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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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-aminolevulinate synthase. Activation of NRF-1 in fibroblasts has been shown to induce increases in cytochrome c expression and mitochondrial respiratory capacity. To further evaluate the role of NRF-1 in the regulation of mitochondrial biogenesis and respiratory capacity, we generated transgenic mice overexpressing NRF-1 in skeletal muscle. Cytochrome c expression was increased 
twofold and -aminolevulinate synthase was increased 50% in NRF-1 transgenic muscle. The levels of some mitochondrial proteins were increased 50–60%, while others were unchanged. Muscle respiratory capacity was not increased in the NRF-1 transgenic mice. A finding that provides new insight regarding the role of NRF-1 was that expression of MEF2A and GLUT4 was increased in NRF-1 transgenic muscle. The increase in GLUT4 was associated with a proportional increase in insulin-stimulated glucose transport. These results show that an isolated increase in NRF-1 is not sufficient to bring about a coordinated increase in expression of all of the proteins necessary for assembly of functional mitochondria. They also provide the new information that NRF-1 overexpression results in increased expression of GLUT4.—Baar, K., Song, Z., Semenkovich, C. F., Jones, T. E,. Han, D.-H., Nolte, L. A., Ojuka, E. O., Chen, M., Holloszy, J. O. Skeletal muscle overexpression of nuclear respiratory factor 1 increases glucose transport capacity.
Key Words: -aminolevulinate synthase • cytochrome c • mitochondria • pyruvate oxidation • respiratory enzymes
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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100 proteins that constitute the enzyme complexes of the respiratory chain (1)
. Nuclear genes encode the other respiratory chain proteins as well as the factors that regulate mitochondrial gene expression, enzymes of the citrate cycle, and the enzymes of the fatty acid and ketone oxidation pathways. Research by a number of groups has provided new insights regarding how the expression of individual mitochondrial proteins and the biogenesis of mitochondria are regulated in mammalian tissues. Scarpulla and co-workers (2
3
4
5)
discovered nuclear respiratory factor 1 (NRF-1) and nuclear respiratory factor 2 (NRF-2), which are key transcriptional activators of nuclear genes encoding a number of mitochondrial constituents. These include various respiratory chain subunits (5)
, -aminolevulinate synthase (ALA synthase) (6)
, mitochondrial transcription factor A (mtTFA) (7)
, and a range of other mitochondrial and nonmitochondrial proteins (5)
. A major breakthrough occurred with the identification and characterization by Spiegelman’s group of peroxisome proliferator-activated receptor (PPAR) 
coactivator 1
(PGC-1) (8
, 9)
. Overexpression and/or activation of PGC-1 was shown to stimulate mitochondrial biogenesis in C2C12 myocytes, cardiac myocytes, and 3T3 adipocytes (9
10
11)
and to increase GLUT4 expression in myocytes (12)
. The increase in mitochondrial biogenesis induced by PGC-1 appears to be mediated at least in part by the coactivation of NRF-1 by PGC-1 (9)
.
Most of the energy required for muscle contraction during prolonged exercise is provided by generation of ATP via mitochondrial respiration. Endurance exercise induces an increase in skeletal muscle mitochondria (13
14
15
16
17)
, resulting in an enhanced capacity to generate ATP via oxidative phosphorylation (18
, 19)
. We have found that NRF-1 expression is increased in skeletal muscle 18 h after a bout of exercise (20)
, and Murakami et al. (21)
have reported that NRF-1 mRNA is increased 6 h after exercise. Although the exercise-induced increase in NRF-1 is relatively small, 50%, its effect on transcription is probably greatly potentiated by the large induction of PGC-1 expression that also occurs in response to a bout of exercise (20)
.
Herzig et al. (22)
found that exposure of BALB 3T3 fibroblasts to serum induces an increase in the expression of cytochrome c and that this effect was mediated by phosphorylation and activation of NRF-1. Despite no increases in other mitochondrial enzymes that were measured, including citrate synthase and cytochrome oxidase, the isolated increase in cytochrome c resulted in a large increase in mitochondrial respiratory capacity. This finding by Herzig et al. (22)
, which was interpreted as indicating that cytochrome c is rate-limiting for mitochondrial respiration, raised the possibility that in addition to increases in the size and number of mitochondria (13
, 16)
, exercise might enhance muscle respiratory capacity via a NRF-1-mediated induction of cytochrome c.
The purpose of this study was to examine the effect of overexpression of NRF-1 in skeletal muscle. We found that cytochrome c expression was increased twofold in skeletal muscles of NRF-1 transgenic mice. The levels of some other mitochondrial proteins were increased 50–60%, while still others were unchanged. Muscle respiratory capacity was unchanged in the NRF-1 transgenic muscles. An unexpected finding that provides new information regarding the role of NRF-1 is that overexpression of NRF-1 resulted in increased expression of myocyte enhancer factor (MEF) 2A and the GLUT4 isoform of the glucose transporter in muscle.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-32P] dCTP was purchased from NEN Life Science Products (Boston, MA, USA). Mouse anti-human monoclonal antibodies against succinate-ubiquinone oxidoreductase 70 kDa subunit, ubiquinone cytochrome c oxidoreductase core 1 subunit, cytochrome oxidase subunit IV, and ATP synthase subunit were obtained from Molecular Probes (Eugene, OR, USA). Rabbit polyclonal antibodies directed against the 19 carboxyl-terminal amino acids of ALA synthase and against the 20 carboxyl-terminal amino acids of citrate synthase were generated by Alpha Diagnostic International (San Antonio, TX, USA). A mouse anti-cytochrome c monoclonal antibody was purchased from PharMingen International (San Diego, CA, USA). A polyclonal antibody against a peptide mapping near the carboxy terminus of PGC-1 and a polyclonal antibody against the carboxy terminus of MEF2A were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). A polyclonal antibody against MEF2D was from Transduction Laboratories (Lexington, KY, USA) and a polyclonal antibody against MEF2C was obtained from Cell Signaling (Beverly, MA, USA). A rabbit polyclonal antibody directed against the carboxy terminus of GLUT4 was a gift from Mike Mueckler (Washington University, St. Louis, MO, USA). A polyclonal antibody against mtTFA was given to us by David A. Clayton (Stanford University, Palo Alto, CA, USA). A polyclonal anti-NRF-1 antibody was a gift from Richard Scarpulla (Northwestern University, Chicago, IL, USA). Horseradish peroxidase-conjugated secondary antibodies were from the Jackson Immunoresearch Laboratories (West Grove, PA, USA). 2-Deoxy-D-[1,2-3H] glucose was obtained from American Radiolabeled Chemicals (St. Louis, MO, USA). D-[-1-14C] Mannitol and [2-14C] Na pyruvate were obtained from Perkin Elmer Life Sciences (Boston, MA, USA). The bicinchoninic (BCA) protein assay kit was purchased from Pierce Chemical (Rockford, IL, USA). All other reagents were purchased from Sigma Chemical (St. Louis, MO, USA).
Construction of transgenic mice
Human NRF-1 cDNA, a gift from Richard C. Scarpulla (Northwestern University) was subcloned downstream of the rat myosin light chain 2 promoter in a construct containing an albumin gene intron and glyceraldehyde-3-phosphate dehydrogenase termination and polyadenylation sequences. Vector sequence was removed and the linearized DNA was injected into C57B1/6 x CBA hybrid embryos. Two independent founders and their nontransgenic littermates were used to establish mouse colonies.
This research was approved by the Animal Studies Committee of Washington University.
Electrophoretic mobility shift assay (EMSA)
Oligonucleotides containing a functional NRF-1 binding site in the ALA synthase promoter were synthesized as described previously (20
, 23)
. Nuclear extracts were prepared by the method of Dignam et al. (24)
as modified by Towler et al. (25)
. Binding assays were performed as described previously (20
, 23)
.
Muscle preparation
Mice were maintained on a diet of Purina chow and water. After an overnight fast, mice were anesthetized with an intraperitoneal injection of sodium pentobarbital 0.5 mg/10 g body weight. Epitrochlearis, triceps, gastrocnemius, and quadriceps muscles were dissected out and trimmed of fat and connective tissue. The epitrochlearis muscles were used for measurement of glucose transport activity. The triceps muscles were used for measurement of pyruvate oxidation, and the gastrocnemius and quadriceps muscles were frozen and stored at -80°C. In some fed mice, blood samples for measurement of glucose were obtained from a tail vein.
Western blot
Gastrocnemius and quadriceps muscles were pooled and homogenized in ice-cold 250 mM sucrose containing 10 mM HEPES, 1 mM EDTA, pH 7.4. Homogenate protein concentrations were measured using a BCA protein assay kit, and homogenate volumes were adjusted to give the same protein concentration in homogenates of muscles from different animals. Aliquots of homogenates were solubilized in Laemmli buffer, subjected to SDS PAGE, and transferred to nitrocellulose membranes. The membranes were blocked overnight at 4°C with 5% non-fat dry milk in phosphate-buffered saline containing 0.1% Tween. The blots were probed with the following antibodies: mouse monoclonal antibodies against succinate-ubiquinol oxidoreductase 70 kDa subunit, ubiquinone cytochrome c oxidoreductase core 1 subunit, cytochrome oxidase subunit IV, cytochrome c, MEF2D, and ATP synthase subunit ; rabbit polyclonal antibodies against ALA synthase, citrate synthase, GLUT4, MEF2A, MEF2C, and mtTFA; and a goat polyclonal antibody against PGC-1. The blots were then incubated with the appropriate horseradish peroxidase-conjugated anti-IgG antibody. Antibody-bound protein was detected using enhanced chemiluminescence and quantified by densitometry.
Measurement of pyruvate oxidation
Triceps muscles were homogenized in 300 mM sucrose containing 10 mM Tris-Cl and 2 mM EDTA, pH 7.4 using a glass Potter-Elvehyjim homogenizer immersed in ice water. The capacity of whole muscle homogenates to oxidize [14C]-labeled pyruvate was determined by measuring the rate of 14CO2 production. The reaction mixture contained in a final volume of 2 mL, 20 mM potassium phosphate buffer, 20 mM KCl, 1.6 mM EDTA, 5 mM MgCl2, 123 mM sucrose, 2 mM Tris-Cl, 2 mM ATP, whole homogenate equivalent to 40 mg muscle, and 10 mM [2-14C] pyruvate, pH 7.2. The reaction mixture was placed in 25 mL flasks fitted with serum caps and hanging wells in a shaking Dubnoff incubator at 30°C. The 14CO2 produced was trapped and radioactivity was determined as described previously (26)
. Oxygen consumption in the presence of nonlimiting amounts of Pi and ADP, with pyruvate plus malate as substrate, was measured in whole muscle homogenates at 30°C as described previously (14)
except that O2 uptake was measured with a Clark-type polarographic oxygen probe (Model 5300, Yellow Springs Instruments Co., Yellow Springs, OH, USA).
Measurement of 2-deoxyglucose (DG) transport
Extensor digitorum longus muscles were incubated in 2 mL Krebs-Henseleit buffer (KHB) containing 8 mM glucose, 32 mM mannitol, and 0.1% BSA in the presence or absence of 2 milliunits/mL insulin at 35°C as described previously (27)
. Muscles were then washed for 10 min at 30°C in KHB containing 40 mM mannitol, 0.1% BSA with or without 2 mU/mL insulin to remove glucose from the extracellular space. The muscles were incubated for 20 min at 30°C in 1.5 mL KHB containing 4 mM 2-deoxy-D-[1,2-3H] glucose (1.5 µCi/mL), 36 mM [U-14] mannitol (0.2 µCi/mL) and insulin, if it was present in the previous incubation, to measure 2DG transport rates (28)
. Extracellular space and intracellular 2DG were determined as described previously (27)
.
Statistics
Values are expressed as means ± SE. Statistically significant differences were determined using unpaired Student’s t tests.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, NRF-1 DNA binding was increased 10-fold in skeletal muscle of the transgenic mice. The magnitude of the increase in muscle NRF-1 was similar in the two lines of transgenic mice.
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Effect of NRF-1 overexpression on mitochondrial enzyme protein levels
Cytochrome c protein was increased twofold, whereas ALA synthase and ubiquinol cytochrome c oxidoreductase core protein I levels were increased by 50% (Fig. 2
). The genes encoding these mitochondrial constituents are known to have NRF-1 recognition sites in their promoters (5)
. The subunit of ATP synthase was also increased 50% (Fig. 2)
; this finding was unexpected, as there is no known NRF-1 binding site in the ATP synthase gene (5)
. There were no significant increases in a number of other mitochondrial proteins measured, including citrate synthase, cytochrome oxidase subunit IV, and succinate ubiquinol oxidoreductase (70 kDa subunit). Levels of the mitochondrial transcription factor mtTFA and the transcriptional coactivator PGC-1 protein were not increased in muscles of the NRF-1 transgenic mice.
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Rate of pyruvate oxidation
To determine whether the change in mitochondrial composition in the muscles of the NRF-1 transgenic mice resulted in an increase in respiratory capacity, we measured the rate of pyruvate oxidation. Both the rate of [14C]-labeled pyruvate conversion to 14CO2 and the rate of O2 consumption with pyruvate plus malate as substrates were measured under conditions in which ADP and Pi availability are not rate limiting. As shown in Fig. 3
, there was no significant difference in respiratory capacity between the NRF-1 transgenic and wild-type muscles.
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Overexpression of NRF-1 results in increased expression of GLUT4 and MEF2A
We routinely measure GLUT4 protein levels in studies of mitochondrial biogenesis because GLUT4 expression and mitochondrial biogenesis appear to be induced by the same stimuli (20
, 29
30
31
32
33
34
35)
. However, as there was no evidence that NRF-1 is involved in regulating GLUT4 expression, we did not expect to find an effect. To our surprise, the GLUT4 protein content of the NRF-1 transgenic muscles was twofold greater than that of the wild-type muscles (Fig. 4
).
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Pessin’s group (36
37
38)
has shown that there is a myocyte enhancer factor 2 (MEF2) binding site in the GLUT4 promoter and that GLUT4 expression in muscle is dependent on binding of a MEF2A-MEF2D heterodimer to this site. As there are no NRF-1 recognition sites in the GLUT4 promoter, we examined the possibility that the increase in GLUT4 in the NRF-1 transgenic muscles might be mediated by enhanced expression of MEF2. As shown in Fig. 4
, there was a significant increase in MEF2A in NRF-1 transgenic muscle whereas MEF2C and MEF2D protein levels were unchanged.
Insulin-stimulated glucose transport is increased in NRF-1 transgenic muscle
To evaluate the functional significance of the increase in GLUT4 content of NRF-1 transgenic muscle, we measured blood glucose concentration in the fed state and the rate of 2-deoxyglucose transport in epitrochlearis muscles stimulated with a maximally effective (2 mU/mL) insulin concentration. Blood glucose concentration in the fed state averaged 284 ± 25 mg/dL in four wild-type and 168 ± 16 mg in four NRF1 transgenic mice (P<0.01). As shown in Fig. 5
, the insulin-mediated increase in glucose transport activity was greater in the NRF-1 transgenic than in the control muscles. The magnitude of the increase in the effect of insulin on glucose transport was roughly proportional to the increase in GLUT4, twofold.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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provides the link between adaptive stimuli and increased mitochondrial biogenesis (8
, 9
, 11
, 20
, 39)
. It has been hypothesized that PGC-1 regulates mitochondrial biogenesis primarily through coactivation of NRF-1 (5
, 9)
. In support of the concept that an increase in NRF-1 activity can mediate an increase in the capacity to generate ATP via mitochondrial respiration, Herzig et al. (22)
found that activation of NRF-1 by exposure of fibroblasts to serum induced an increase in mitochondrial respiratory capacity. However, this enhancement of oxidative capacity appeared to be due to an isolated induction of cytochrome c rather than to an increase in mitochondrial biogenesis. Skeletal muscle adapts to the energy demands of endurance exercise with increases in the size and number of mitochondria (13
, 16)
. Murakami et al. (21)
have reported that NRF-1 is increased 6 h after exercise. In contrast, Pilegaard et al. (40)
did not observe an increase in NRF-1 mRNA after a bout of exercise that induced a sevenfold increase in PGC-1 mRNA (40)
. We have found that a prolonged bout of exercise results in a large induction of PGC-1 expression and modest increases in NRF-1 and NRF-2 that precede the increments in muscle respiratory capacity and mitochondrial enzymes induced by endurance exercise (20)
. The purpose of the present study was to further evaluate the role of NRF-1 in the regulation of muscle respiratory capacity using transgenic mice that overexpress NRF-1 in their skeletal muscles.
There was a twofold increase in cytochrome c protein in skeletal muscle in the NRF-1 transgenic mice. NRF-1 was originally identified as an activator of cytochrome c expression (5)
, and it is now well established that NRF-1 plays a major role in the adaptive increases in cytochrome c induced by stimuli involved in the regulation of cytochrome c expression, such as exposing fibroblasts to serum (22)
or electrical stimulation of cardiac myocytes (41)
. In addition to the NRF-1 binding site, the cytochrome c promoter contains recognition sites for the cAMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors and for SP1 (5)
; these factors have also been implicated in the regulation of cytochrome c expression (22
, 42
, 43)
. To our knowledge, the present results provide the first evidence that an isolated increase in NRF-1, i.e., in the absence of stimuli that result in increases in CREB/ATF and/or SP1, can bring about increased cytochrome c expression. This finding implies that the constitutively expressed levels of these other transcription factors in skeletal muscle are sufficient to permit induction of cytochrome c by an increase in NRF-1 expression.
There are two NRF-1 binding sites in the promoter of the ALA synthase gene, and it has been shown that these NRF-1 binding sites are necessary for promoter activity (6)
. In fact, the role of NRF-1 in controlling ALA synthase expression is so well established that we used the NRF-1 recognition sequence from the ALAS synthase promoter to quantify NRF-1 DNA binding activity in the EMSA. In the present study, a 10-fold increase in NRF-1 in the muscle of the NRF-1 transgenic mice was associated with only a 50% increase in ALA synthase expression. In contrast, a 50% increase in NRF-1, induced by a bout of exercise (20)
or by raising cytosolic Ca2+ by exposing L6 myocytes to caffeine (39)
, was associated with a greater than twofold increment in ALA synthase protein. Similar differences in response were seen in a study on HeLa cells in which overexpression of UCP-1 resulted in a modest induction of NRF-1 and a large increase in ALA synthase expression, whereas a high level of NRF-1 overexpression resulted in a smaller increase in ALA synthase (23)
. Thus, it seems probable that the relatively small induction of ALA synthase by the massive increase in NRF-1 in the transgenic muscles is due to the requirement for concomitant increases of other transcription factors, NRF-1 phosphorylation, and/or coactivation by PGC-1 for optimal stimulation of ALA synthase expression by NRF-1 (5)
. The absence of increases in other transcriptional activators or of the coactivating activity of PGC-1 likely also accounts for the relatively weak induction of core protein 1. The finding that mtTFA was not increased in the NRF-1 transgenic muscles, which helps explain why overexpression of NRF-1 did not result in an increase in functional mitochondrial, is likely due to a requirement for both NRF-1 and NRF-2 for stimulation mtTFA expression (5)
.
The respiratory capacity of the muscles of the NRF-1 transgenic mice was not increased despite a large increase in cytochrome c. Thus, in contrast to the finding that an increase in cytochrome c in fibroblasts in culture increases their respiratory capacity (22)
, our results show that cytochrome c concentration is not rate-limiting for mitochondrial respiration in adult skeletal muscle. PGC-1 is a powerful coactivator of NRF-1, and it has been postulated that increased transactivation of NRF-1 regulated genes could be the major mechanism by which PGC-1 induces an increase in mitochondrial biogenesis (9
, 44)
. However, it is clear from the present results that an isolated increase in NRF-1 is not sufficient to bring about a coordinated increase in the expression of all of the proteins necessary for the assembly of functional mitochondria. In addition to coactivation of NRF-1, PGC-1 coactivates PPAR (45)
and induces increased expression of NRF-1 and NRF-2 (9)
. It seems reasonable that increases in the concentrations and/or transcriptional activity of all three of these factors, and probably additional transcription factors, account for the stimulation of mitochondrial biogenesis by PGC-1.
The adaptive stimuli that have been shown to induce increases in skeletal muscle mitochondria, including exercise, hyperthyroidism, lowering of high energy phosphates resulting in activation of AMP kinase, and raising cytosolic Ca2+, also bring about increased expression of the GLUT4 isoform of the glucose transporter in muscle (20
, 29
, 31
, 33
34
35
, 46
47
48)
. We therefore routinely also measure muscle GLUT4 concentration in studies of mitochondrial biogenesis and, as a consequence, detected a functionally significant increase in GLUT4 protein concentration in the muscles of the NRF-1 transgenic mice.
Pessin’s group has shown that the promoter of the GLUT4 gene contains a MEF2 binding site that is essential for activation of transcription (36
, 38)
and that MEF2A binds to this element as a MEF2A-MEF2D heterodimer (37)
. They also found that insulin deficiency, which results in a marked decrease of GLUT4 in insulin-sensitive tissues (49
, 50)
, causes a selective down-regulation of MEF2A (38)
. The addition of MEF2A to nuclear extracts from insulin-deficient, diabetic rat muscle reversed a reduction in binding to the MEF2 element, leading Thai et al. (38)
to conclude that MEF2A is necessary for expression of GLUT4 in striated muscle and is responsible for hormonal/metabolic regulation of the GLUT4 gene (38)
. Studies of L6 myotubes and rat epitrochlearis muscles showing that activation of AMP kinase (32
, 51)
or raising cytosolic Ca2+ (32)
induces increases in MEF2A, MEF2D, and GLUT4, and the present finding that an isolated increase in NRF-1 results in increased expression of both MEF2A and GLUT4, support this conclusion.
On the other hand, Michael et al. (12)
found that transfection of myotubes with PGC-1 resulted in an increase in GLUT4 expression mediated by coactivation by PGC-1 of MEF2C rather than MEF2A. In the present study, MEF2C was not increased in muscle in the NRF-1 transgenic mice. It seems possible that either MEF2A or MEF2C can mediate increased GLUT4 expression, depending on metabolic state and the inducing stimulus. PGC-1 increased GLUT4 expression by coactivation of MEF2C in the study by Michael et al. (12)
. In the present study and in a previous study of the effects of raising cytosolic Ca2+ or activating AMPK, increased expression of GLUT4 was associated with increases in MEF2A protein (32)
. Thus, it may be that the initial stimulus for increased GLUT4 expression is provided by coactivation of MEF2C by PGC-1 and the increase in GLUT4 is subsequently maintained by increased expression of MEF2A. It is of course also possible that other transcription factors are involved in mediating the increase in GLUT4 expression found in the NRF-1 transgenic muscles.
In addition to their roles in regulating expression of various mitochondrial proteins, NRF-1 and NRF-2 are transcriptional regulators of a number of key enzymes in other pathways involved in substrate metabolism (5)
. It is interesting that even though it is not a transcriptional activator of the GLUT4 gene, NRF-1 indirectly regulates the expression of GLUT4, which is rate-limiting for glucose transport into muscle and is therefore another key regulator of substrate metabolism. It is currently not known whether NRF-1 is a transcriptional activator of MEF2A. So, whether the increased expression of MEF2A in NRF-1 transgenic muscles is mediated directly by NRF-1 or is a secondary consequence of another action of NRF-1 is an open question.
NRF-1 increases rapidly in skeletal muscle after a bout of exercise (20)
. PGC-1, a coactivator of NRF-1 (8
, 9
, 11)
, also increases rapidly in muscle after exercise (20)
. Our finding that overexpression of NRF-1 results in enhanced GLUT4 expression in muscle helps to explain one of the mechanisms responsible for the concomitant increases in the capacities for glucose transport and oxidative generation of ATP in skeletal muscle adapting to endurance exercise (14
, 16
, 18
, 47)
.
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ACKNOWLEDGMENTS |
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Received for publication February 6, 2003. Accepted for publication April 25, 2003.
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