1 School of Health Sciences, Deakin University, Burwood, Victoria 3125; 2 Metabolic Research Unit, School of Health Sciences, Deakin University, Geelong, Victoria 3217, Australia; 3 Department of Kinesiology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
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ABSTRACT |
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The effects of a single bout of exercise
and exercise training on the expression of genes necessary for the
transport and -oxidation of fatty acids (FA), together with the gene
expression of transcription factors implicated in the regulation of FA
homeostasis were investigated. Seven human subjects (3 male, 4 female,
28.9 ± 3.1 yr of age, range 20-42 yr, body mass index 22.6 kg/m2, range 17-26 kg/m2) underwent a
9-day exercise training program of 60 min cycling per day at 63% peak
oxygen uptake (
O2 peak; 104 ± 14 W). On days 1 and 9 of the program, muscle
biopsies were sampled from the vastus lateralis muscle at rest, at the
completion of exercise, and again 3 h postexercise. Gene
expression of key components of FA transport [FA translocase
(FAT/CD36), plasma membrane-associated FA-binding protein],
-oxidation [carntine palmitoyltransferase(CPT) I,
-hydroxyacyl-CoA dehydrogenase] and transcriptional control [peroxisome proliferator-activated receptor (PPAR)
, PPAR
,
PPAR
coactivator 1, sterol regulatory element-binding protein-1c]
were unaltered by exercise when measured at the completion and at
3 h postexercise. Training increased total lipid oxidation by 24% (P < 0.05) for the 1-h cycling bout. This increased
capacity for lipid oxidation was accompanied by an increased expression
of FAT/CD36 and CPT I mRNA. Similarly, FAT/CD36 protein abundance was
also upregulated by exercise training. We conclude that enhanced fat
oxidation after exercise training is most closely associated with the
genes involved in regulating FA uptake across the plasma membrane
(FAT/CD36) and across the mitochondrial membrane (CPT I).
mRNA; fat transporters; human
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INTRODUCTION |
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ENDURANCE EXERCISE
TRAINING elicits many skeletal muscle adaptations, including an
increased capacity for oxidative metabolism of fatty acids (FA) and
carbohydrates. An increase in FA oxidation is facilitated by increased
capacities for FA uptake into the myocyte (21), their
subsequent mitochondrial transport, and -oxidation (17,
38). With exercise training, these increments have been
associated with the upregulation of membrane-associated FA transport
proteins, FA-binding protein (FABPPM) (22), FA translocase (FAT/CD36) (5), the mitochondrial transporter
carnitine palmitoyltransferase I (CPT I) (4), and a key
enzyme of
-oxidation,
-hydroxyacyl-CoA dehydrogenase
(
-HAD) (38).
The molecular mechanisms initiated by increased physical activity that
enable the increased protein abundance of components of the FA uptake
and -oxidative pathway are undoubtedly complex. There are multiple
steps important in the regulation of cellular protein, including gene
transcription, mRNA stability, protein translation rate, translation
efficiency, posttranslational modifications, and protein degradation.
As a significant and sustained physiological stressor, it is not
surprising that endurance exercise may regulate protein level by
modifications at multiple sites. Many studies have now demonstrated
that a bout of sustained muscular activity exerts the capacity to
transiently activate the expression of many genes (2). For
example, GLUT4, hexokinase, and uncoupling protein (UCP)-3 gene
expression are observed to peak from within 30 min to 3 h after
exercise (23, 24).
Whether the expression of genes involved in FA uptake and -oxidation
is upregulated rapidly after exercise is not known. Moreover, it has
not yet been determined whether prior short-term training has any
impact on the regulation of these genes. Therefore, in the present
study, we have examined the transient and chronic changes in key genes
integral to FA uptake (FAT/CD36, FABPPM) and oxidation (CPT
I,
-HAD) in skeletal muscle. The transient changes in gene
expression were measured before and after 9 days of exercise training,
a period known to increase FA oxidation in human skeletal muscle
(38).
Transcriptional control of the key genes necessary for FA uptake and
oxidation has been shown to be under the regulation of several
transcription factors, including the peroxisome proliferator-activated receptor (PPAR) isoforms PPAR and PPAR
(8, 30), the
recently identified PPAR
coactivator-1 (PGC-1) (35,
40), and the sterol regulatory element-binding protein-1c
(SREBP-1c) (12, 29). It has yet to be established whether
changes in expression of these nuclear transcription factors precede
the changes in the expression of genes involved in FA metabolism. A
further aim of the present study was to examine the expression of
FA-related transcription factors (PPAR
, PPAR
, PGC-1, and
SREBP-1c) before and after 9 days of exercise training.
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METHODS |
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Subjects.
Seven healthy, untrained subjects [3 male, 4 female, 28.9 ± 3.1 yr of age, range 20-42 yr, body mass index 22.6 kg/m2
(range 17-26 kg/m2), peak oxygen uptake
(O2 peak) 37.1 ± 2.7 ml · kg
1 · min
1]
volunteered to participate in the study (Table
1). Female subjects were premenopausal,
and subjects were not on medication at the time of the intervention.
Informed, written consent was obtained from each subject after a verbal
and written explanation of the experimental protocol and its potential
risks. The study was approved by the Deakin University Ethics Committee
and was in accordance with National Health and Medical Research Council
guidelines.
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Experimental protocol.
Seven days before commencement of the training protocol, subjects
attended the laboratory for O2 peak
determination. This was measured with a metabolic cart (Gould Metabolic
Systems, Dayton, OH) during incremental exercise to exhaustion on a
cycle ergometer (Quinton Excalibur, Groningen, The Netherlands).
Muscle analysis: real-time RT-PCR.
Total RNA was isolated using FastRNA Kit-Green (BIO 101, Vista, CA)
protocol and reagents (10). Total RNA concentration was
determined spectrophotometrically at 260 nm. First-strand cDNA was
generated from 1 µg of RNA using AMV RT (Promega, Madison, WI) as
previously described by Wadley et al. (41). The cDNA was
stored at 20°C for subsequent analysis.
|
Immunoblot analysis. For detection of FAT/CD36 and FABPPM, we used a monoclonal antibody against human CD36 (provided by Dr. N. N. Tandon) and a rabbit polyclonal anti-FABPPM antiserum (provided by Dr. J. Calles-Escandon), respectively, as previously described (27). Muscle samples were electrophoresed on 10% SDS-polyacrylamide gels and transferred onto Immobilon polyvinylidene difluoride membranes. Membranes were incubated for 2 h with either the monoclonal CD36 antibody (1:500) or the polyclonal FABPPM antibody (1:200). Secondary complexes were generated using anti-mouse IgG horseradish peroxidase secondary antibody (1:10,000; Santa Cruz Biotechnology, Santa Cruz, CA) for FAT/CD36 and donkey anti-rabbit IgG horseradish peroxidase-conjugated secondary antibody (1:3,000; Amersham) for FABPPM. Enhanced chemiluminescence detection (Hyperfilm-ECL; Amersham, Oakville, ON, Canada) was performed, with band densities obtained by densitometry.
Blood analysis.
Blood samples were drawn from the intravenous catheter, placed into
heparinized vials, and spun at 4°C. Plasma was stored at 20°C.
Plasma glucose and lactate were measured in duplicate using an
automated glucose/lactate analyzer (EML 105, Rodiometer, Copenhagen,
Denmark). The mean intra-assay CV for the glucose and lactate assays
were 0.1% and 3%, respectively.
Statistical analysis.
All data are presented as means ± SE. Two-way ANOVA with repeated
measures was used to determine the main effects of time and/or training
on the response (O2 during exercise,
heart rate during exercise, and glucose, lactate, and gene expression).
Post hoc analysis was performed to determine differences between groups with the Newman-Keuls test where appropriate. Paired-sample
t-tests were performed to reveal differences pre- and
posttraining. A value of P
0.05 was considered
statistically significant.
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RESULTS |
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Physiological variables.
Mean intensity of the 60-min exercise bout was 63 ± 2%
O2 peak. Heart rate significantly
decreased posttraining (P = 0.009), whereas
plasma lactate and glucose levels remained unchanged (Table 1). The
average RER during the 60-min exercise was significantly lower
posttraining (P = 0.016) (Fig.
1). This corresponded to a small, but
significant, increase in fat oxidation (4.5 g) during the 60-min
exercise (P = 0.008).
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FA transporter mRNA and protein.
In untrained subjects, a single bout of cycle ergometer exercise for
1 h did not alter the mRNA abundance of FAT/CD36 immediately after
the completion of the exercise bout or again when measured 3 h
postexercise (Fig. 2A).
However, after 9 days of exercise there was a significant (36%,
P = 0.04, treatment effect) increase in FAT/CD36 gene
expression compared with the untrained state (Fig. 2A). With
this exercise training, FAT/CD36 was again unaltered by an acute
exercise bout, with no alteration in gene expression compared with the
resting values, of the samples analyzed immediately and 3 h after
the exercise bout. The increased level of gene expression posttraining
was matched with a significant increase in FAT/CD36 protein
abundance (Fig. 3A,
P = 0.03). In contrast, FABPPM gene expression was unaltered by both acute exercise bout and exercise training (Fig. 2B). Similarly, FABPPM protein
content did not differ in the trained, compared with untrained, muscle
samples (Fig. 3B).
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Oxidative enzymes.
CPT I gene expression did not change after the 60-min bout of exercise
or at 3 h postexercise. However, after 9 days of exercise, there
was a significant (57%, P = 0.03, treatment effect)
increase in CPT I gene expression (Fig. 2C) compared with
the untrained state. -HAD gene expression was unchanged after the
acute exercise bout and remained unchanged 3 h postexercise. No
change in
-HAD gene expression was observed after exercise training.
Transcription factors in skeletal muscle.
Analysis of four FA-associated transcription factors demonstrated no
acute regulation of their gene expression immediately and 3 h
after the single exercise bout (Fig. 4).
The expression of PPAR, SREBP-1c, and PGC-1 genes all remained
unaltered by prior training and after the last exercise bout. However,
the gene expression of PPAR
was significantly (P = 0.04, treatment effect) reduced after training (Fig. 4B).
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DISCUSSION |
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In the present study, we have examined, in human skeletal muscle,
the effects of a single bout of exercise and exercise training on the
expression of genes involved in FA uptake and oxidation, as well as
their regulatory transcription factors. Several novel observations were
made in this study. First, an acute bout of exercise (60 min, 63%
O2 peak), whether performed in the
untrained or the trained state, did not significantly alter the
expression of genes involved in FA uptake and metabolism (FAT/CD36, FABPpm, CPT I,
-HAD) or their transcription factors (PPAR
,
PPAR
, PGC-1, SREBP-1c) measured immediately at the cessation of
exercise or 3 h postexercise. Second, the exercise training (9 days, 60 min/day, 63%
O2 peak)
increased FA oxidation during exercise; yet this was accompanied by an
increase in the expression of just two of the selected genes (FAT/CD36
and CPT I), with the expression of all remaining genes remaining
constant. The exception was the expression of PPAR
, which was
lowered by training. Therefore, the capacity for increased FA oxidation
induced by exercise training is most closely associated with genes
involved in regulating FA uptake across the plasma membrane (FAT/CD36)
and across the mitochondrial membrane (CPT I).
In this study, 9 days of repeated exercise increased total fat oxidation over the course of 1 h by 24%, which equated to 4.5 g of additional fat oxidized. Adaptations of a similar magnitude have been reported previously in comparable short-term training programs (38), as well as in training programs in excess of 8 wk (14, 19). Despite the current debate regarding the relative contributions of intracellular lipids and blood-borne FA to lipid oxidation in muscle (11), there is evidence to suggest that increases in muscle fat oxidative capacity require a concurrent increase in FA uptake into the skeletal muscle cell (21). The results of the present study demonstrated a significant increase (36%) in FAT/CD36 gene expression in response to the moderate-intensity exercise training. This was accompanied by a comparable increase in the protein abundance of FAT/CD36 in trained, compared with untrained, skeletal muscle. These data are consistent with the observation that mRNA abundance of FAT/CD36 is upregulated by muscle contractile activity (5), which in this study was demonstrated to enhance FAT/CD36 protein abundance. Thus an increase in FAT/CD36 gene expression, translated into increased protein content, provides a plausible mechanism whereby FA uptake and oxidation are increased in trained skeletal muscle of humans.
Skeletal muscle FA transport may involve a family of membrane-bound putative transporters. An additional member of this family, FABPPM was also investigated in this study. FABPPM protein abundance has been shown to increase in human skeletal muscle after single-legged exercise training (22). In the present study, there was no evidence of increased FABPPM mRNA or protein after short-term training in humans. It is possible, then, that the absence of the response in this study is due to the lower intensity of exercise stimulation or the total time period of activation. Alternatively, it might also be suggested that the current study provides evidence of selectivity in the regulation of the analyzed FA transport proteins FABPPM and FAT/CD36. It has been speculated that these FA transporters may operate cooperatively (28), although recent data demonstrate differential regulation in insulin-resistant tissues (27). Further analysis of the actions of FAT/CD36 and FABPPM to determine their independent and possible cooperative roles in the transport of FA across the muscle plasma membrane is required.
Mitochondrial biogenesis is an important component of the adaptive
response to endurance exercise training (18); yet the impact of sustained muscular activity on the expression of nuclear gene-encoded mitochondrial proteins is highly variable. In chronically electrically stimulated rat tibialis anterior, the expression of a
nuclear-encoded subunit of cytochrome c increased only
marginally after 5 days (13). This increase was due to
increased mRNA stability rather than to the activation of mRNA
transcription. In contrast, it has recently been demonstrated that
there is a rapid induction of nuclear genes involved in mitochondrial
function, including CPT I and UCP-3, after an exhaustive exercise bout
at the completion of 5 days of training (34). The results
of the present study demonstrate that a single exercise bout, of 1 h duration, failed to elicit increased mRNA abundance of CPT I
postexercise, although with training, CPT I mRNA levels were increased.
It is not possible to conclude whether these increases in CPT I gene
expression are the net result of increased mRNA synthesis or mRNA
stability. Furthermore, it is difficult to ascertain why there was no
adaptive increase in -HAD mRNA, given the downstream role of this
enzyme in FA oxidation. These data suggest that the increased
availability of CPT I mRNA, and thus protein synthesis, represents the
key site for the adaptive regulation of
-oxidative capacity with exercise training. The downstream enzymes, such as
-HAD, are potentially in sufficient excess to catalyze the increased FA flux
after exercise training.
From the present study, the genes upregulated by training (FAT/CD36 and
CPT I) may have been activated progressively subsequent to each
exercise bout. It could be hypothesized that the expression of these
genes, which were responsive only to repeated exercise (training), may
have occurred as a function of the cumulative actions of a sensitive
transcription factor pathway (32). Thus this study sought
to examine whether the gene expression of several transcriptional
regulators of FA uptake and oxidation could account for the increased
abundance of FAT/CD36 and CPT I mRNA. Important in the regulation of FA
homeostasis is the PPAR family of transcription factors, of which there
are three distinct subtypes (,
, and
) (9).
Recently, Horowitz et al. (19) demonstrated a twofold induction in skeletal muscle PPAR
protein content after 12 wk of
endurance training in women. This may reflect the role of PPAR
in
regulating lipid-sensitive gene expression (27) but also the possible link between PPAR
activation and improved skeletal muscle insulin action (42). However, the present study
failed to demonstrate a change in the expression of mRNA levels of
PPAR
, either after a single exercise bout or after 9 days of
training. Although the training protocol adopted by Horowitz et al. was longer (12 wk) and was undertaken at a lower intensity (50%
O2 peak), it is unlikely that these
differences would significantly modulate the synthesis of PPAR
,
suggesting that significant posttranslational control might be
important in the regulation of PPAR
protein abundance.
The PPAR isoform has been identified as a potential regulator of
skeletal muscle FA metabolism, with the PPAR
-specific agonist troglitazone upregulating UCP3 mRNA in rat (31) and
FAT/CD36 protein in human skeletal muscle cell lines (8).
Additionally a significant positive relationship has been demonstrated
between the abundance of the PPAR
and CPT I genes in human skeletal
muscle (25). However, the present study has demonstrated a
significant (20%) decrease in PPAR
mRNA expression after 9 days of
training, demonstrating a dissociation of the relationship
between PPAR
and CPT I with exercise training. These data suggest
that factors other than PPAR
mRNA abundance are important in the
adaptive control of CPT I, but does not exclude the possibility of a
role for the PPAR
protein.
The transcriptional control of FA-specific genes has been shown to extend beyond PPAR regulation. Although there have apparently been no specific examination of the actions of PGC-1 and SREBP-1c in human skeletal muscle, expression of these proteins has been identified in this tissue (6, 26). Goto et al. (16) examined the responsiveness of PGC-1 gene expression to exercise in rat skeletal muscle. Two hours of swimming exercise training per day for 7 days resulted in a 163% increase in epitrochlearis muscle PGC-1 mRNA. In contrast, we were unable to demonstrate any change in PGC-1 mRNA levels in human skeletal muscle either acutely or after 9 days of endurance training. Additionally, no impact of cycle ergometer exercise was demonstrated on the gene expression of SREBP-1c.
Recently, there has been much interest in sex differences in lipid metabolism after endurance exercise, with many (15, 20, 39) studies demonstrating that females have a lower RER during submaximal exercise. However, the impact of endurance training on enzymatic adaptations appears to be similar between the sexes (7). For this reason, we sought not to examine sex differences in detail. On analysis, no significant sex differences were observed in gene expression responses to exercise training.
In the present study, the mRNA abundance of FAT/CD36, a plasma membrane
FA transporter, and CPT I, the rate-limiting mitochondrial FA
transporter, were both increased after 9 days of moderate-intensity exercise training. These data were further corroborated with the analysis of FAT/CD36 protein abundance matching the activation of the
gene. However, genes coding for complementary components of the FA
transport and oxidation pathways, FABPPM and -HAD, were
unaltered by exercise training. Thus the adaptive increase in FA uptake
and oxidation after exercise training in humans is linked to activation
of key genes that encode responsive components of the FA-uptake and
oxidative pathway. Further analysis was made of the gene expression of
regulatory transcription factors implicated in the regulation of
skeletal muscle FA metabolism. Of the measured transcription factor
genes (PPAR
, PPAR
, PGC-1, and SREBP-1c), all failed to increase
either after an acute exercise bout or after training. Therefore, the
results of the present study were unable to provide evidence that
increased gene expression of transcription factors mediates the
increased mRNA abundance of FAT/CD36 and CPT I after exercise training.
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ACKNOWLEDGEMENTS |
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We thank Dr N. N. Tandon (Otsuka Research Maryland, Besthesda, MD) and Dr. J. Calles-Escandon (SmithKlineBeecham, Miami, FL) for providing the antibodies for FAT/CD6 and FABPPM, respectively. We also thank Dr. Andrew Garnham for excellent medical skills, and the technical assistance of Julie Miller and Robyn Murphy.
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FOOTNOTES |
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These studies were supported by grants from Deakin University and the Canadian Institutes of Health Research (to A. Bonen).
Address for reprint requests and other correspondence: D. Cameron-Smith, School of Health Sciences, Deakin University, Burwood, Victoria 3125, Australia. (E-mail: davidcs{at}deakin.edu.au).
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.
First published March 12, 2002;10.1152/ajpendo.00475.2001
Received 22 October 2001; accepted in final form 6 March 2002.
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