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mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle
1Department of Physiology and Pharmacology, Section of Molecular Exercise Physiology, 2Department of Laboratory Medicine, Division of Clinical Physiology, Huddinge University Hospital, 3Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and 4Department of Medicine, Duke University, Durham, North Carolina 27708
Submitted 23 July 2003 ; accepted in final form 9 September 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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(PGC-1)/mitochondrial transcription factor A (Tfam) pathway is involved in exercise-induced mitochondrial biogenesis. In the present study, nine healthy men performed two 45-min bouts of one-legged knee extension exercise: one bout with restricted blood flow, and the other with nonrestricted blood flow to the working muscle. Muscle biopsies were obtained from the vastus lateralis muscle before exercise and at 0, 30, 120, and 360 min after the exercise bout. Biopsies were analyzed for whole muscle, as well as fiber-type specific mRNA expression of myocyte-enriched calcineurin interacting protein (MCIP)-1, PGC-1, and downstream mitochondrial transcription factors. A novel finding was that, in human skeletal muscle, PGC-1 mRNA increased more after exercise with restricted blood flow than in the nonrestricted condition. No changes were observed for the mRNA of NRF-1, Tfam, mitochondrial transcription factor B1, and mitochondrial transcription factor B2. Muscle fiber type I and type II did not differ in the basal PGC-1 mRNA levels or in the expression increase after ischemic training. Another novel finding was that there was no difference between the restricted and nonrestricted exercise conditions in the increase of MCIP-1 mRNA, a marker for calcineurin activation. This suggests that calcineurin may be activated by exercise in humans and does not exclude that calcineurin could play a role in PGC-1 transcription activation in human skeletal muscle. gene expression; ischemia; monocyte-enriched calcineurin interacting protein-1; mitochondria; muscle biopsies
(PGC-1) is one of the factors that plays a probable role in this process.
PGC-1 has the ability to bind to and affect a number of transcription factors. A coactivator does not bind directly to DNA but regulates specific cellular programs through interaction with other DNA-binding regulatory factors, such as specific transcription factors. PGC-1 has been implicated as an important determining factor of fiber type as well as the oxidative capacity of muscle fibers (16). When expressing PGC-1 at physiological levels, Lin et al. (16) showed that 10% of type II fibers were converted to type I fibers in the transgenic mice. Furthermore, this transgenic PGC-1 expression induced the expression of mitochondrial genes. PGC-1 transcriptionally activates the nuclear respiratory factors (NRF)-1 and -2, which are known to be important for mitochondrial biogenesis, and is also a coactivator of NRF-1. Furthermore, PGC-1 coactivates the peroxisome proliferator-activated receptors- and -
, which regulate fatty acid uptake and 
-oxidation, as well as uncoupled respiration through the regulation of uncoupling protein transcripts (20, 29).
For mitochondrial biogenesis in skeletal muscle to be induced, it is essential that genes from the nuclear and mitochondrial genomes be expressed in a coordinated fashion (13). Candidate coordinators are NRF-1 and -2, with binding sites in the promoter region of several nuclearly encoded mitochondrial proteins, such as mitochondrial transcription factor A (Tfam), that directly affects mitochondrial DNA transcription and replication (25). Tfam was previously thought to be the only transcription factor needed for mitochondrial transcription and replication. Recently, it was shown that additional transcription factors may influence the transcription of human mitochondrial DNA in vitro (11), namely mitochondrial transcription factors B1 (TFB1M) and B2 (TFB2M). It is not yet known which regulatory factors control their respective expression, but recognition elements in their sequences for different transcription factors, for example NRF-2, have been described (21).
Contractile activity-induced metabolic perturbation has repeatedly been suggested as an important condition for induction of mitochondrial biogenesis (23, 30). For example, ischemic exercise has been shown to induce a higher citrate synthase activity, a marker for mitochondrial content, than exercise with normal blood flow at identical mechanical work loads (23). A higher degree of muscle activation and higher intracellular calcium levels for a given force output are necessary during exercise with a greater level of metabolic perturbation (26). Thus a possible mechanism behind the enhanced mitochondrial biogenesis after repeated bouts of exercise is calcium signaling through calcium-activated systems (6). In fact, it has been reported that overexpression of calcium/calmodulin-dependent protein kinase IV strongly induces PGC-1 mRNA expression in parallel with increased mitochondrial DNA content and relative amount of type I fibers (28). Earlier enzymatic measurements of the level of calcineurin activation have been difficult in vivo. However, recently it has been shown that myocyte-enriched calcineurin interacting protein 1 (MCIP-1) mRNA reflects the activated state of the calcineurin system and therefore could be used as a marker for activated calcineurin in vivo (31).
The hypotheses of the present study were that 1) exercise increases PGC-1 mRNA levels and to a greater extent during exercise with enhanced metabolic perturbation, 2) a greater increase is observed in the more oxidative type I fibers than in type II fibers, 3) calcineurin activation occurs in parallel with PGC-1 mRNA expression, and 4) the gene expression of suggested downstream mitochondrial transcription factors is related to the increase in PGC-1 mRNA expression.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Nine healthy men participated in the experimental part of the study. Their average (range) age, height, and weight were 23 (18-26) yr, 180 (170-188) cm, and 74 (65-84) kg, respectively. To control for effects from the biopsy procedure itself, 10 additional healthy male control subjects were included. Their average (range) age, height, and weight were 24 (20-29) yr, 180 (174-190) cm, and 74 (65-92) kg, respectively.
Before the study, the experimental protocol was explained to all subjects, and informed consent was obtained. The study was approved by the Ethics Committee of the Karolinska Institutet.
Exercise Model
A method first described by Eiken and Bjurstedt (9) was employed for induction of restricted blood flow and reduced oxygen delivery during exercise. For exercise under restricted blood flow, the chamber pressure acting on the exercising leg was elevated to 50 mmHg above atmospheric pressure. This has been shown to reduce leg blood flow during one-legged cycle exercise by 15-20% (24). Exercise under nonrestricted blood flow was performed by using the same experimental arrangements but at normal atmospheric pressure.
Experimental Protocol
At least 1 wk before the first experiment, each subject was familiarized twice with the experimental model and procedures. During familiarization, the maximal one-legged knee extension performance capacity was determined under normal, nonrestricted blood flow conditions in a test where the work load, beginning at 5 W, was increased by 5 W at 1-min intervals to fatigue. Five subjects were randomly selected to perform the first exercise bout under nonrestricted blood flow conditions, and the remaining four subjects performed exercise under restricted blood flow conditions first. The dynamic constant-load knee-extension exercise (45 min, 60 rpm) was performed in a similar fashion described earlier (12). There was a washout period of 10 days between the two exercise bouts. Each voluntary contraction extended the leg from 70 to 150° knee angle. Flexion was performed passively by using the ergometer flywheel momentum to reposition the leg for the next extension. The relative work load subsequently used in the experiments was 26 ± 4% (SD) of the one-legged peak load in the restricted blood flow condition. In absolute terms, it was 10 ± 1 W.
To evaluate exercise-induced differences between the two conditions, heart rate was continuously recorded from the ECG by means of a linear beat-to-beat meter, systolic arterial blood pressure was determined by the cuff method in the supine position, local rate of perceived exertion (L-RPE) was estimated by Borg's 6-20 RPE-scale (5), and venous blood samples were obtained before and after 15, 30, and 45 min of exercise for lactate determination by a fluorometric enzymatic procedure as described previously (12).
Muscle Biopsies and RNA Extraction
Muscle biopsies were obtained from the vastus lateralis muscle before exercise in the leg not about to exercise, and at 0, 30 min, 2 h, and 6 h after the exercise bout in the exercised leg by using the percutaneous needle biopsy technique (3). All biopsy samples were frozen within 10-15 s in liquid nitrogen and stored at -80°C until further analysis. A small portion of the preexercise biopsies and the biopsies taken 2 h after exercise with restricted blood flow was freeze-dried, and 
400 single fibers were dissected out. These were classified histochemically as either fiber type I or II and thereafter divided into separate pools of type I and type II fibers, e.g., 200 type I and type II fibers, respectively (10). In the control subjects, resting biopsies were taken at the same four time points as for the exercised leg in the experimental part of the study.
Total RNA from biopsy samples and from the two fiber pools was extracted by the acid phenol method as described previously (7). Total RNA from each biopsy was quantified spectrophotometrically by absorbance at 260 nm and controlled by visual inspection of the denaturing gels. Two micrograms of total RNA from each sample and all the RNA from the fiber pools were reverse transcribed by Superscript RNase H reverse transcriptase (GIBCO BRL) using random hexamer primers, according to the manufacturer's specifications.
mRNA Measurements
Real-time PCR was used for measurement of specific mRNAs (ABI-PRISMA 7700 Sequence Detector, Perkin-Elmer Applied Biosystems, Foster City, CA). Oligonucleotide primers and TaqMan probes were designed by using Primer Express version 1.5 (Perkin-Elmer Applied Biosystems). As endogenous control to correct for potential variation in RNA loading and quantification, -actin was used. The oligonucleotide sequences for the primer pairs and probes used for PGC-1, MCIP-1, NRF-1, Tfam, TFB1M, and TFB2M are shown in Table 1. -Actin primers and probe were supplied as a TaqMan Reagents kit from Applied Biosystems with either a TAMRA quencher or Dark Quencher [part no. 4310881E (TAMRA), 4326315E (DQ)] and used according to the manufacturer's instructions. All reactions were performed in 96-well MicroAmp Optical plates. Amplification mixes (25 µl) contained the diluted cDNA sample, 2X TaqMan Universal PCR Mastermix, forward and reverse primers, and probe for the specific mRNAs, as well as -actin mix. Thermal cycling conditions included 2 min at 50°C and 10 min at 95°C before the onset of the PCR cycles, which consisted of 40 cycles at 95°C for 15 s and 65°C for 1 min. Control experiments revealed approximately equal efficiencies over different starting template concentrations for target genes and -actin. Target gene and -actin were amplified in multiplex experiment in triplicate, and all samples from an individual subject were analyzed simultaneously in one assay run. Relative quantification of the samples was carried out by using dilution curves for each target gene run in multiplex with -actin, similar to that of a standard curve.
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Statistics
If not otherwise stated, values are expressed as means ± SD. Hemodynamic parameters, venous lactate, L-RPE, and mRNA levels were statistically analyzed with a two-way (time and exercise condition) parametric ANOVA. As a post hoc test to locate the point of interaction, planned comparison was used. A P value of <0.05 was considered as significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The exercise-induced increase in heart rate was not significantly different between the two exercise conditions (Table 2). The exercise-induced systolic arterial blood pressure and the average L-RPE were significantly higher (P < 0.05 and P < 0.01, respectively) during exercise with restricted compared with nonrestricted blood flow (Table 2). Increased venous plasma lactate was observed at the onset of exercise (P < 0.01) with restricted blood flow but not during exercise with nonrestricted blood flow (Fig. 1).
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mRNA Expression
PGC-1. There was a greater exercise-induced PGC-1 mRNA increase after exercise with restricted blood flow (P < 0.01; Fig. 2A) compared with the nonrestricted condition. PGC-1 mRNA increased significantly between 30 min and 2 h after exercise (P < 0.05) in both exercise conditions (fold change restricted blood flow leg: 7.88 ± 4.08; nonrestricted blood flow leg: 2.41 ± 1.30), and the levels remained elevated 6 h after exercise (fold change restricted blood flow leg: 7.91 ± 4.63; nonrestricted blood flow leg: 2.71 ± 1.58). In the control subjects, a small but significant fold change of 1.39 ± 0.11 was observed 6 h after the first biopsy (Fig. 2A).
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There was no basal difference in PGC-1 mRNA expression between type I and type II fibers. An induction of PGC-1 mRNA was observed 2 h after exercise in both type I and type II muscle fibers without any fiber-type difference (Fig. 3A).
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MCIP-1. Exercise induced an increase in MCIP-1 mRNA expression 2 h after exercise (P < 0.05; fold change in restricted blood flow leg: 2.42 ± 1.03; in nonrestricted blood flow leg: 3.57 ± 2.02) with no statistical difference between the two exercise conditions (Fig. 2B). There was no significant effect of the biopsy procedure itself on MCIP-1 mRNA expression (Fig. 2B).
NRF-1, Tfam, TFB1M, and TFB2M. There was no change in NRF-1, Tfam, TFB1M, and TFB2M mRNA levels with exercise in either of the two exercise conditions (Table 3). Also, no difference was observed between type I or type II fibers in regard to basal or exercise expression of NRF-1, Tfam (Fig. 3B), TFB1M, and TFB2M.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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mRNA increased more after restricted blood flow exercise. Second, mRNA for MCIP-1, a marker for calcineurin activation, increased after exercise in both conditions.
In a previous study (2), our laboratory showed that Tfam protein increases in human skeletal muscle after 4 wk of training, which suggests an activation of the PGC-1-NRF pathway in response to physical activity. In fact, in a recent study (19), it was shown that PGC-1 mRNA increased up to 10-fold 2 h after a 3-h exercise bout. That finding lends further support to the involvement of this pathway in human physical activity adaptation.
In the present study, PGC-1 mRNA increased at 6 h after the first biopsy in the nonexercised/control group. This illustrates the importance of methodological controls when repetitive biopsies are taken. We do not know, however, whether the biopsy procedure itself or other changes over time induced this increase after 6 h. The regulating mechanisms behind pretranslational activation of PGC-1 are not known. In the present study, the observation that the increase of the PGC-1 gene expression was enhanced after exercise with restricted blood flow indicates that factors related to cell metabolism may be of importance. When the metabolic perturbation is enhanced, the degree of fatigue is increased, which requires a higher degree of muscle activation and higher intracellular calcium levels for a given force output (26). Therefore, as has been suggested earlier, the regulating role of calcium-activated kinases and/or AMP-activated protein kinase may be considered (27, 28). Supporting this, Ojuka et al. (18) found significantly increased PGC-1 protein levels after intermittent caffeine-induced calcium increases in L6 myotubes. That MCIP-1 mRNA increased with exercise in the present study may support that calcineurin is activated concomitant with the increase in PGC-1. However, the enhanced PGC-1 mRNA expression in the restricted condition was not accompanied by a concurrent increase in MCIP-1 mRNA expression, suggesting that other factors are important as well.
Skeletal muscle fiber type I and type II showed similar basal PGC-1 mRNA levels, and the expression level increased for both fiber types after restricted exercise. This was slightly surprising because PGC-1 has been shown to be preferentially expressed in type I-rich muscles in mice (16). However, it is important to consider the species differences in fiber-type composition and in the adaptation to exercise. For example, the transformation from fast to slow fiber type in response to electrical stimulation occurs much earlier in rabbits than in rats (8, 15).
The induction of PGC-1 mRNA in the present study was not followed by any transcriptional change for the downstream factors NRF-1, Tfam, TFB1M, and TFB2M in response to exercise independent of blood flow condition. There may be several different reasons for this. In a study on swimming rats (1), PGC-1 protein did not increase until 18 h after the end of exercise, i.e., much later than the period studied in the present investigation. Thus it is not possible to exclude that the time between the exercise bout and the final biopsy was too short to detect transcriptional changes for mitochondrial factors downstream of PGC-1. In both the present study and in the study by Pilegaard et al. (19), exercise did not influence NRF-1 mRNA levels. In the present study, Tfam mRNA expression after exercise did not change. In contrast to this, Pilegaard et al. (19) reported that Tfam mRNA increased threefold 6 h after the end of a 3-h exercise bout. The discrepancy between their finding and ours may very well depend on the different exercise durations. Furthermore, it is interesting to observe that the exercise-induced Tfam mRNA expression occurred without a concurrent mRNA increase of the suggested upstream transcription factor NRF-1. However, Murakami et al. (17) reported increased NRF-1 mRNA levels 6 h after a 90-min bout of treadmill running in rats. Based on our findings and those of Pilegaard et al. (19), it may be speculated that regulation of NRF-1 activity may be determined by other factors, such as interaction with other factors, covalent modification, and intracellular localization. Considering its possible role in response to exercise, the regulation of NRF-1 may occur at the posttranscriptional level or it could also be that exercise-related transcriptional regulation of Tfam is not solely related to NRF signaling. Support for such a posttranscriptional regulation comes from the report by Baar et al. (1), in which they reported an increase in NRF-1 protein binding after one bout of exercise.
In conclusion, factors related to cell metabolism seem to be of importance for the induction of PGC-1 mRNA in human skeletal muscle. This is based on the novel observation that PGC-1 mRNA increases more after exercise in a blood flow-restricted exercise condition than in the control condition. Also novel, the calcium-activated kinase MCIP-1 mRNA increased after both ischemic and control exercise. This suggets that calcineurin may be activated by exercise in humans and does not exclude that calcineurin could play a role in PGC-1 transcription activation in human skeletal muscle.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This work was supported by the Swedish Research Council (6622), the Swedish National Centre for Research in Sports (53/02), the Swedish Heart-Lung Association (200041647), and the Magn. Bergvall Foundation. J. Norrbom and H. Ameln have PhD training grants from the Swedish National Centre for Research in Sports (160/02 and 162/03, respectively).
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FOOTNOTES |
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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.
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Significant difference between 30 min and 2 h after exercise between the restricted and nonrestricted exercise conditions (P < 0.05). 
Significant difference between the first biopsy and the biopsy taken 6 h later in the nonexercising control subjects. B: 1 bout of exercise induced an increased MCIP-1 mRNA expression 2 h after exercise (P < 0.05). There was no difference between the 2 exercise conditions. The biopsy procedure itself did not affect MCIP-1 mRNA expression. *Significant difference between rest (pre) and 2 h after exercise in both restricted and nonrestricted exercise conditions (P < 0.05). Values are means ± SE; n = 9. Control, resting biopsies in control subjects.