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Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
1Correspondence: Washington University School of Medicine, Department of Medicine, Campus Box 8113, 4566 Scott Ave., St. Louis, MO 63110, USA. E-mail: jhollosz{at}im.wustl.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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twofold increases in full-length muscle PGC-1 mRNA and PGC-1 protein, which were evident 18 h after exercise. A smaller form of PGC-1 increased after exercise. The exercise induced increases in muscle NRF-1 and NRF-2 that were evident 12 to 18 h after one exercise bout. These findings suggest that increases in PGC-1, NRF-1, and NRF-2 represent key regulatory components of the stimulation of mitochondrial biogenesis by exercise and that PGC-1 mediates the coordinated increases in GLUT4 and mitochondria.—Baar, K., Wende, A. R., Jones, T. E., Marison, M., Nolte, L. A., Chen, M., Kelly, D. P., Holloszy, J. O. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1.
Key Words: GLUT4 • mitochondrial biogenesis • NRF-1 • NRF-2
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. This adaptation includes increases in components of the mitochondrial respiratory chain (2)
, ATP synthase (3)
, enzymes of the citrate cycle (4
, 5)
, and enzymes involved in fatty acid (6
, 7)
and ketone oxidation (5
, 8)
. It appears to be mediated by increases in the rates of synthesis rather than decreases in the rates of degradation of mitochondrial proteins (9)
and results in increments in the size and number of mitochondria in skeletal muscles (10)
. A change in their composition makes them more like cardiac muscle mitochondria (11)
. This enhancement of muscle respiratory capacity plays a major role in improvements in exercise performance and endurance induced by training (11
12
13
14)
. Another component of this adaptation is an increase in the GLUT4 isoform of the glucose transporter (15
16
17)
. Chronic electrical stimulation of the nerve innervating a fast-twitch muscle at the firing frequency of nerves innervating slow-twitch muscles induces an increase in mitochondria, but differs from exercise in that it results in the conversion of fast-twitch to slow-twitch muscles (18
, 19)
. Despite considerable research, little is known about the mechanisms by which exercise stimulates mitochondrial biogenesis or GLUT4 expression (20)
.
During the past decade, there have been major advances in the elucidation of how mitochondrial biogenesis is regulated in mammalian tissues. In a series of studies, Scarpulla and co-workers (21
22
23)
discovered two transcription factors, which they termed nuclear respiratory factor 1 (NRF-1) and nuclear respiratory factor 2 (NRF-2), that are key transcriptional activators of nuclear genes encoding a range of mitochondrial enzymes. NRF-1- and/or NRF-2-responsive regulatory elements have been identified in the promoters of many nuclear genes including those encoding cytochrome c (22)
, 
-aminolevulinate (ALA) synthase (24)
, which is the rate-limiting enzyme for heme synthesis, and mitochondrial transcription factor A (23)
, which stimulates mitochondrial DNA transcription and replication.
More recently, Spiegelman’s group has identified an inducible coactivator of nuclear receptors, cloned from brown adipose tissue on the basis of its interaction with PPAR
, which they named PPAR coactivator-1 (PGC-1) (25)
. They found that ectopic expression of PGC-1 increased expression of mitochondrial enzymes in 3T3 adipocytes and stimulated mitochondrial biogenesis in C2C12 myocytes (25
, 26)
. Further evidence that PGC-1 promotes mitochondrial biogenesis was provided by the finding that cardiac-specific overexpression of PGC-1 in transgenic mice resulted in massive proliferation of mitochondria (27)
. The effect of PGC-1 on mitochondrial biogenesis is probably explained at least in part by the finding that in addition to being a coactivator of PPAR, PGC-1 coactivates NRF-1 (26)
and PPAR
(28)
. PPAR has been shown to play a key role in the transcriptional control of the mitochondrial enzymes involved in ß-oxidation of fatty acids (29
, 30)
. Adenovirus-mediated expression of PGC-1 in cultured muscle cells results in a large increase in GLUT4, providing evidence that PGC-1 can control GLUT4 gene expression (31)
.
It seemed these findings might have relevance to the mechanisms by which endurance exercise induces increases in mitochondria and GLUT4. The present study was therefore designed to determine whether increases in PGC-1, NRF-1, and NRF-2 may be involved in the initial adaptive response to exercise. We have examined the short-term effects of exercise on the expression of PGC-1, NRF-1, and NRF-2 in rat muscle. Our results show that a single exercise bout induces rapid increases in PGC-1, NRF-1, and NRF-2.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-32P] dCTP and [32P]dATP were purchased from NEN Life Science Products (Boston, MA). Reagents for isolation of mRNA were obtained from Ambion (Austin, TX). Rabbit polyclonal antibodies directed against the 19 carboxyl-terminal amino acids of ALA synthase (32)
and against the 20 carboxyl-terminal amino acids of citrate synthases were generated by Alpha Diagnostic International (San Antonio, TX). A rabbit polyclonal antibody directed against the carboxyl terminus of GLUT4 was a gift from Mike Mueckler (Washington University, St. Louis, MO). A mouse anti-human cytochrome oxidase subunit I monoclonal antibody was purchased from Molecular Probes (Eugene, OR). A mouse anti-cytochrome c monoclonal antibody was purchased from PharMingen International (San Diego, CA). Polyclonal antibodies against peptides mapping near the carboxyl terminus and the amino terminus of PGC-1 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Horseradish peroxidase-conjugated secondary antibodies were from The Jackson Laboratory. All other reagents were purchased from Sigma (St. Louis, MO).
Animals and exercise program
Three-month-old male Wistar rats were obtained from Charles River (Wilmington, MA) and maintained on a diet of Purina chow and water. The rats were accustomed to swimming for 10 min/day for 2 days. They were then exercised by a modification (17)
of the procedure of Ploug et al. (33)
, which involves swimming for two 3 h long bouts separated by a 45 min rest, during which the rats were kept warm and given food and water. The rats swam in groups of five or six in steel barrels 47 cm in diameter filled to a depth of 60 cm, with water maintained at 35°C. Some rats performed this exercise program once and then were anesthetized for removal of muscles 3, 6, 12, or 18 h after cessation of exercise. Other groups of rats were exercised for 3 or 5 days using the same protocol and studied 18 h after the last exercise bout. The animals had free access to food before and after exercise. Exercised and control rats were anesthetized with an intraperitoneal injection of pentobarbital, 5 mg/100 g body weight; triceps muscles were dissected out, trimmed of fat and connective tissue, frozen, and stored at -80°C. The anesthetized rats were killed by exsanguination. This research was approved by the Animal Studies Committee of Washington University.
Western blot
Triceps muscles were homogenized in 29 volumes of ice-cold 10 mM HEPES, 1 mM EDTA, 250 mM sucrose, pH 7.4, buffer. Aliquots of homogenate were solubilized in Laemmli sample buffer, subjected to SDS-PAGE, and electrophoretically transferred to nitrocellulose. Membranes were blocked overnight at 4°C with 5% nonfat dry milk in phosphate-buffered saline containing 0.1% Tween. Blots were probed with the following primary antibodies: a rabbit polyclonal antibody directed against the carboxyl terminus of -aminolevulinate synthase; a rabbit polyclonal antibody directed against the carboxyl terminus of citrate synthase; a polyclonal antibody directed at the carboxyl terminus of GLUT4; a polyclonal antibody against the carboxyl terminus of PGC-1; a polyclonal antibody against the NH2 terminus of PGC-1; a monoclonal antibody against cytochrome oxidase subunit I; and a monoclonal antibody against cytochrome c. This was followed by incubation with appropriate horseradish peroxidase-conjugated anti-IgG antibody. Antibody-bound protein was detected using enhanced chemiluminescence.
Northern blot
Total RNA was isolated from triceps muscles after homogenization in 10 volumes of Trizol reagent using a polytron homogenizer. Messenger RNA was isolated from 150 µg of total RNA using a MicroPoly (A) Pure kit (Ambion) and electrophoresed on a 1% agarose gel containing 0.67M formaldehyde. The RNA was transferred to nitrocellulose using a Genie transfer system (Idea Scientific, Minneapolis, MN) and cross-linked using a Stratalinker 1800 (Stratagene, San Diego, CA). Membranes were prehybridized in ULTRAhyb (Ambion). DNA probes were labeled using a Strip Ez labeling kit. After hybridization overnight at 42°C in ULTRAhyb containing radiolabeled cDNA probe, 106 cpm/mL, the blots were washed, exposed to X-ray film, and analyzed using autoradiography. The probes were 1.5 kb of the -skeletal actin gene (Stratagene), the 2.4 kb cDNA of the full-length PGC-1 gene, probe 1 corresponding to nucleotide 42–612 of the PGC-1 mRNA, probe 2 (nucleotides 349-1056), probe 3 (nucleotides 1056–1557), and probe 4 (nucleotides 1039–2382).
Electrophoretic mobility shift assay
Oligonucleotides A and B, containing a functional NRF-1 binding site in the -aminolevulinate synthase promoter (24)
, were synthesized as follows (the recognition sequence for NRF-1 is underlined): oligo A, 5' G GCC GCT GCG CAT GCG C TGT G 3'; oligo B, 3-GG CGA CGC GTA CGC GAC ACC C 5'. Oligonucleotides C and D, containing a functional NRF-2 binding site in the cytochrome oxidase subunit IV promoter, were synthesized as follows (the recognition sequence is underlined): oligo C, 5' GATC CGG GAC CC G CTC TTC CGG T CG CGA A 3'; oligo D, 3' GCC CTG GG C GAG AAG GCC A GC GCT TTC GA 5'. Probes were labeled using Klenow in reaction mixtures containing [-32P]dCTP.
Nuclear extracts were prepared by the method of Dignam et al. (34)
as modified by Towler et al. (35)
. Binding assays were performed for 30 min at 20°C in a total volume of 20 µL containing 50,000 cpm 32P-labeled oligos, 10 µg of acetylated bovine serum albumin, and 0.01 µg/µl poly-dI: dC. Preliminary experiments were performed to determine the range of input nuclear protein that generated a linear response for the gel shift signal on autoradiographs. Quantitative binding experiments were performed under conditions of probe excess. After 20 min at room temperature, binding reactions were loaded on prerun 7% native gels. Gel-shifted bands were competed away with an excess of unlabeled oligonucleotide. For supershifting, reactions included 1 µL of undiluted goat anti-NRF-1 antiserum or anti-NRF-2 antiserum (kindly provided by Richard Scarpulla, Northwestern University) or 1 µL of undiluted control antiserum (rabbit anti-ALA synthase antiserum). DNA binding was quantified using imaging densitometry.
Statistical analysis
Results are expressed as mean ± SE. The significance of differences between two groups was assessed using Student’s unpaired t test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 5 days of the exercise program induced significant increases in ALA synthase, citrate synthase, cytochrome oxidase subunit I, cytochrome c, and GLUT4 protein concentrations. ALA synthase and GLUT4 have short half-lives and increase rapidly in skeletal muscle in response to exercise (17
, 36)
. The concentrations of ALA synthase and GLUT4 after 5 days of exercise probably represent their new steady-state concentration, as there was no significant difference between their concentrations after 3 days (data not shown) and after 5 days of exercise. Cytochrome c and citrate synthase appear to have half-lives in the range of 6–8 days, and they increase with a half-time of 7 days in response to a constant daily exercise stimulus (9)
. There is no previous information regarding the time course of the adaptive increase in muscle cytochrome oxidase subunit I to exercise; however, it appears from the present results to increase at least as rapidly as citrate synthase and cytochrome c. The magnitude of this adaptive response is similar to that induced by 6 days of a treadmill running program used in earlier studies (36)
.
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PGC-1 Gene transcription in skeletal muscle increases rapidly after a bout of exercise
The level of PGC-1 mRNA was determined by Northern blot using a full-length PGC-1 probe. PGC-1 from triceps muscles of sedentary rats migrates as a single band on a 1% agarose gel (above the 28S rRNA band) (Fig. 2
). There was a twofold increase in the full-length PGC-1 mRNA evident in muscles taken 6 h after exercise (Fig. 2)
. A smaller PGC-1 transcript had appeared 6 h after a single bout of exercise (Fig. 2)
. Accumulation of a smaller form of the PGC-1 mRNA in muscle 6 h after exercise was a consistent finding in muscles from six rats.
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Determination of the identity of the smaller inducible PGC-1 transcript
To determine what component of the PGC-1 coding region is represented in the smaller mRNA, four partial overlapping PGC-1 cDNA probes were used (Fig. 2)
. Probe 1 corresponds to nucleotides 42–612, probe 2 to nucleotides 349-1056, probe 3 to nucleotides 1056–1557, and probe 4 to nucleotides 1039–2382. All four probes identify the full-length PGC-1 mRNA (Fig. 2
, top band). However, only probes 1, 2, and 4 bind to the shortened form of PGC-1. These data suggest that the smaller form of the PGC-1 mRNA is the result of a differential splicing event that results in the removal of internal exons, including the large exon 8.
PGC-1 gene expression is increased after a bout of exercise
As shown in the Western blot in Fig. 3
, PGC-1 protein concentration was increased in triceps muscle 18 h after a single bout of exercise. The magnitude of this increase was twofold (Fig. 3)
. An increase in PGC-1 protein of similar magnitude was seen 18 h after the fifth bout of exercise (data not shown). This finding is important because increases in mRNA do not always result in a parallel increase in protein. There was an increase in a smaller protein, which, like the full-length form, was completely competed away with a PGC-1 blocking peptide. The size of this smaller PGC-1 protein (34 kDa) is consistent with that of the smaller PGC-1 mRNA, which appears to be missing exon 8. Antibodies directed at the amino terminus (Fig. 3A
) and the carboxyl terminus (Fig. 3A
) recognized the shorter PGC-1 protein. It will be interesting to determine whether this smaller PGC-1 protein is in fact the translation product of the shortened PGC-1 mRNA and whether it has functional significance.
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Effect of exercise on expression of NRF-1 and NRF-2
NRF-1 protein binding was detected by electrophoretic mobility shift assay using an oligonucleotide containing a NRF-1 binding site from the ALA synthase promoter. NRF-2 protein binding was determined using an oligonucleotide containing the NRF-2 protein-binding site from the cytochrome oxidase subunit IV promoter. The NRF-1-specific band is shown by the arrow in Fig. 4
A; quantitative analysis is shown in Fig. 4C
. There was a 50% increase in NRF-1 binding in eight of nine muscles 18 h after the exercise; in other muscle, an increase was evident 12 h after exercise. This finding of an increase in NRF-1 DNA binding is in keeping with the observation of Murakami et al. (37)
of a 50% increase in NRF-1 mRNA in soleus muscle of rats 6 h after a bout of running. In the case of NRF-2, gel shift activity was increased 12 h and/or 18 h after exercise, suggesting that the peak of the increase occurred between these two points. Figure 4B
shows the increase in NRF-2 binding in a muscle taken 18 h after exercise; the lower portion shows the densitometric quantitation. The postexercise value, which represents the average of the 12 h and 18 h values, was increased by 56%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Forced expression of PGC-1 resulted in the induction of mitochondrial biogenesis in some cell types in culture, including 3T3 adipocytes (25)
, C2C12 myocytes (26)
and neonatal cardiac myocytes (27)
, whereas cardiac-specific overexpression of PGC-1 in transgenic mice caused a massive proliferation of mitochondria (27)
. Adenovirus-mediated expression of PGC-1 in L6 myotubes induced a large increase in GLUT4 expression (31)
. Endurance exercise provides a powerful stimulus for mitochondrial biogenesis and GLUT4 expression in skeletal muscle (11
, 15
16
17)
. The finding that PGC-1 appears to play a key role in mitochondrial biogenesis and GLUT4 expression led us to investigate the possibility that an increase in PGC-1 expression might be involved in the early adaptive response of skeletal muscle to exercise. While this study was in progress, Goto et al. (38)
reported that PGC-1 mRNA was increased 50% after 3 days of exercise training and twofold after 5 days of training. We observed an increase in the full-length PGC-1 mRNA. However, this twofold increase was already evident 18 h after a single bout of exercise. Our Northern blots showed an increase in a smaller mRNA molecule evident within 6 h after exercise, which is likely to represent an alternatively spliced form of PGC-1 mRNA. More important, a single exercise bout resulted in a twofold increase in PGC-1 protein concentration that was evident 18 h after exercise. Increments in mRNA are often loosely referred to as increases in gene expression. This is of course incorrect, because increased gene expression and its associated phenotypic/functional manifestations do not take place until there is an increase in the concentration of the protein encoded by the gene. Gene expression can be controlled at various points beyond transcription, so the extent to which a protein will increase in response to an adaptive stimulus cannot be predicted from the increase in mRNA. This makes the measurement of protein concentrations critical when studying the adaptive responses to exercise or other stimuli.
PGC-1 contains a number of distinct regions that appear to be important for its function. The amino-terminal 120 amino acids contain a region sufficient to cause trans-activation when associated with the Ga14 DNA binding domain (25)
. Just carboxyl-terminal from this region is an LXXLL motif that allows coactivator interactions (25)
. Within the amino-terminal 50% of the PGC-1 molecule are the binding sites for NRF-1, PPAR, and PPAR, (25
, 26
, 28)
. The carboxyl terminus contains an SR domain and a RNA binding domain, which together are thought to interact with the carboxyl-terminal domain of RNA polymerase II (25)
. Therefore, we used cDNA probes to various regions of the full-length message to obtain preliminary information as to which part of the mRNA was missing in the smaller induced PGC-1 transcript. All the probes we tested recognized the full-length mRNA (Fig. 3)
. However, the shorter PGC-1 transcript was recognized only by probes 1, 2, and 4. This suggests that the alternatively spliced form of the PGC-1 mRNA lacks exon 8 and possibly exons 5, 6, or 7. The Western blot data also demonstrate that the smaller form of PGC-1 contains the amino terminus and the carboxyl terminus.
This is not the first description of an alternatively processed form of PGC-1. Kakuma et al. (39)
have described a similar variant form of PGC-1 in brown adipose tissue of rats that binds to probes equivalent to our probes 1 and 2, but not to a probe equivalent to our probe 3. This form of PGC-1 was induced in brown adipose tissue by exposure of rats to cold and by hyperleptinemia (39)
. Taken together, Kakuma et al.’s and our findings suggest that a PGC-1 mRNA variant(s) lacking exon 8 increases as part of the adaptive response to various stresses. We do not currently know the biological significance of this differential processing. We do not know whether the smaller PGC-1 protein that appeared in response to exercise is the translational product of the shortened PGC-1 mRNA, although its size based on the results of the Western blots is consistent with this possibility. Even though these findings and questions are peripheral to the purpose of the present study, they are potentially interesting and appear worth pursuing in a follow-up investigation.
PGC-1 has been termed a thermogenic coactivator because it is induced in the brown fat of mice exposed to cold (25)
. An increase in UCP-1 is a major component of this adaptation resulting in uncoupled respiration and heat production (25)
. Apparently, forced expression of PGC-1 in C2C12 myocytes, in addition to inducing mitochondrial biogenesis, causes a partial uncoupling of respiration (26)
. In adult skeletal muscle, in vivo cold exposure induces increased thermogenesis by means of shivering (40)
, which, because it involves contractile activity, can be thought of as a form of exercise. The adaptive increase in mitochondria induced in skeletal muscle by exercise functions to increase the capacity for ATP generation via oxidative phosphorylation and thus increases the maximum capacity for energy generation and reduces the disturbance in intracellular homeostasis during submaximal exercise (11
, 13
, 14)
. Clearly, the induction of uncoupled respiration in response to exercise would be counterproductive, and it is well documented that the mitochondria from muscle that has adapted to endurance exercise are tightly coupled (2
, 6
, 41)
. That an increase in PGC-1 induces an increase in mitochondria in striated muscle without an uncoupling of respiration is evidenced by the study of Lehman et al. (27)
, who showed that forced expression of PGC-1 in cardiac myocytes induced a large increase in mitochondria with tightly coupled respiration.
The finding that PGC-1 controls GLUT4 gene expression helps explain the mechanisms underlying the coordinate regulation of mitochondrial biogenesis and GLUT4 expression in response to various stimuli. Besides exercise, these include hyperthyroidism (42
, 43)
, lowering of muscle ATP and phosphocreatine levels by creatine depletion (44)
, and activation of AMP kinase (45
, 46)
. Activation of AMP kinase appears to be the mechanism by which exercise stimulates muscle glucose transport (47
48
49)
. Stimulated muscle glucose transport is normally proportional to the muscles’ GLUT4 content (17
, 50
, 51)
. Thus, PGC-1 coordinately regulates the capacity of muscle to take up glucose and to oxidize it.
Mitochondria contain their own genome, which encodes 13 of the > 100 proteins that make up the enzyme complexes of the respiratory electron transport chain (52)
. The others are products of nuclear genes. Nuclear genes also provide the factors that regulate mitochondrial DNA transcription and replication, and they encode enzymes of the citrate cycle and of fatty acid and ketone oxidation. A fundamental question is, How is the transcription of nuclear and mitochondrial genes coordinated during both steady-state conditions and adaptive responses to changes in energy demand? Scarpulla and co-workers (21
22
23)
have identified two transcription factors, NRF-1 and NRF-2, that appear to play a major role in this integrative function. Functional recognition sites for one or both of these transcription factors have been identified in the promoters of nuclear genes that encode subunits of the respiratory chain enzyme complexes, some of the mitochondrial matrix enzymes, and mtDNA transcription and replication factors (21
22
23
24
, 53
, 54)
.
PGC-1 has been shown to coactivate NRF-1, to increase NRF-1 and NRF-2 gene expression, and to stimulate mitochondrial biogenesis (26)
. In light of the results of this study, it seems probable that increased expression of PGC-1, acting in concert with increases in NRF-1 and NRF-2, plays a major role in stimulating mitochondrial biogenesis by exercise. The discovery that PGC-1 stimulates GLUT4 expression (27)
, together with the present finding that PGC-1 expression increases after a bout of exercise, strongly suggests that PGC-1 is involved in mediating the coordinate increase in muscle GLUT4 and mitochondria induced by exercise. However, in view of the importance of this adaptation for survival in situations requiring prolonged strenuous exercise, it also seems possible that additional (i.e., redundant) mechanisms have evolved for stimulating mitochondrial biogenesis and GLUT4 expression that await discovery.
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ACKNOWLEDGMENTS |
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Received for publication May 30, 2002. Accepted for publication August 9, 2002.
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coactivator-1 promotes cardiac mitochondrial biogenesis. J. Clin. Invest. 106,847-856[Medline]
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I. Walter and F. Seebacher Molecular mechanisms underlying the development of endothermy in birds (Gallus gallus): a new role of PGC-1{alpha}?< |
