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Physiol. Genomics 35: 45-54, 2008. First published June 3, 2008; doi:10.1152/physiolgenomics.90217.2008
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Received 11 April 2008; accepted in final form 27 May 2008.
Physiological Genomics 35:45-54 (2008)
1094-8341/08 $8.00 © 2008 American Physiological Society

PGC-1{alpha} increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4

Carley R. Benton 1,*, Yuko Yoshida 1,*, James Lally 1, Xiao-Xia Han 1, Hideo Hatta 2 and Arend Bonen 1

1 Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
2 Department of Life Sciences, College of Arts and Sciences, University of Tokyo, Tokyo, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We examined the relationship between PGC-1{alpha} protein; the monocarboxylate transporters MCT1, 2, and 4; and CD147 1) among six metabolically heterogeneous rat muscles, 2) in chronically stimulated red (RTA) and white tibialis (WTA) muscles (7 days), and 3) in RTA and WTA muscles transfected with PGC-1{alpha}-pcDNA plasmid in vivo. Among rat hindlimb muscles, there was a strong positive association between PGC-1{alpha} and MCT1 and CD147, and between MCT1 and CD147. A negative association was found between PGC-1{alpha} and MCT4, and CD147 and MCT4, while there was no relationship between PGC-1{alpha} or CD147 and MCT2. Transfecting PGC-1{alpha}-pcDNA plasmid into muscle increased PGC-1{alpha} protein (RTA +23%; WTA +25%) and induced the expression of MCT1 (RTA +16%; WTA +28%), but not MCT2 and MCT4. As a result of the PGC-1{alpha}-induced upregulation of MCT1 and its chaperone CD147 (+29%), there was a concomitant increase in the rate of lactate uptake (+20%). In chronically stimulated muscles, the following proteins were upregulated, PGC-1{alpha} in RTA (+26%) and WTA (+86%), MCT1 in RTA (+61%) and WTA (+180%), and CD147 in WTA (+106%). In contrast, MCT4 protein expression was not altered in either RTA or WTA muscles, while MCT2 protein expression was reduced in both RTA (–14%) and WTA (–10%). In these studies, whether comparing oxidative capacities among muscles or increasing their oxidative capacities by PGC-1{alpha} transfection and chronic muscle stimulation, there was a strong relationship between the expression of PGC-1{alpha} and MCT1, and PGC-1{alpha} and CD147 proteins. Thus, MCT1 and CD147 belong to the family of metabolic genes whose expression is regulated by PGC-1{alpha} in skeletal muscle.

transfection; CD147; monocarboxylate transporter


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
LACTATE WAS CONSIDERED to be a metabolic waste product produced primarily during glycolysis in skeletal muscle. However, it is now well known that this metabolite can be oxidized in skeletal muscle and the heart (cf Ref. 17). Lactate can be shuttled from its site of production into neighboring muscle cells or into the circulation. Lactate transport across the plasma membrane occurs via pH sensitive monocarboxylate transporters (cf. Ref. 18), among which MCT1 and MCT4 appear to be the most important in rat skeletal muscle (7, 8, 32, 33). Little is known about MCT2, although it is present in skeletal muscle (2, 60). CD147 is required to target MCT1 and 4 to the plasma membrane (14, 24, 54, 55). The distribution patterns of MCT1 and 4 among metabolically heterogeneous skeletal muscles and the heart suggest that these proteins favor lactate import and export, respectively (7, 33). When the aerobic capacity of muscle is increased, only MCT1, not MCT4, protein expression is increased, and this has been associated with an increased uptake of lactate into skeletal muscle (8, 32). Whether MCT2 adapts to chronically increased muscle activity is not known.

The molecular basis for the contraction-induced increase in MCT1 protein expression remains unknown. However, in recent years PGC-1{alpha} has been identified as a key coactivator of selected transcription factors that induce an oxidative phenotype in skeletal muscle (cf Refs. 19, 28). In PGC-1{alpha} null mice, mitochondrial density is reduced (27) while in PGC-1{alpha}-overexpressing mice there is a pronounced mitochondrial proliferation (26, 46). It is now also known that PGC-1{alpha} induces, in muscle, the expression of genes involved in oxidative phosphorylation, and in lipid oxidation and trafficking (cf Refs. 19, 28). In L6 and C2C12 muscle cells (36) and in mature skeletal muscle (3) PGC-1{alpha} also induced the expression of GLUT4. Whether other transporters, such as MCTs are also upregulated by PGC-1{alpha} is not known. However, the available evidence suggests that MCT1 may well be regulated by PGC-1{alpha}. For example, MCT1, but not MCT4, correlates highly with the oxidative capacity of skeletal muscle (7, 8, 32, 33) and lactate-induced upregulation of MCT1, but not MCT4, is accompanied by a concurrent increase in PGC-1{alpha} mRNA (20). In addition, promoter analyses of MCT1, 2 and 4 (49) have shown that the MCT1 promoter contains two peroxisome proliferator-activated receptor response elements (PPRE) while MCT2 and MCT4 each contain one PPRE. Taken altogether, these lines of evidence suggest that 1) the difference in the protein expression of MCT1 may be associated with differences in PGC-1{alpha} among different types of skeletal muscle, 2) chronic muscle contraction may upregulate PGC-1{alpha} and MCT1, and 3) PGC-1{alpha} may induce the protein expression of MCT1 and CD147, which may increase the rate of lactate uptake into muscle.

Altering PGC-1{alpha} expression in vivo is not without pitfalls. In recent years it has become apparent that ablation (27, 29) or massive overexpression of PGC-1{alpha} (26, 38) in rodents has led to unexpected phenotypes, which have compromised muscle function and metabolism (26, 27, 29). This has led Handschin and Spiegelman (19) to speculate that only a moderate overexpression of PGC-1{alpha} may be required to observe physiologically desirable effects while avoiding unexpected anomalies. By controlling the upregulating of PGC-1{alpha} overexpression to be within physiological limits in rat muscle in vivo, we (3) do not observe the unusual phenotypes that have been reported in PGC-1{alpha} transgenic animals (26, 38). Specifically, inducing a modest PGC-1{alpha} protein expression improved mitochondrial fatty acid oxidation and insulin-stimulated glucose transport, as well as upregulating some of the genes involved in these processes (3).

To examine whether PGC-1{alpha}, when overexpressed within physiological limits, differentially regulated MCT1, 2, and 4 in rat skeletal muscle, we compared the relationship between PGC-1{alpha} and MCTs in several different experiments. First we examined the relationships between PGC-1{alpha} and MCT1, 2, and 4, and CD147 among six metabolically heterogeneous rat skeletal muscles. Next, we transfected PGC-1{alpha} into a rat muscles, in vivo, to determine whether this coactivator 1) increased the protein expression of MCT1, 2, and 4, and CD147, and 2) increased the rate of lactate uptake. Finally, we also examined the effects of chronic muscle stimulation on PGC-1{alpha} and on MCT1, 2, and 4. Our data indicate that PGC-1{alpha} induces the protein expression of MCT1 and CD147, resulting in an increased rate of lactate uptake. Moreover, combining the data from these three experiments indicates that there is a linear relationship between PGC-1{alpha} and MCT1 protein expression in skeletal muscle. Our work demonstrates that MCT1, but not MCT2 and 4, belongs to the family of metabolic genes whose expression is regulated by PGC-1{alpha} in skeletal muscle.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals
Male Sprague-Dawley rats 9–12 wk old (300–400 g) were used in all experiments. All animals were housed in a temperature-controlled room with a 12 h reversed light-dark cycle. Rats were fed water and standard rat chow ad libitum. Experimental procedures followed the Canadian Council on Animal Care (CCAC) guidelines for humane care and ethical treatment of animals. In addition, all experimental procedures were approved by the Animal Care Committee at the University of Guelph, acting on behalf of CCAC.

Materials
Proteins were determined with commercially available antibodies from the following sources: goat anti-rabbit secondary antibodies from Chemicon International (Temecula, CA) and donkey anti-rabbit secondary antibody from Amersham Biosciences (Oakville, Ontario). Anti-MCT1, MCT2, and MCT4 were prepared by Operaon (Tokyo, Japan) and have been used in some of our previous studies (2, 16, 21, 53, 60). Anti-Cd147 was obtained from Santa Cruz Biotechnology (Santa Cruz, CA) and anti-AMPK{alpha}2 was obtained from Upstate (Lake Placid, NY). All other reagents were obtained from Sigma-Aldrich (St. Louis, MO).

Comparison of PGC-1{alpha} With MCTs and CD147 in Rat Muscles
Tissue harvesting.
Rats (n = 5) were anaesthetized with Somnotol (6 mg/100 g body wt ip). Metabolically heterogeneous skeletal muscles [extensor digitorum longus (EDL), red tibialis anterior (RTA), white tibialis anterior (WTA), soleus, plantaris, red gastrocnemius, and white gastrocnemius] were excised, freeze clamped in liquid nitrogen, and stored at –80°C for future analysis.

Protein isolation and Western blotting.
Muscles were homogenized and proteins separated using SDS-PAGE, followed by Western blotting as we have previously described (7, 8, 13, 60). Signals were detected using enhanced chemiluminescence (Perkin Elmer Life Science, Boston, MA) and were subsequently quantified by densitometry by Gene Tool as per the manufacturer's instructions (SynGene, ChemiGenius2; Perkin-Elmer, Woodbridge, ON, Canada). All membranes were stained with Ponceau S to confirm equal loading and to enable normalization for purposes of densitometry.

Transfecting Skeletal Muscle In Vivo With PGC-1{alpha}
Plasmid DNA preparation.
The PGC-1{alpha} expression construct (gift from Dr. B. Spiegelman, Dana Farber Cancer Institute, Harvard University, Boston, MA) was produced by subcloning the PGC-1{alpha} coding sequence into a mammalian expression vector (pcDNA 1.0; Invitrogen, Burlington, ON, Canada). The pcDNA3.0 vector was used for control experiments (Invitrogen, Burlington, ON, Canada). PGC-1{alpha}-pcDNA and pcDNA3.0 plasmid stocks for electroporation were produced, as we have recently reported (3), by large-scale plasmid isolation from transformed Escherichia coli cells (One-Shot; Invitrogen, San Diego, CA) using commercially available kits (GIGA-prep kits; Invitrogen, Burlington, ON, Canada).

Electrotransfection of DNA.
Electrotransfection of DNA into rat hindlimbs was performed as we have described previously (12, 22), with some modifications (3). Briefly, animals were anaesthetized with Isoflurane (Aerrane; Baxter, Mississauga, ON, Canada). Once the animal was sedated, the lower hindlimb was shaved and sterilized (iodine and 70% ethanol). To increase transfection efficiency (34, 48) 100 µl of hyaluronidase (0.15 U/µl in 50% vol/vol saline) was injected through the skin and into the tibialis anterior (TA) muscle. Thereafter, rats were allowed to recover for 2 h, as was done previously (25, 34, 48). TA muscles of rats were electrotransfected with PGC-1{alpha}-pcDNA plasmid (500 µg PGC-1{alpha} in 50% vol/vol saline). Plasmid DNA and hyaluronidase were both injected via a short (1.25 cm) 27-gauge needle inserted through the skin, into the TA muscle, parallel to the orientation of the muscle fibers. Electrotransfection with empty pcDNA3.0 plasmid (500 µg pcDNA in 50% vol/vol saline) did not alter the parameters under consideration (unpublished observations) or any other metabolic parameters (3). Immediately following the injection of DNA, a pair of 0.8-cm diameter plate electrodes, attached to a set of ruled calipers (BTX, San Diego, CA), was applied onto the skin that overlays the TA muscle. Electroporation of the intact TA muscle was performed as we have described previously (3, 12, 15, 37). Briefly, nine electric pulses were administered (180 V/cm, 1 Hz, 20 ms in duration) with anode and cathode electrodes alternating between the lateral and medial aspects of the hindlimb and traversing along the TA from proximal to distal, after each set of three pulses (ECM 830 Square Wave Electroporator; BTX, San Diego, CA). After the pulse delivery, the rats were provided with an analgesic [Temgesic, subcutaneous 37 mg/100 g body mass; Reckitt and Benckiser Healthcare (UK) Ltd., Hull, UK] and allowed to recover. Muscle tissue was sampled 2 wk after transfection as recommended previously (4). Muscles from anesthetized rats were harvested, processed, and analyzed for selected proteins by Western blotting as described above.

Lactate uptake in control and PGC-1{alpha} transfected perfused rat hindlimb muscle.
In another group of rats (n = 4) PGC-1{alpha} was transfected into WTA muscle. After 2 wk, animals were perfused briefly (3 min) with lactate (1 mM), as we have done previously to measure the initial rate of lactate uptake (8, 32, 33). Briefly, rats were anesthetized as above and surgically prepared for hindlimb perfusion. After heparinizing rats with 1,000 IU heparin (500 units/ml) injected into the inferior vena cava, we inserted catheters into the inferior vena cava and aorta. The rat was put inside a Plexiglas cabinet containing the perfusion apparatus and maintained at 37°C. The rats were killed by injections of 1 ml of 10% (wt/vol) KCl into the heart after the onset of perfusion. A cell-free gassed (95% O2-5% CO2) Krebs-Henseleit buffer containing 4% bovine serum albumin pH 7.4 and 10 mM glucose was used as the perfusate. A one-pass system (20 ml/min) was used, and therefore the venous outflow was discarded. The perfusate was supplemented with L-lactate (1 mM) and 5 µCi [U-14C]lactate/100 ml and with 5 µCi [3H]mannitol/100 ml to account for the extracellular distribution space of lactate. At the end of perfusion, muscles were rapidly extracted and frozen in liquid nitrogen. Lactate accumulation in muscle was determined as we have previously reported (8, 32, 33). We have expressed rates of lactate uptake on a per minute basis.

Chronic Stimulation of Rat Hindlimb Muscles
Rat RTA and WTA were chronically stimulated as we have previously described (5, 8, 31, 32). Briefly, in anesthetized rats, two stainless steel electrodes were sutured to the underlying muscle on either side of the common peroneal nerve. These electrodes were then passed subcutaneously from the thigh, exteriorized at the back of the neck, and subsequently attached to a miniature electronic stimulator. The overlying muscle was sutured, and the skin was stapled. Muscles from the contralateral limb were used as a nonstimulated, internal control and were therefore sham-operated. Only when animals had regained at least 100% of their preoperative body weight (5 days) and had recovered from surgery for a minimum of 6–7 days, was chronic stimulation initiated. The common peroneal nerve was stimulated at 12 Hz, 24 h/day for 7 days. Thereafter, muscles were removed from anesthetized rats, frozen in liquid nitrogen, and stored at –80°C. PGC-1{alpha}, MCT1, 2, and MCT4 protein levels were measured in control and chronically stimulated RTA and WTA muscles.

Statistics
Comparisons between muscle fiber composition and PGC-1{alpha} protein expression, as well as between PGC-1{alpha} and selected proteins, were made using least squares linear regression. For these purposes the means of the data were used as has been done previously for these types of comparisons (3, 7, 33, 35). Repeated measures analyses of variance were used to compare the effects of chronic muscle stimulation and PGC-1{alpha} transfection on protein expression in muscle, as well as for the effects of PGC-1{alpha} transfection on lactate uptake. Post hoc analyses, when warranted, were performed using Fisher's least squares difference test. All data are reported as means ± SE.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Representative Western blots for PGC-1{alpha}, MCT1, MCT2, MCT4, and CD147 in six rat hindlimb muscles are shown in Fig. 1. AMPK{alpha}2 was used as loading control since it does not correlated with muscle fiber composition (3). The molecular weights of these proteins correspond closely to those reported by others (3, 24, 58). A positive relationship was observed between PGC-1{alpha} and MCT1 among metabolically heterogeneous muscle (Fig. 2A). In contrast, PGC-1{alpha} was not correlated with MCT2 (Fig. 2B) and was negatively correlated with MCT4 (Fig. 2C). CD147 was correlated with the oxidative capacity of the muscles examined (Fig. 3A) and with PGC-1{alpha}, MCT1, and MCT4 (Fig. 3, B, C, and E), but not MCT2 (Fig. 3D), protein expression.


Figure 1
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  		Fig. 1. Representative blots of PGC-1{alpha}, MCT1, MCT2, MCT4, CD147, and Akt{alpha}2 proteins in metabolically heterogeneous rat hindlimb muscles. EDL, extensor digitorum longus; RTA, red tibialis anterior; WTA, white tibialis anterior; PL, plantaris; RG, red gastrocnemius; WG, white gastrocnemius.

 

Figure 2
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  		Fig. 2. Relationship between PGC-1{alpha}, MCT1 (A), MCT2 (B), and MCT4 (C) in metabolically heterogeneous rat hindlimb muscles (means ± SE). Correlation coefficients are based on the means of data. OD, optical density.

 

Figure 3
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  		Fig. 3. Relationship between CD147 and the oxidative muscle fiber composition (A), PGC-1{alpha} (B), MCT1 (C), MCT2 (D), and MCT4 (E) in metabolically heterogeneous rat hindlimb muscles (means ± SE). Oxidative muscle fiber composition of rat muscles were obtained from one of our recent studies [see Table 1 in Benton et al. (3)]. Correlation coefficients are based on the means of data. In some instances the error bars are less than that of the plotting symbol.

 
Effects of PGC-1{alpha} Overexpression on MCT1, 2, and 4, and Lactate Uptake in Muscle
After electrotransfecting muscles with PGC-1{alpha}-pcDNA, the PGC-1{alpha} protein expression was increased by 23 and 25% in RTA and WTA muscles, respectively (Fig. 4A, P < 0.05). Transfection of PGC-1{alpha} increased MCT1 by 16% in RTA muscle (P < 0.05) and by 28% in WTA muscle (P < 0.05, Fig. 5A). In contrast, PGC-1{alpha} overexpression did not alter MCT2 (P > 0.05, Fig. 5B) or MCT4 (P > 0.05, Fig. 5C) protein expression in either in RTA or WTA muscles.


Figure 4
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  		Fig. 4. Effects of PGC-1{alpha}-pcDNA transfection (A) and chronic muscle stimulation (B) on the protein expression of PGC-1{alpha} protein in RTA and WTA rat muscles (means ± SE, n = 4–5 muscles). Paired statistical analyses were used between control and experimental muscles. *P < 0.05, WTA vs. RTA; **P < 0.05, stimulated or transfected muscle vs. respective control muscle.

 

Figure 5
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  		Fig. 5. Effect of transfecting muscle with PGC-1{alpha}-pcDNA on MCT1 (A), MCT2 (B), and MCT4 (C) in RTA and WTA rat muscles (means ± SE); n = 4–5 muscles. Representative Western blots for MCT1, 2, and 4 are shown. Paired statistical analyses were used between control and experimental muscles. *P < 0.05, WTA vs. RTA, **P < 0.05, transfected muscle vs. respective control muscle.

 
In a separate group of animals we also examined the effects of PGC-1{alpha} overexpression on muscle lactate uptake. In this experiment PGC-1{alpha} (+56%), MCT1 (+47%), and CD147 (+29%) were increased but not MCT2 and 4 proteins (Fig. 6). In addition, the rate of lactate uptake into perfused rat muscle was increased by 21% (control: 0.06 ± 0.006 nmol·mg–1·min–1; PGC-1{alpha} transfected: 0.072 ± 0.004 nmol·mg–1·min–1; P < 0.05) (Fig. 6).


Figure 6
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  		Fig. 6. Effects of PGC-1{alpha} transfection into WTA muscle on PGC-1{alpha}, CD147, MCT1, 2, and 4 protein expression and on the initial rates of lactate (La) uptake into hindlimb perfused muscles (means ± SE). Note, to facilitate comparisons data are expressed as %; each WTA control muscle was set to 100%, and the transfected WTA muscle was expressed relative to the control muscle. Paired statistical analyses were used between control and experimental muscles; n = 4 animals. Control and transfected WTA muscles were obtained from the same animals. *P < 0.05, transfected muscle vs. control muscle.

 
Chronic Muscle Stimulation
Chronic muscle stimulation increased MCT1 protein in RTA (+61%) and WTA (+180%) (P < 0.05, Fig. 7A). The relative (%) changes in MCT1 were greater in WTA than in RTA (P < 0.05), although the absolute increase ({Delta} arbitrary optical density units/µg protein) were similar in RTA and WTA muscles. Concomitant with these changes in MCT1, MCT2 protein was decreased somewhat in RTA (–14%) and WTA (–10%) muscles (P < 0.05, Fig. 7B), while the protein expression of MCT4 was not altered in either RTA or WTA (P > 0.05, Fig. 7C). A chronic contraction-induced increase in CD147 was observed in WTA (+106%, P > 0.05) but not RTA muscle (Fig. 7D).


Figure 7
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  		Fig. 7. Effects of chronic muscle stimulation on MCT1 (A), MCT2 (B), MCT4 (C), and CD147 (D) in WTA and WTA rat muscles (means ± SE); n = 9–11 muscles for MCT1 and 4, and n = 4–5 muscles for MCT2 and CD147. Representative Western blots for MCT1, 2, and 4 are shown. Paired statistical analyses were used between control and experimental muscles. *P < 0.05, WTA vs. RTA, **P < 0.05, stimulated muscle vs. respective control muscle.

 
Chronic muscle stimulation also increased the protein expression of PGC-1{alpha} in RTA (+26%) and in WTA (+86%) muscles (P < 0.05, Fig. 4B). As with MCT1, the relative (%) increase in WTA PGC-1{alpha} was greater than in RTA PGC-1{alpha} (P < 0.05).

Comparison of PGC-1{alpha}, MCT1, and CD147 in control, chronically stimulated, and PGC-1{alpha} transfected muscles
From the three foregoing experiments we were able to compare the relationship among PGC-1{alpha}, MCT1, and CD147 in control, chronically stimulated and PGC-1{alpha}-transfected muscles. This revealed that the positive relationships observed among metabolically heterogeneous muscles (i.e., between PGC-1{alpha} and MCT1, PGC-1{alpha} and CD147, MCT1 and CD147; Figs. 2 and 3) were maintained when these relationships were examined in RTA and WTA muscles when the various experimental conditions were examined simultaneously (Fig. 8, A–C).


Figure 8
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  		Fig. 8. Relationships between PGC-1{alpha} and MCT1 proteins (A), PGC-1{alpha} and CD147 proteins (B), and MCT1 and CD147 proteins (C) in control, PGC-1{alpha}-transfected muscles, and chronically stimulated muscles (means ± SE). Correlation coefficients are based on the means of MCT1, PGC-1{alpha}, and CD147 proteins. In some instances the error bars are less than that of the plotting symbol.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
A number of studies have shown that PGC-1{alpha} induces genes involved with fatty acid oxidation and oxidative phosphorylation (3, 19, 28). The present study indicates that PGC-1{alpha} also induces genes that are not involved in fatty acid metabolism, namely, the monocarboxylate transporter MCT1 and its chaperone CD147. The physiological consequence is an increase in muscle lactate uptake. On the other hand, PGC-1{alpha} does not appear to regulate the expression of MCT2 or MCT4. We speculate that the contraction-induced increase in MCT1 is mediated, in part, by PGC-1{alpha}.

Positive Relationship Between PGC-1{alpha} and MCT1 in Skeletal Muscle
In recent years a number of studies have provided convincing evidence that PGC-1{alpha} induces an oxidative phenotype in skeletal muscle (3, 19, 28). For this reason the observed relationships between PGC-1{alpha} and MCT1 and 4 in the present study were not unexpected, given our previous observations between muscle fiber composition and the protein expression of MCT1 and 4 (7, 33). The lack of any relationship between MCT2 protein expression and the oxidative capacities of different muscles was unexpected, given that this protein avidly transports pyruvate (9, 30), and therefore, a greater MCT2 presence might have been expected in oxidative muscles rich in mitochondria. Since MCT1 and PGC-1{alpha} are highly correlated in metabolically different types of skeletal muscle, it appears that PGC-1{alpha} may regulate the expression of MCT1.

Relationship Between CD147 and Muscle Fiber Composition, PGC-1{alpha}, and MCT1 in Skeletal Muscle
The present study is the first to examine the relationship between CD147 and muscle fiber composition and PGC-1{alpha} and MCT proteins in skeletal muscle. This protein is required to shepherd MCT1 and 4, but not MCT2, to the plasma membrane (24). The positive correlations between CD147 and the oxidative capacity of muscle and the protein expression of PGC-1{alpha} and MCT1 appear to suggest that with a greater expression of MCT1 in oxidative muscles concomitantly more CD147 is also required. Coordinating the expression of MCT1 and CD147 via PGC-1{alpha} would therefore seem to make sense.

Transfecting PGC-1{alpha} Into Muscle Induces the Expression of MCT1 but not MCT2 or 4
Since massive overexpression or ablation of PGC-1{alpha} has led to unexpected anomalies (26, 27, 29, 38), Handschin and Spiegelman (19) have suggested that a moderate overexpression of PGC-1{alpha} may be sufficient to observe physiologically desirable effects. In the present study, we have transfected PGC-1{alpha} into red and white compartments of the tibialis muscle in one hindlimb. The transfection-induced changes in PGC-1{alpha} protein expression in muscle were kept within a physiological range, namely, within the range of differences in PGC-1{alpha} protein observed among metabolically heterogeneous rat muscles (present study) and within a range that can be induced in electrically stimulated rodent (23) and exercised human muscle (45). This modest overexpression in a single muscle is unlikely to 1) alter whole body fuel homeostasis or 2) induce an unusual phenotype.

The PGC-1{alpha} overexpression induced the protein expression of MCT1, just as we (3) have recently shown for a number of other proteins and mitochondrial DNA, when using this transfection approach in rat muscle in vivo. In contrast, PGC-1{alpha} transfection failed to alter the expression of MCT2 and 4. These studies add MCT1 to a growing list of genes whose expression is regulated by PGC-1{alpha}. While initial studies indicated that such genes were restricted to fatty acid oxidation, the tricarboxylic acid cycle, the electron transport chain, and oxidative phosphorylation (cf Refs. 19, 28), recent studies have shown that PGC-1{alpha} also induces the expression of other genes, including the substrate transporters GLUT4 and FAT/CD36 (3, 36). These substrate transporters [GLUT4 (35) and FAT/CD36 (6)], as well as MCT1 (32, 33), are highly correlated with the oxidative capacities of skeletal muscle. Given this close association between substrate transport with the oxidative capacity of skeletal muscle, it is perhaps not surprising that expression of GLUT4 and FAT/CD36, as well as MCT1, occurs in concert with changes in the oxidative capacities of skeletal muscle, processes that are coordinated by PGC-1{alpha}. Wu et al. (57) have pointed out the advantages of this biologic strategy; namely, a coactivator such as PGC-1{alpha}, which can interact with multiple transcription factor families, allows for the coordination of many otherwise unrelated transcriptional regulators into a program of whole body physiology. Thus, MCT2 and 4, which have no obvious association with the oxidative capacity of muscle (present study and Refs. 7, 8), are therefore not expected to be regulated by PGC-1{alpha}, as was shown in the present study.

Concomitant Changes in PGC-1{alpha} and MCT1, not MCT2 or 4, in Chronically Contracting Muscle
In the present study PGC-1{alpha} was upregulated by chronic muscle contraction, as has also been observed by others using this experimental model (23). Prolonged exercise also increases PGC-1{alpha} protein expression in animals (51) and in humans (45). This contraction/exercise-induced upregulation of PGC-1{alpha} appears to be attributable to calcium release that activates the p38 MAPK signaling pathway, which stimulates PGC-1{alpha} promoter activity (1, 56).

Along with the contraction-induced upregulation of PGC-1{alpha}, chronic muscle stimulation also increased MCT1 protein, but not MCT2 or 4. This contraction-induced upregulation of MCT1, but not MCT4, has also been observed in previous studies from our laboratory (8, 32). However, this is the first report to document that chronic muscle stimulation also fails to alter MCT2 protein expression. In view of the experiments showing that PGC-1{alpha} induces the expression of MCT1 but not MCT2 or 4 (present study), it would appear that the contraction-induced increase in PGC-1{alpha} was at least one factor contributing to the upregulation of MCT1. It cannot be stated with certainty that the muscle contraction-induced changes in MCT1 are solely due to PGC-1{alpha}, as many signaling pathways are activated by muscle contraction. Nevertheless, the present studies have provided the most direct evidence to date that PGC-1{alpha} is involved in upregulating the expression of MCT1. Therefore, the chronic stimulation-induced PGC-1{alpha} upregulation likely also contributes to the increased expression of MCT1 in that model.

The failure to observe any contraction-induced changes in MCT2 and 4 is likely attributable to the fact to the fact that they are not regulated by PGC-1{alpha} (present study). However, other studies have shown that MCT4 can be upregulated when training intensity is very intense (10, 59), but PGC-1{alpha} may (11) or may not be upregulated by very intense exercise (A. Bonen, M. Robinson, T. Graham, unpublished observations). Thus, other factors likely contribute to regulating MCT2 and 4. MCT4 expression during hypoxia is increased through a hypoxia-inducible factor 1{alpha}-mediated mechanism (52), while little is known about the mechanisms regulating MCT2 expression. Since MCT4 is inversely related to the oxidative capacity of muscle, a possible candidate regulating MCT4 is the transcriptional co-repressor RIP 140, which downregulates mitochondrial biogenesis and the capacity for oxidative metabolism (40, 50). Alternatively, for MCT4, and possibly MCT2, posttranscriptional mechanisms may also be involved in regulating protein expression, as a number of studies have shown that MCT4 protein can be upregulated independent of any changes in MCT4 mRNA (8, 13, 16, 20).

PGC-1{alpha} Appears to Regulate MCT1 and CD147 in Resting and Chronically Contracting Muscles
A very tight regulation of MCT1 by PGC-1{alpha} appears to be occurring in skeletal muscle. For example, when we combined the results from the various experiments in which we examined the same skeletal muscles (RTA and WTA) at rest, after 7 days of muscle contraction and 2 wk after transfecting muscles with PGC-1{alpha}, there was a linear relationship between PGC-1{alpha} and MCT1, and PGC-1{alpha} and CD147 (see Fig. 8). We interpret this to indicate that under all these differing conditions PGC-1{alpha} is likely one of the key regulators of MCT1 protein expression and its chaperone CD147.

Functional Consequences of PGC-1{alpha}-mediated Upregulation of MCT1
In previous studies in which we examined lactate uptake in metabolically heterogeneous muscles and in chronically stimulated muscles we found a highly positive relationship between MCT1 protein and the rate of lactate uptake 1) among rat hindlimb muscles at rest (r = 0.90, Ref. 33) and 2) in chronically stimulated muscles (r = 0.93, Ref. 32). We have long proposed that MCT1 is likely the key transporter facilitating the uptake of lactate into muscle (7, 8, 32, 33), but not into mitochondria (60), since mitochondria do not directly oxidize lactate (42–44, 47, 60). The present experiments provide further evidence that lactate uptake is indeed facilitated by MCT1, since the PGC-1{alpha}-induced increase in MCT1 resulted in an increased rate of lactate uptake.

It has previously been shown that CD147 is required to target MCT1 and 4 to the plasma membrane (24, 39, 41, 54, 55). MCT2 associates with gp70 rather than CD147 (54). In the present study, PGC-1{alpha} induced the upregulation of both CD147 and MCT1. This likely allowed MCT1 to be targeted to the plasma membrane, given that lactate uptake was increased in PGC-1{alpha}-transfected muscles. In other studies in which we have transfected MCT1 into muscle, in the absence of a co-overexpression with CD147, we have found that the overexpressed MCT1 protein is not targeted to the plasma membrane (Y. Yoshida and A. Bonen, unpublished observations).

Summary
We have examined whether PGC-1{alpha} regulated the expression of the monocarboxylate transporters MCT1, 2, and MCT4 and the glycoprotein CD147. Our studies demonstrate that among metabolically heterogeneous muscles 1) a high correlation existed among PGC-1{alpha}, MCT1, and CD147; 2) PGC-1{alpha} overexpression in vivo increased MCT1, CD147, and lactate uptake; and 3) chronic muscle contraction increased PGC-1{alpha}, MCT1, and CD147 proteins. In none of these studies was there any evidence linking MCT4 or MCT2 expression with PGC-1{alpha}. Thus, our studies have shown that MCT1 and CD147 belong to family of metabolic genes whose expression, in skeletal muscle, is regulated by PGC-1{alpha}.


   GRANTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
These studies were supported by grants from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Canada Research Chair program.


   ACKNOWLEDGMENTS
 
C. R. Benton was supported by an Ontario Graduate Student award. A. Bonen is the Canada Research Chair in Metabolism and Health.


   FOOTNOTES
 
Address for reprint requests and other correspondence: A. Bonen, Dept. of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada (e-mail: abonen{at}uoguelph.ca).

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.

* C. R. Benton and Y. Yoshida contributed equally to this study. Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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