulating the expression of TNFRII and IL-6R
mRNA in L6 cells after 24 h incubation, implying that this
cytokine may be the mediator of the adaptation seen in vivo after
endotoxin injection. No response to TNF-
was seen at earlier time
points (within 12 h; data not shown). Compared with other cell
types, skeletal muscle is a tissue that responds to cytokines slowly
(41). iNOS mRNA expression in myotubes was seen after
6 h incubation with cytokines, and iNOS protein was detectable
only after 12 h stimulation by cytokines (32). By
contrast, such induction occurs within 2 h in macrophages
(41). TNF-
downregulated TNFRI mRNA within 30 min and
increased the expression of IFN-
and TNF-
mRNA within 4 h in
rat tracheal epithelial cells (1). Therefore, it may take
a longer time to observe the muscle's response to cytokines compared
with fast-reacting cell types.
The various biological activities of TNF- are thought to be mediated
by two isotypes of receptors. It is not clear why only the mRNA level
of TNFRII, not TNFRI, is modified in response to TNF-
stimulation
and endotoxin challenge. Most of the known TNF-
responses are
mediated via TNFRI (p55), and this notion has been confirmed in vivo.
Mice deficient in TNFRI were resistant to endotoxic shock
(20) and tumor-induced protein breakdown in skeletal
muscle (29). However, TNFRII is associated with thymocyte
proliferation, and cytotoxicity may be a function of TNFRII alone or
together with TNFRI (20). Furthermore, TNF-
upregulated
the mRNA abundance of TNFRII but not TNFRI in human malignant
epithelial cells (22). Based on the present results, it is
hard to draw any conclusion on the participation of individual
cytokines in modulating muscle metabolism. The upregulation of IL-6R is
not surprising because TNF-
induces the production of IL-6
(13, 37). It can be speculated that some of
the effects assumed to be caused by TNF-
are mediated by IL-6.
Soluble receptors of the TNF receptor and IL-6R families are known to exist, and the circulating levels of soluble receptors are increased in various pathophysiological conditions (19, 37). Soluble receptors may act as agonists or antagonists of cytokine action (36, 37). Taking all of these factors into consideration, the significance of the mRNA expression for cytokine receptors described in the present study should be interpreted with caution, because no evidence has been provided for an increase in the corresponding protein levels or any correlation between receptor mRNA level and net biological effects.
TNFRI, IL-1RI, IL-1RII, and IFNR did not respond to TNF- at the
concentration used within 24 h of stimulation. Additionally, it
remains unknown how long the induction of TNFRII and IL-6R is sustained
and when the peak response occurs. More experiments on the time course
may elucidate these points. The concentration of TNF-
(10 ng/ml)
used in the experiment is common for in vitro studies. The level used
here is higher than physiological concentrations but relatively low
compared with other published studies (14). Peak serum
TNF-
levels were ~2 ng/ml in patients injected with endotoxin
(7), whereas TNF-
exerted its highest inhibitory effect
on protein synthesis in human myoblasts at the concentration of 100 ng/ml (14). Further dose-response experiments may reveal the threshold concentration of TNF-
necessary for in vitro
stimulation of cytokine receptor mRNA expression in L6 cells and the
concentration for maximal stimulation. Under conditions of maximal
stimulation, it may be possible hereafter to study at the protein level
with ligand-binding experiments. To fully evaluate the significance of
cytokine receptor modulation in skeletal muscle, the upregulation of
gene expression of cytokine receptors has to be associated with the
modification of specific biological activities.
We noted that the mRNA level of all six cytokine receptors was stimulated by the combination of cytokines with endotoxin. The synergy between cytokines and other factors such as endotoxin may be necessary to see the full scope of a biological response, as in the stimulation of nitric oxide release through iNOS induction (2, 41). The synergy seems to be operative at the level of cytokine receptor mRNA expression and may provide a mechanism for sensitization of cytokine responses at the tissue level. The exact role of each cytokine in muscle is intriguing and as yet difficult to elucidate. Further study with gene knock-out animals may be helpful in revealing the relations between the regulation of muscle biological activity and specific cytokine(s).
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ACKNOWLEDGEMENTS |
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This work was supported by the Natural Sciences and Engineering Research Council of Canada.
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FOOTNOTES |
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Address for reprint requests and other correspondence: V. Baracos, Dept. of Agricultural, Food and Nutritional Sciences, Univ. of Alberta, Edmonton, Alberta, Canada T6G 2P5 (E-mail: vickie.baracos{at}ualberta.ca).
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. §1734 solely to indicate this fact.
Received 14 September 1999; accepted in final form 1 February 2000.
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