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CRH-ACTH-POMC-ADRENAL |
Department of Vegetative Physiology (K.W., R.J.W.), University of Köln, Köln 50931, Germany; Department of Physiology II (P.B., Z.M.), University of Heidelberg, Heidelberg 69120, Germany; Department of Molecular Pathology (J.-H.K.), University Hospital of Tübingen, Tübingen 72076, Germany; and Department of Animal Physiology (M.K.), University of Marburg, Marburg 35043, Germany
Address all correspondence and requests for reprints to: Katharina Weber, Ph.D., Department of Vegetative Physiology, University of Köln, Robert-Koch-Strasse 39, 50931 Köln, Germany. E-mail: katharina.weber{at}uni-koeln.de
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mitochondria are the main source of ATP in almost all cells and are responsible for approximately 90% of total oxygen consumption. However, 20–30% of the resting metabolic rate (RMR) is not explained by mitochondrial ATP synthesis but rather due to futile proton cycling across the proton leak of the inner mitochondrial membrane (3). It was reported that dexamethasone, a glucocorticoid hormone analog, stimulates transcription of genes encoded on mitochondrial DNA (mtDNA) in some hepatoma cell lines (4, 5). A rise of mitochondrial transcripts was also found in colon epithelium of rats after dexamethasone injection. This was interpreted as a compensatory stimulation of mitochondrial biogenesis preventing limitation of ATP supply to the stimulated Na+ transport occurring under these conditions (6). In the same study, an increase of cytochrome c oxidase subunit I (CO I) mRNA was also reported for skeletal muscle. This led us to the hypothesis that high glucocorticoid hormone levels may stimulate mitochondrial proliferation mainly in skeletal muscle, thus contributing significantly to the rise of RMR occurring under such circumstances. Thus, the effect of dexamethasone on mitochondrial transcript levels was initially studied in skeletal muscle and other rat tissues as well as in various cell lines. Quadriceps muscle as well as the mouse skeletal muscle cell line C2C12 was chosen for further investigation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell culture
Mouse C2C12 myoblasts were maintained in DMEM containing
10% FCS. Upon confluence, the medium was changed to DMEM containing
2% horse serum, which had been depleted of steroid hormones by
treatment with activated charcoal (7). After 3 d,
when myoblasts had fused to myotubes, medium containing dexamethasone
or control medium was added and cells were harvested for analysis
after further 3 d. In some experiments, RU 486 (10
µM) was added together with dexamethasone. Media were
replaced daily, and lactate was analyzed in the removed samples. Reuber
hepatoma cells (H-4-II-E) were cultivated in DMEM containing 10% FCS.
SV40-tranformed Chinese hamster embryo cells (CO60), which had been
engineered to constitutively overexpress the glucocorticoid hormone
receptor were described in detail previously (COR cells)
(8). For total protein and DNA analysis, cells were lysed
in perchloric acid, centrifuged, the denatured protein pellet was
dissolved in NaOH and assayed by the Bradford method (9).
Total DNA was measured in the supernatant after complete nucleic acid
hydrolysis by pentose analysis (10).
Isolation and blotting of nucleic acids
RNA was isolated from tissue pulverized under liquid nitrogen
according to Chomczynski and Sacchi (11). RNA was isolated
from cultured cells using a commercially available RNA extraction kit
(RNeasy, QIAGEN, Hilden, Germany). Mitochondrial
transcript levels were assayed in rat tissues by slot blot analysis
using a rat CO III probe. Steady-state levels of mitochondrial mRNAs
were analyzed in detail by Northern blots (quadriceps muscle, C2C12
myotubes, hepatoma cells, COR cells) using formaldehyde containing
agarose gels, nitrocellulose and the capillary transfer method, loading
5 µg of tissue RNA and 10 µg of cell RNA per lane. To measure mtTFA
mRNA in rat quadriceps, 25 µg of total RNA was loaded onto the
gel.
Hybridization of RNA blots
Blots were prehybridized for 2 h and hybridized
overnight at 42 C (prehybridization: 40% formamide; 5x SSC
(1x SSC = 0.15 M NaCl, 0.015 M
Na-citrate); 50 mmol/liter phosphate buffer, pH 7.4; 10x
Denhardt’s solution (1x Denhardt’s = 0.2 g Ficoll/liter, 0.2 g
polyvinylpyrolidone/liter, 0.2 g BSA/liter); 0.2% SDS; 500 µg/ml
salmom sperm DNA; hybridization: 50% formamide; 3x SSC; 10
mmol/liter phosphate buffer, pH 7.4; 2x Denhardt’s solution; 0.2%
SDS, 170 µg/ml salmom sperm DNA). cDNA probes isolated from
appropriate plasmids or PCR products labeled to high specific
radioactivity by the random priming method were used for hybridization
(12). Probes for mitochondrial transcripts were described
in detail previously (13). After hybridization, blots were
washed at 42 C (2 x 15 min in 2x SSC, 0.1% SDS followed by
2 x 15 min in 0.1x SSC, 0.1% SDS). A mouse full-length
uncoupling protein (UCP)-3 cDNA was cloned by RT-PCR. Poly A+ RNA
isolated from skeletal muscle was reverse transcribed using SuperScript
II with random hexamers (Life Technologies, Karlsruhe,
Germany). A full-length UCP-3 fragment was amplified from cDNA
by PCR using the primer 5' CTA ATG GAG TGG AGC CTT AGG-3' (forward) and
primer 5'-GCC TGC TTG CCT TGT TCA-3' (reverse). The PCR product at a
size of 1093 bp was gel-extracted, ligated by T/A cloning in
pGEM-T, and transformed into Escherichia coli
DH5
for amplification.
To measure mtTFA mRNA, a 1550-bp probe encoding mouse mTFA cloned into the EcoRI site of pBS-KS was used (14); in this case, hybridization temperature was 38 C, yeast total tRNA was used instead of salmon sperm DNA for blocking and only two washes were employed after hybridization (2 x 15 min, 0.1x SSC, 0.1% SDS, 38 C). Between hybridizations, blots were stripped from the previous probe (4 x 5 min incubations in boiling 0.01x SSC, 0.01% SDS) and were finally hybridized to cytosolic 28S tRNA for normalization. For this, hybridization temperature was 44 C and the last two washing steps were performed at 50 C. Blots were exposed to x-ray films, and the films were evaluated densitometrically using a video camera-based analysis system and AIDA software version 1.0 (Raytest, Straubenhardt, Germany). For quantitation, densitometric data for mitochondrial transcripts were normalized to the 28S rRNA signal, taking care that the signal was in the linear range of the film.
Immunoblotting
Small pieces of frozen tissue or cell pellets were
homogenized in 62.5 mM Tris (pH 6.8), 2% SDS, 10%
glycerol at 95 C using a small glass-Teflon homogenizer. Protein
samples (20 µg) were run on 12.5% slab gels (8 x 7 x 0.15
cm) and a 3% stacking gel at 100 V, for 3 h. Proteins were
transferred to nitrocellulose in an electroblot apparatus in 154
mM glycin, 20 mM Tris (pH 8.3) and 20%
methanol at 30 V, 100 mA for 3 h. Blots were subsequently blocked
in 20 mM Tris, pH 7.5, 150 mM NaCl, 0.5%
Tween, 2% BSA, and 1% milk powder for 2 h and incubated
overnight in the same buffer containing rabbit antiserum raised against
mouse mtTFA (15) in a 1:1000 dilution or a polyclonal
antibody against UCP-3 (Alexis Biochemicals, Grumberg, Germany)
in a 1:1000 dilution. As a positive control, the mouse UCP-3 protein
was overexpressed in HEK293 cells by transient transfection. For this,
the UCP-3 insert was excised from pGEM-T-UCP-3 with
NotI/ApaI and subcloned into a CMV-driven
expression vector (pEGFP-N1, CLONTECH Laboratories, Inc.).
After washing, protein bands were visualized by incubation with
donkey-antirabbit IgG antiserum, horseradish-peroxidase conjugated and
chemiluminescence detection (ECL, Amersham Pharmacia Biotech, Freiburg, Germany). Chemiluminescent blots were
exposed to x-ray films and bands of interest were evaluated
densitometrically using a video camera based analysis system and the
AIDA, Version 1.0, software (Raytest).
Determination of CO activity
For analysis of the mitochondrial marker enzyme,
cytochrome c oxidase, a small piece of frozen muscle (20–30 mg)
was homogenized with a glass homogenizer and pestle in 1 ml of ice-cold
phosphate buffer (100 mmol/liter, pH 7.0). C2C12 muscle cells were
rinsed with PBS, harvested by scraping them off the culture plates and
homogenized in 500 µl of the same buffer. Maximal enzyme activity was
determined spectrophotometrically by measuring the rate of oxidation of
reduced horse heart cytochrome c (Sigma,
Taufkirchen, Germany), reflected by the change in absorbance at 550 nm
(16). The protein concentration of the homogenates was
measured using BSA as standard (9). Enzyme activity was
then expressed as enzymatic units (µmol cytochrome c
min-1 mg protein-1),
using the millimolar extinction coefficient of 29.5 for reduced horse
heart cytochrome c.
Lactate production
For quantitation of lactate production, the cell culture media
were deproteinized with 1/10 volume of 6 M perchloric acid
and centrifuged for 20 min at 20,000 x g. The
supernatant was neutralized with 1/10 volume of 6
M KOH, KClO4 was pelleted
and the resulting supernatant was used for assaying lactate
concentration by a spectrophotometric test using lactate dehydrogenase
coupled to NAD+-reduction.
Statistical evaluation of results
Results are expressed as mean values ± SD and
groups were compared by t test; P < 0.05
was assumed to be statistically significant.
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Results |
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shows that this mRNA was significantly
increased in quadriceps and soleus muscle. These were chosen because
they represent skeletal muscle mainly composed of type II
fast-glycolytic or type I slow-oxidative fibers, respectively. CO III
mRNA was significantly decreased in liver but was rather unchanged in
kidney and colon epithelium. The decrease of mitochondrial gene
expression in liver was also confirmed by significantly lower levels of
12S rRNA (not shown).
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) shows a marked
stimulation of mtDNA transcription by dexamethasone. Quantitative data
for mitochondrially encoded transcripts are given in Fig. 2B. As
examples for respiratory chain subunits encoded by the nucleus, the
mRNA for cytochrome c also slightly increased after dexamethasone
treatment (0.61 ± 0.11 vs. 0.81 ± 0.05, control
vs. dexamethasone, P < 0.01), whereas no
significant increase was found for mRNA for CO subunit VIc (0.81
± 0.30 vs. 0.91 ± 0.33). Levels of the mRNA for the
nuclear encoded mitochondrial transcription factor A were also found to
be similar after 3 d of dexamethasone treatment (0.45 ± 0.13
vs. 0.55 ± 0.13, control vs. dexamethasone,
P = NS). Because this is a low abundance transcript, in
contrast to mRNAs for respiratory chain subunits, mtTFA mRNA levels
were also normalized to GAPDH mRNA to exclude nonlinearity of the 28S
rRNA signal on these blots. However, also the mtTFA/GAPDH ratio was
similar in the two groups (0.76 ± 0.15 vs. 0.80
± 0.10). In addition, levels of mtTFA protein were analyzed by Western
blotting and were found to be similar in quadriceps muscle of control
and dexamethasone treated rats (data not shown).
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Effects of dexamethasone on mitochondrial biogenesis in C2C12
cells
Among the tissues investigated in this study, the stimulatory
effect of glucocorticoid hormone on mitochondrial biogenesis seemed to
be rather specific for skeletal muscle. To further confirm this cell
specificity, mouse C2C12 myotubes were treated with dexamethasone for
3 d. To maximize the effect of the hormone, cells were cultivated
in medium containing serum which had been stripped of endogenous
steroid hormones. No obvious differences in myotube morphology or
fusion index was observed between the two groups. Also, the protein to
DNA ratio (mg/mg) as a marker for myotube differentiation was similar,
116 ± 19 in control vs. 100 ± 22
(P = NS) in dexamethasone treated cells.
Mitochondrial transcripts markedly increased in the presence of 1
µM dexamethasone (Fig. 3A),
but not at the lower concentration of 0.1 µM. MtTFA
protein was measured by Western blotting and, like in quadriceps
muscle, was found to be rather unchanged under all conditions (Fig. 3B). In an independent experiment, the increase of mitochondrial
transcripts was shown to be ablated by the presence of the
glucocorticoid hormone receptor antagonist RU 486 (10 µM)
(Fig. 3C). The normalized CO III mRNA rose from 1.35 ± 0.11 in
controls to 2.30 ± 0.14 after dexamethasone (1 µM)
treatment (P < 0.001) but remained unchanged in the
presence of RU 486 during dexamethasone treatment (1.35 ± 0.11
vs. 1.50 ± 0.57, P > 0.67 control
vs. dexamethasone + RU 486). Similar results were obtained
for CO II mRNA, together providing strong evidence that hormone action
was due to binding to steroid hormone receptors.
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). For representation, the data of d 2
are shown in Fig. 4. The mRNAs for CO
subunits II and III were significantly increased already 24 h
after dexamethasone treatment and remained elevated about 2-fold,
whereas 12S rRNA levels rose with a delay. Also, the nuclear encoded
cytochrome c mRNA was elevated, whereas mtTFA levels remained
unchanged again. The mRNA for CO subunit VIc could not be measured in
the mouse cell line with the rat probe that was used. Also given are
the data for UCP-3 mRNA, which will be discussed below.
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To show that the expanded OXPHOS capacity was actually used for
oxidative energy metabolism, the release of lactate into the cell
culture medium was analyzed. Lactate production increased gradually in
control myotubes (Fig. 5, upper
panel), reflecting increasing cell mass. It was significantly
lower already after 1 d of dexamethasone treatment and decreased
continually over the observation period of 3 d, indicating a shift
to ATP production by oxidative phosphorylation. To exclude
that this was due to the slightly different cell masses of control
vs. dexamethasone-treated myotubes (see above), in another
experimental series total cellular protein per dish was determined and
lactate production was found to be 13.8 ± 2.0 vs.
6.1 ± 1.1 mmol mg protein-1
day-1 (control vs. dexamethasone,
P < 0.01) at d 3.
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, lower panel). Lactate
production steadily increased over time, probably due to increasing
cell number in control cells. This was ablated by dexamethasone;
however it is clear that the hormone effect was much less pronounced
compared with fully differentiated myotubes (Fig. 5, upper
panel).
Effects of dexamethasone on mitochondrial biogenesis in other cell
lines
We found that dexamethasone stimulated mitochondrial biogenesis
rather specifically in skeletal muscle in vivo. Thus, we
investigated whether the glucocorticoid hormone effect was also
specific for differentiated skeletal muscle cells in vitro.
Indeed, in our hands, no changes of mitochondrial transcripts were
found in hepatoma H4-II-E cells (21A ). To exclude
the possibility that the absence of hormone effect is due to low levels
of glucocorticoid receptors in the cell strains we used, dexamethasone
was also applied to COR cells, SV40-tranformed Chinese hamster embryo
cells that had been engineered to constitutively overexpress the
glucocorticoid receptor (8). However, also in this cell
line, no changes of mitochondrial transcript levels were observed upon
glucocorticoid hormone addition (Fig. 6A, P = NS), and lactate production was similar in both
groups (Fig. 6B, P = NS).
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) nor protein (Fig. 7B). In C2C12
myotubes, there was even a tendency toward lower levels of UCP-3 mRNA
following glucocorticoid hormone exposure (Fig. 7C and Table 1).
Unfortunately, the UCP-3 protein was below the limits of detection in
myotube lysates and even in fractions of these cells enriched in
mitochondria (not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As it was shown before in several other models, also upon high glucocorticoid levels, mitochondrial biogenesis was stimulated primarily by up-regulation of transcription of the mitochondrial genome. Transcript levels of mtDNA, in particular mitochondrial mRNAs, generally correlate well with functional mitochondrial mass, either when different tissues are compared (19, 20) as well as under conditions of stimulated mitochondrial biogenesis (reviewed in Ref. 21). This was confirmed in the present study. Concomitant with 2-fold elevated levels of mitochondrial mRNAs, we found a 2-fold increase of cytochrome c oxidase activity in quadriceps muscle. Similarly, mitochondrial mRNAs rose 2- to 3-fold in dexamethasone treated myotubes together with a 2.5-fold induction of cytochrome c oxidase activity. To show that elevated respiratory chain activity was actually used for enhanced aerobic metabolism, lactate production was measured in myotubes and found to be clearly decreased upon dexamethasone treatment.
In contrast, no significant changes of mitochondrial parameters were found in undifferentiated myoblasts nor in H4-II-E hepatoma cells (21A ), although this cell line had been used before by others to study dexamethasone effects on mtDNA transcript levels (4, 5). This may be due to strain differences, different serum lots, different cell confluence or other factors. To exclude the possibility that it is due to low levels of glucocorticoid receptors in the strain used, cells were also used that constitutively overexpress the glucocorticoid receptor (8). However, also in the COR cells, dexamethasone did not affect mitochondrial biogenesis. Thus, increased occupancy of glucocorticoid receptors alone is not sufficient to increase mitochondrial gene expression. One possibility is that some unknown, additional permissive factor(s) is/are present in differentiated skeletal muscle cells that, together with occupied GR, act(s) on nuclear genes controlling mitochondrial biogenesis. Alternatively, energy demanding processes may be up-regulated specifically in skeletal muscle by glucocorticoids, which then modulate mitochondrial biogenesis to cover the expanded ATP-turnover. Strong support for the involvement of additional factors comes from the fact that cyt c mRNA was increased in both rat muscle and mouse myotubes upon dexamethasone, but no glucocorticoid responsive element can be found in the rat and mouse cyt c promoters, using the MatInspector software (22).
How does dexamethasone stimulate transcription of mtDNA, which is an important step in mitochondrial biogenesis? The mtTFA gene [tfam (23)], which was shown to be up-regulated in several models, does not seem to be a target for the glucocorticoid pathway because the mtTFA mRNA was unchanged in both models. Indeed, also the mtTFA promoter of the rat and mouse does not contain obvious glucocorticoid responsive elements. Recently, convincing evidence was provided that a glucocorticoid receptor is present within mitochondria in several cell types (24), and that mtDNA contains putative GR binding consensus sequences (25). It was thus proposed that glucocorticoids stimulate mtDNA transcription by a direct interaction with a mitochondrial GR. Such a mechanism was convincingly shown to operate for thyroid hormone via the mitochondrial T3 receptor p43 (26). In this case, mtTFA seems to regulate the overall activity of the mtDNA transcription machinery, whereas mitochondrial p43 upon T3-binding regulates in a very subtle way the mRNA/rRNA ratio due to selection of the mtDNA transcription start site (27). The functionality of the mitochondrial GR, however, has not been demonstrated yet. Upon addition of RU486, the stimulatory effect of dexamethasone was ablated, so no evidence indicative for some novel way of glucocorticoid hormone action could be shown using this tool. However, because the mitochondrial GR is highly homologous to the cytosolic receptor, RU486 may also antagonize the mitochondrial GR. Thus, at the moment, our data cannot contribute to the question whether the mitochondrial GR is functional and is involved in up-regulation of mtDNA transcription under high circulating glucocorticoid levels.
Finally, what causes elevated RMR upon high cortisol levels? One alternative mechanism to augmented ATP-turnover may be increased expression of UCP. UCP-3 is a potential candidate because this protein is expressed in skeletal muscle (28) and was shown to be induced by thyroid hormone, which also increases RMR (29). Mice overexpressing human UCP-3 in muscle are hyperphagic, but lean, providing strong evidence that high levels of UCP-3 indeed stimulate RMR in vivo (30). A 2-fold, although insignificant increase of UCP-3 mRNA has been reported in muscle of rats treated with dexamethasone (31) and also, UCP-3 expression is under the control of circulating fatty acids (32) and insulin (33). Thus, we reasoned that a direct effect of dexamethasone on UCP-3 expression alone, the hyperlipedemia and hyperinsulinemia following high circulating glucocortocoids, or a combination of these factors may up-regulate the UCP-3 gene. However, no changes of UCP-3 expression could be seen after dexamethasone treatment, neither in muscle nor in myotubes. Thus, glucocorticoids do not significantly change UCP-3 expression in skeletal muscle, neither directly, as shown in vitro nor indirectly via other systemic and metabolic effects, as shown in vivo. Uncoupling therefore does not seem to contribute to elevated RMR under high glucocorticoid levels.
Alternatively, can the increase of mitochondrial mass alone, without a concomitant rise of ATP-turnover, explain the elevated RMR induced by high cortisol levels? In humans, at a constant infusion of 200 µg/kg·h of hydrocortisone, which led to a 6-fold elevation of circulating cortisol, a 13% increase of whole body REE was reported (1). These are cortisol levels that are reported during severe stress (34). It is reasonable to postulate that glucocorticoid receptors were saturated under this regime, but also in the models used here, so that maximal effects were probably observed in all systems. It is also reasonable to assume that the 2-fold elevation of cytochrome c oxidase in our models reflects a 2-fold increase of electron transport chain activity. Thus, we have to ask whether a 2-fold increase of mitochondrial content in skeletal muscle tissue might be able to cause a 13% elevation of total body RMR. Muscle contributes to total body RMR to about 30% (13–42%) (35) in rats, and about 30% of it is due to the futile cycling of protons, the proton leak (36), which thus accounts for about 10% of RMR. Therefore, increasing mitochondrial mass in muscle by a factor of two, without changing coupling of electron flow to ATP-synthesis, could lead to a rise of total body RMR by about 20%.
In conclusion, high levels of circulating glucocorticoid hormones alone, without the contribution of hyperlipedemia and hyperinsulinemia, are sufficient to increase mitochondrial mass; however, only in skeletal muscle cells, and this alone might explain the increased RMR observed in humans. The molecular mechanisms have to be studied in more detail because no glucocorticoid responsive elements are found in important nuclear genes encoding mitochondrial key proteins. Lack of stimulation of mtTFA expression, in the presence of stimulated transcription of mtDNA, may indicate the direct involvement of the mitochondrial glucocorticoid receptor. If stimulation of this pathway alone would expand mitochondrial functional equivalents, this would imply that an increase of mtDNA transcription is sufficient to stimulate overall mitochondrial biogenesis, which has not been shown under physiological conditions so far.
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Acknowledgments |
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Footnotes |
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Abbreviations: CO, Cytochrome c oxidase; GR, glucocortocoid hormone receptor; mtDNA, mitochondrial DNA; mtTFA, mitochondrial transcription factor A; OXPHOS, oxidative phosphorylation; REE, resting energy expenditure; RMR, resting metabolic rate; UCP, uncoupling protein.
Received July 10, 2001.
Accepted for publication October 1, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 plays
a direct role in regulation of mitochondrial RNA synthesis. Mol Cell
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