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1 School of Biomedical Sciences, University Medical School, Queen's Medical Center, Nottingham NG7 2UH; 2 Dept. of Pharmacology, Queen Mary and Westfield College, University of London, London E1 4NS; and 3 Muscle and Exercise Physiology Group, Manchester Metropolitan University, Alsager ST7 2HL, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Prolonged treatment with the
2-adrenoceptor agonist clenbuterol (1-2
mg · kg body mass
1 · day 1)
is known to induce the hypertrophy of fast-contracting fibers and the
conversion of slow- to fast-contracting fibers. We investigated the effects of administering a lower dose of clenbuterol (250 µg · kg body mass1 · day
1) on skeletal muscle myosin heavy chain (MyHC)
protein isoform content and adenine nucleotide (ATP, ADP, and AMP)
concentrations. Male Wistar rats were administered clenbuterol
(n = 8) or saline (n = 6)
subcutaneously for 8 wk, after which the extensor digitorum longus
(EDL) and soleus muscles were removed. We demonstrated an increase of
type IIa MyHC protein content in the soleus from ~0.5% in controls
to ~18% after clenbuterol treatment (P < 0.05), which was accompanied by an increase in the total adenine nucleotide pool (TAN; ~19%, P < 0.05) and energy charge
[E-C = (ATP + 0.5 ADP)/(ATP + ADP + AMP); ~4%;
P < 0.05]. In the EDL, a reduction in the content of
the less prevalent type I MyHC protein from ~3% in controls to 0%
after clenbuterol treatment (P < 0.05) occurred without any alterations in TAN and E-C. These findings demonstrate that
the phenotypic changes previously observed in slow muscle after
clenbuterol administration at 1-2 mg · kg body
mass1 · day1 are also observed at a
substantially lower dose and are paralleled by concomitant changes in
cellular energy metabolism.
2-adrenoceptor agonist; adenosine 5'-triphosphate; energy charge; myosin heavy chain protein composition
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CLENBUTEROL is a
synthetic 2-adrenoceptor agonist that has been used
clinically to induce bronchial dilation after inhalation (typical dose
0.60-0.86 µg daily). Its primary advantage over other
bronchodilators is its much longer half-life (29). It has
also been utilized in the livestock industry at higher doses (2-5
mg · kg body mass1 · day1)
to increase lean muscle mass and reduce fat content, a phenomenon that
is known as repartitioning. Typically, daily treatment with clenbuterol
at this higher dose has been shown to induce an increase in rat
skeletal muscle mass of 10-20% (13, 26, 33). This is
particularly significant, because the increase in mass occurs independently of any contraction-induced hypertrophy (2, 13, 16). Muscle growth under these conditions is characterized by an
increase in the cross-sectional area of fast-contracting fibers, as
determined by use of histochemical methods (20, 26, 38). Evidence for slow-fiber hypertrophy is equivocal (25, 38). However, prolonged treatment for a period of 6-8 wk has been shown to result in the conversion of slow-contracting fibers to
fast-contracting fibers in the soleus, and to a lesser extent in the
extensor digitorum longus (EDL) (7, 9, 38).
Despite the generally accepted observation that prolonged clenbuterol treatment causes a slow-to-fast fiber type conversion in rat skeletal muscle (38), we are unaware of any data relating to the effects of clenbuterol on muscle energy metabolism. This is surprising, given the primary link between changes in cellular energy charge and the initiation of skeletal muscle growth (3). Indeed, fast-contracting muscle is known to have a higher adenine nucleotide content and energy charge than slow-contracting muscle (12).
The anabolic effect of clenbuterol has raised the possibility that it
may be useful as a treatment for loss of skeletal muscle mass due to
limb immobilization (24). Previously, an investigation of
the effects of 4 wk of daily clenbuterol treatment (~0.26
µg · kg body
mass1 · day1) on knee extensor
strength in humans after meniscectomy failed to demonstrate a
significant increase in absolute strength. However, a significantly
more rapid rehabilitation of strength was observed in the
clenbuterol-treated patients compared with controls (27). Importantly, in the same trial, clenbuterol treatment did not ameliorate the reduction in muscle cross-sectional area due to injury.
Therefore, we investigated the effects of 8 wk of clenbuterol treatment
on slow- and fast-contracting muscle of the rat at a higher dose (250 µg · kg body
mass1 · day1), which is within the
range known to induce hypertrophy (33). Our aims were,
first, to characterize whether this dose would induce slow-to-fast
changes in myosin heavy chain (MyHC) protein isoform content similar to
those reported for prolonged higher-dose treatment, and, second, to
investigate whether any such changes were accompanied by alterations in
cellular energy metabolism, a point that has not been investigated to date.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Protocol
The study involved two groups of male Wistar rats (control, n = 6; treatment, n = 8). The starting body mass was 330-350 g, and the animals were 11-12 wk of age (Charles River, Margate, UK). The treatment and control groups were administered 250 µg · kg body mass1 · day1 of clenbuterol and an
isovolume of saline, respectively, by subcutaneous bolus injection for
8 wk. This length of treatment was chosen because it has been
previously reported to result in a change in fiber-type composition of
rat skeletal muscle (38). All animals were weighed at
least weekly, and food and water consumption was determined daily.
Clenbuterol was not given on the final day, and the animals were killed
in a randomized order. The soleus and the EDL muscles of the left limb
were freeze-clamped in situ with precooled tongs, stored in liquid
nitrogen, and then freeze-dried at a later date. The soleus and the EDL
were selected because they are ideal for comparison of predominantly
slow-contracting (soleus, 85% slow-twitch fibers) and fast-contracting
(EDL, 96% fast-twitch fibers) muscles (8). After this,
the corresponding muscles were dissected from the contralateral limb
and were weighed.
SDS-PAGE
Frozen muscle samples, each from individual animals, were used to determine MyHC isoform expression. Approximately 10 µg of muscle tissue were homogenized in 100 µl of sample buffer, containing 62.5 mM Tris · HCl, 2.3% SDS (wt/vol), 10% glycerol (vol/vol), 5% 2-mercaptoethanol (vol/vol), and 0.001% bromophenol blue (wt/vol). After homogenization, samples were prepared for SDS-PAGE by heating to 60°C for 10 min in the sample buffer, followed by centrifugation at 12,000 g for 5 min at 4°C. Samples were then further diluted by a factor of 10 in sample buffer.MyHC composition of the control and treated samples was determined using one-dimensional gel electrophoresis (SDS-PAGE) according to the method of Talmadge and Roy (35). Approximately 1-2 µg of protein were loaded onto 8-cm-long slab gels (SE245, Hoefer Scientific, San Francisco, CA) and electrophoresed for 24-28 h at 4°C by use of discontinuous SDS-PAGE (4:1% stacking and 8:1% resolving gel). After electrophoresis, the gels were fixed for 1 h in 5% acetic acid and 50% ethanol and were then rinsed overnight in 5% acetic acid and 5% ethanol. The gels were then silver-stained using a modified method of Oakley et al. (30), and quantitative measurements were made by laser densitometry. Each optical density obtained was then expressed as a percentage of total MyHC content for the corresponding gel.
Muscle Metabolite Analysis
A portion of freeze-dried muscle was dissected free of visible connective tissue and blood and was powdered, and an aliquot (~10 mg dry weight) was extracted in 0.5 M perchloric acid containing 1 mM EDTA. The samples were then centrifuged, and the supernatant was neutralized with 2.2 M KHCO3 and stored frozen at
80°C.
Spectrophotometric analysis of ATP, ADP, AMP, phosphocreatine (PCr),
and creatine concentrations was performed at a later date
(17). Total creatine (TCr) was calculated to correct the
adenine nucleotide concentrations for contamination with nonmuscle
constituents (TCr = PCr + creatine).
Calculations and Statistics
All data are reported as means ± SE. Total adenine nucleotides (TAN) = [ATP]+[ADP]+[AMP], and energy charge (E-C) = [ATP] + 0.5 [ADP]/[ATP] + [ADP] + [AMP] were calculated. Comparisons between groups were made using one-way ANOVA, and when a significant F value was found (P
0.05), a Fisher's post hoc test was used to identify any significant
differences. Where appropriate, a comparison of differences in the
percentage of type I and type IIa, IIx, and IIb MyHC protein contents
between control and clenbuterol groups was made using an unpaired
Student's t-test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MyHC Content
Control animals.
In the soleus (n = 5), the MyHC protein content was of the
slow-contracting type I isoform (99.5 ± 0.5%), and the remainder was type IIa (0.5 ± 0.5%); Fig. 1.
In the EDL (n = 6), the MyHC content was of the
fast-contracting type II isoforms (97.3 ± 1.8%), and the
remainder of the slowly contracting type I isoform (2.8 ± 1.8%).
Further analysis of the gels for EDL demonstrated that the type II
isoforms were IIa (17.7 ± 11.6%), IIx (37.5 ± 7.1%), and
IIb (42.1 ± 10.3%).
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Clenbuterol-treated animals. In the soleus (n = 5), the type IIa MyHC protein isoform became apparent in all samples after clenbuterol treatment (18.2 ± 5.2%; P < 0.05 compared with respective controls); the remainder were type I (81.8 ± 5.2%) (Fig. 1). In the EDL (n = 8), there was no type I MyHC protein detected in any of the samples after treatment (P < 0.05 compared with controls). Statistical comparison between IIa and IIx bands of EDL in clenbuterol-treated (7.5 ± 5.4% and 43.1 ± 8.8%, respectively) vs. control animals was not performed because of the overlap of these bands. The percentage of IIb MyHC content (49.5 ± 9.2%) was not different from respective EDL controls.
Muscle Metabolites
Control animals.
The ATP concentration of the EDL was higher (64%, P < 0.05) than that of the soleus (Table 1),
but there was no significant difference in the concentration of ADP
between the muscles. The AMP concentration of the soleus was higher
(50%, P < 0.05) than that of the EDL. These
differences in adenine nucleotides resulted in a higher TAN (53%,
P < 0.05) in the EDL compared with the soleus (Fig.
2). The E-C of the soleus was lower
(4.4%, P < 0.05) than that of the EDL (Fig.
3). Finally, TCr was higher (44%,
P < 0.05) in the EDL [144.0 ± 5.9 mmol/kg dry
mass (dm)] compared with the soleus (100.0 ± 1.5 mmol/kg dm).
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Clenbuterol-treated animals. There was an increase in ATP (29%) and reductions in ADP (26%) and AMP (33%) concentrations in the soleus after clenbuterol treatment compared with the control animals (Table 1). As a result of these changes, the TAN of the soleus increased by 19%. However, it remained 28% (P < 0.05) and 30% (P < 0.05) lower than the TAN of the EDL in the control and clenbuterol-treated animals, respectively (Fig. 2). The E-C of the soleus also increased after clenbuterol treatment, such that it was no different from the value in EDL of control and clenbuterol-treated animals (Fig. 3). There was no change in adenine nucleotide content of the EDL after clenbuterol treatment. Similarly, TCr was not different between the control and treatment groups for either the soleus or the EDL.
Muscle Mass
There was no significant difference in soleus mass between the control and clenbuterol-treated groups (Fig. 4). However, EDL mass was significantly greater (20%) in the treatment group compared with the control group (Fig. 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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It was our aim in this study to investigate whether an 8-wk period
of daily clenbuterol administration, at a dose of 250 µg · kg
body mass1 · day1, would induce
changes in MyHC protein isoform composition and adenine nucleotide
content in fast- and slow-contracting rat skeletal muscles. We have
reported an increase of type IIa MyHC protein content in the soleus
muscle after clenbuterol treatment compared with controls. Furthermore,
this change was paralleled by increases in the TAN pool and the E-C of
the soleus. There was no type I MyHC protein in the EDL after
clenbuterol treatment, suggesting that this muscle was also becoming
faster. However, unlike the soleus, this change was not accompanied by
increases in the TAN pool and the E-C. After clenbuterol treatment, the
mass of the EDL was greater than that of the control group.
The TAN pool in skeletal muscle is a highly regulated feature, with fast-contracting muscle demonstrating a larger TAN pool compared with slow muscle. This is a result of its higher resting ATP content, which in turn reflects the contractile characteristics and the high anaerobic ATP turnover of fast contracting muscle (12). In the present study, we have demonstrated that clenbuterol treatment induced increases in both ATP and TAN contents in the soleus. However, both contents remained lower (~30%) than those observed in the EDL (from the control group). These findings suggest that some slow fibers were undergoing transition toward the adenine nucleotide profile of fast fibers. Accordingly, there was expression of type IIa MyHC protein in the soleus of the clenbuterol group. Taken together, these findings indicate that clenbuterol was capable of inducing metabolic adaptations in parallel with changes in contractile protein isoform content.
In addition to the increase in the TAN of the soleus after treatment, we demonstrated an increase in the cellular E-C. An increase in resting ATP/ADP ratio or E-C is one feature associated with an increase in mitochondrial content (10). This suggests, therefore, that the increased E-C after clenbuterol treatment in the present study may have been related to an increase in mitochondrial content. In support of this suggestion, it has been reported that 7-8 wk of clenbuterol administration can increase soleus muscle citrate synthase activity in obese female Zucker rats (36).
It has previously been reported that prolonged clenbuterol treatment,
albeit at a higher doses (~1-2 mg · kg body
mass1 · day1) than that used in the
present study, can increase the ratio of fast-twitch to slow-twitch
fibers in the EDL (7, 9, 38). In support of this
observation, there was no expression of type I MyHC protein in the EDL
after clenbuterol treatment (Fig. 1). Given that type I fibers
represent a very small proportion of the total fiber pool in EDL, it is
not surprising that TAN and E-C were unchanged after clenbuterol treatment.
We were also able to demonstrate that 8 wk of low-dose clenbuterol
treatment resulted in an increase in EDL mass compared with the control
group. This finding is consistent with previous reports that
treatment with 1-2 mg · kg body
mass1 · day1 of clenbuterol
increases the cross-sectional area of type II, but not type I, fibers
(20, 26, 38).
In the present study, clenbuterol treatment increased the content of
type IIa MyHC proteins in the soleus and reduced type I MyHC proteins
in the EDL muscles. These observations are consistent with a previous
report of an ~8% greater type II fiber content in the soleus and a
2% lower type I fiber content in the EDL (38) after
prolonged clenbuterol treatment. Recently it has been shown that this
fiber-type switching in soleus is due to an increase in IIa, IIx, and
IIb MyHC protein contents (9). It seems unlikely that the
above changes in MyHC protein isoform content of the soleus and the EDL
muscles were due to stimulation of 2-adrenoceptors, because these receptors are downregulated by 50% within 2-3 wk of
daily -agonist administration (e.g., 21, 34), and fiber-type changes
have only been reported after 6-8 wk of treatment. It is possible
that these alterations in protein isoform content were due to
stimulation of 3-adrenoceptors, which are known to be
less susceptible to downregulation (5, 28) and which have been reported to be present in the soleus but not in the EDL. Alternatively, it is possible that prolonged clenbuterol treatment may
affect hormone- or growth-factor receptor population densities.
In summary, we have demonstrated that prolonged low-dose clenbuterol
treatment increased the content of type IIa MyHC protein in the soleus.
Concomitant with this change was an increase in the TAN and the E-C.
These findings are in accordance with previously reported changes in
muscle composition after clenbuterol administration at higher doses. In
the EDL, a reduction in the less prevalent type I MyHC protein isoform
occurred without any alterations in the TAN pool and E-C of this
muscle. This may have been due to the relatively small fiber-type shift
being masked by the high fast fiber population of the EDL (~97% fast
muscle fibers). Finally, we have confirmed that a dose of 250 µg · kg body mass1 · day1
is sufficient to induce hypertrophy of EDL.
Perspectives
We have investigated the effects of the anabolic agent clenbuterol on skeletal muscle adenine nucleotide metabolism because of the proposed central role of the cellular E-C in metabolic control (1). For example, a number of studies have shown that catabolic states such as sepsis and trauma are associated with marked reductions in the TAN and cellular E-C (6, 37). We have demonstrated that clenbuterol increased the type IIa MyHC isoform content, the TAN pool, and the cell E-C of soleus but not of EDL. The mechanism by which these changes occur, however, remains unclear. Future work would add to our knowledge by elucidating whether the increase in type IIa MyHC protein expression of soleus observed in the present study is accompanied by an increase in mitochondrial content and/or function. In addition, a time-course study might establish whether changes in adenine nucleotide metabolism are linked to changes in MyHC protein isoform expression.| |
ACKNOWLEDGEMENTS |
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We thank Dr. Steve Demont (Glaxo Pharmaceuticals, London, UK) for the generous gift of clenbuterol.
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FOOTNOTES |
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P. E. Rajab was funded by a Medical Research Council (UK) studentship.
Address for reprint requests and other correspondence: P. E. Rajab, School of Biomedical Sciences, Univ. Medical School, Queen's Medical Center, Nottingham NG7 2UH, United Kingdom.
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 24 April 1998; accepted in final form 2 May 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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