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1 Department of Anatomy, University of Bern, 3000 Bern 9
2 Nestlé Research Center, Nestec, CH-1000 Lausanne 26
3 Department of Clinical Research (Magnetic Resonance Spectroscopy and Methodology), University of Bern and Inselspital Bern, 3010 Bern, Switzerland
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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(PPAR-), the master regulator of lipid metabolism. Moreover, a significant correlation existed between LPL mRNA and the absolute rate of IMCL repletion determined by magnetic resonance spectroscopy after exhaustive exercise. Additionally, the LIPE mRNA level correlated with ultrastructurally determined IMCL content and mitochondrial volume density. The present data point to a training-induced, selective increase in mRNA levels of enzymes which are involved in metabolization of intramuscular FA, and these data confirm the well-established phenomenon of enhanced lipid utilization during exercise at moderate intensity in muscles of endurance-trained subjects. 1H-magnetic resonance spectroscopy; electromagnetic morphometry; gene expression; mRNA; reverse transcriptase-polymerase chain reaction
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Consistent with the increased importance of FA fueling prolonged muscle contractions, endurance training leads to increased capacity for FA oxidation and increased use of lipids as a substrate both with regard to relative and absolute exercise intensities (27, 51–53). On the ultrastructural level, this is indicated by an increase in mitochondrial volume density and content of IMCL with bicycle training and long-distance running in muscles that are recruited during this type of endurance exercise [e.g., M. vastus lateralis (25, 26, 30)]. Similarly, in a recent 1H-magnetic resonance spectroscopy (1H-MRS) study, we found IMCL content and absolute IMCL utilization at an exercise intensity near 50% 
O2 max to be almost doubled in M. tibialis anterior (TA) of endurance-trained duathletes compared with untrained subjects (12). Surprisingly, IMCL repletion rates in TA muscle over the first 24 h after exercise were similar for trained and untrained subjects if those were given the same high- or low-fat diets.
Successively aligned transport, storage, and conversion steps are involved in metabolization of FA in skeletal muscle (Fig. 1; 19, 27, 40, 51). Endothelial lipoprotein lipase (LPL) and several facilitative transport proteins are involved in transporting FA from the vasculature through the interstitium into the myocellular compartment where FA may be stored as IMCL or transferred to the mitochondria for immediate oxidation (19, 31, 40, 48). In this regard, the muscle fatty acid binding protein (H-FABP, also FABPc) is believed to play a main role in the intramyocellular transport of free FA (19). Diacylglycerol O-acyltransferase 1 (ARGP1) is essentially involved in the storage of FA as IMCL by joining the third FA to diacylglycerol (42). Hormone-sensitive lipase (HSL) has been shown to liberate free FA from IMCL for mitochondrial oxidation (31, 36). Carnitine palmitoyltransferase I (CPT I) is a key enzyme for the uptake of FA into the mitochondrial matrix, and long-chain acyl-coenzyme A dehydrogenase (LCAD) is involved in mitochondrial oxidation of the main FA component (reviewed in Refs. 28 and 31). Cytochrome c oxidase 1 (COX I) is a major mitochondrially encoded enzyme of oxidative phosphorylation, being responsible for the final electron transfer to O2. With respect to metabolization of CHO in muscle cells, the muscle form of 6-phosphofructokinase (PFK-A) has been shown to be a main control step for entry of sugars into the glycolytic pathway (31).
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and PPAR-
(13), are increased in TA muscle of endurance-trained subjects. Conversely, it was speculated that 3) gene expression of enzymes involved in glycolysis and storage of FA in the form of IMCL is invariant between TA muscle of trained and untrained subjects. Last, it was tested to which extent mRNA levels of factors involved in import, breakdown, and mitochondrial oxidation of FA, respectively, correlate with depletion and repletion rates of IMCL, as well as with mitochondrial volume densities. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Determination of IMCL utilization with 1H-MRS.
It has previously been shown that the noninvasive 1H-MRS technique is reliable to quantify IMCL content and utilization in human TA muscle (12, 29). The kinetics of IMCL depletion and repletion have been described earlier (12) but were recalculated for the present publication (see Statistical data analysis, below). Briefly, IMCL content in TA of each subject was monitored by 1H-MRS on a clinical 1.5 T MR scanner using a short echo time PRESS localization technique (20-ms echo time, 3-s repetition time) and with reference to the water signal for standardization. 1H-MRS was performed before and after a 2-h depletion run on a treadmill at around 50% of peak O2. Because of the fact that exercise at 50% O2 max was performed close to the walk-gait transition, the relative intensity was slightly higher in trained than in untrained subjects (53 ± 1% vs. 48 ± 2% of O2 max). The rate of IMCL repletion during recovery from exhaustive exercise was calculated from the difference in IMCL content measured 1 h and 30 h after the 2-h exercise (12). The subjects did not consume any food in the first hour after exercise, but they ingested five meals containing 55% of the energy as fat until 30 h after exercise as described in Ref. 12. This high-fat diet was composed of normal foods and an experimental liquid formula, contributing one-third of the energy (12). Nutrient composition was calculated from standard food tables and manufacturers’ label information. The experimental liquid formulas were based on skim milk powder, maltodextrin (Glucidex C19; Roquette, Lestrem, France), water, and Sanolio oil. Quantitative energy intake for each subject was set to correspond to that of athletes in training (52 kcal·kg-1·24 h-1).
Biopsies.
Using the Bergstrom technique (3), we took biopsies from the middle portion of the TA muscle at rest after a training abstinence of minimally 2 days. The sampling was done 4–8 wk after treadmill running and 1H-MRS. This interval between the IMCL depletion intervention and the "steady-state" biopsies was chosen because exercise rapidly affects gene expression in the recovery phase from exercise (44, 48). One part of the muscle tissue sample was immediately frozen in isopentane cooled by liquid nitrogen and then stored in the latter for further analysis. The other part was fixed in buffered glutaraldehyde solution and processed for morphometric analysis by electron microscopy (9).
Morphometric determination of IMCL content and mitochondrial volume density.
Biopsy samples fixed in glutaraldehyde were dehydrated in increasing ethanol concentrations and embedded in Epon. After cutting ultrathin sections (50–70 nm) on a LKB Ultrotome III, uranyl acetate and lead citrate staining was performed as described previously (9). A Philips 300 transmission electron microscope was used for recording micrographs on 35-mm films. At a final magnification of x24,000 volume densities of mitochondria and of IMCL per muscle fiber volume were determined using standard morphometric procedures (55).
Fiber type analysis.
Cryosections of 15 µm from each biopsy were subjected to fiber type analysis by ATPase staining as described previously (5). On average, 180 fibers per biopsy were typed.
RNA isolation and real-time PCR.
Cryosections from TA muscle were sampled in frozen tubes (10 mm3 per sample), and RNA was extracted and quantified as described previously (56). A total of 600 ng of RNA was reverse transcribed using the Omniscript Reverse Transcriptase kit (Qiagen, Basel, Switzerland) with random hexamers. cDNAs were amplified using real-time PCR with a GeneAmp 5700 Sequence Detection System (PerkinElmer, Rotkreuz, Switzerland) with gene-specific primers (Table 1) that were designed using Primer Express Software v2.0 (PerkinElmer). Amplification and detection of the LPL, LIPE, and 18S cDNAs was performed using TaqMan universal PCR MasterMix (Applied Biosystems, Rotkreuz, Switzerland) with TaqMan probes (Table 1) and reagents supplied in x20 ribosomal 18S mix (Applied Biosystems) were used to amplify 18S RNA. Amplification of all other cDNAs was done with SYBR Green chemistry (SYBR Green PCR Master mix; Applied Biosystems). Each PCR reaction was set up in triplicate, and amplicon length was verified by gel electrophoresis. Quantification of amplified cDNA was done as described previously (17) with the modification that relative cDNA amounts were put into relation to 18S RNA concentrations in agreement with the proposition of Bustin (10). The standardized values hence lead to an estimation on the level of individual RNAs in each muscle sample.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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O2 max and a trend for a lower respiratory exchange ratio (RER) measured during the 2-h exercise at 50% of O2 max in the trained compared with the untrained subjects. Average IMCL utilization in TA muscle over the 2-h exercise period was 72% larger in the trained compared with the untrained group, and average IMCL repletion during 29 h of recovery was 44% larger in trained vs. untrained subjects, but because of marked individual variation, these differences did not reach the level of statistical significance. IMCL content as determined by either 1H-MRS or electron-microscopic (EM) morphometry was 56% and 76% larger in trained than in untrained subjects, respectively. Mitochondrial volume density was 23% higher in the trained vs. the untrained group, but again the individual variation prevented all differences in ultrastructural variables from being statistically significant. The percentage of type I fibers was over 75% in both trained and untrained subjects.
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(PPARG) and mRNAs for enzymes involved in storage of FA as IMCL (diacylglycerol O-acyltransferase 1, DGAT), in ß-oxidation of long FA (long-chain acyl-coenzyme A dehydrogenase, ACADL), and in glycolysis (muscle phosphofructokinase, PFKM) were not significantly different in TA between the groups (Fig. 2).
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O2 max, volume density of mitochondria in TA, and electron microscopically determined IMCL content (Fig. 5). O2 max was also significantly correlated with the mRNA for LPL (r = 0.63; P = 0.038). IMCL utilization rate did not significantly correlate with the levels of any measured transcript involved in local FA metabolism, whereas a significant correlation could be established between the mRNA level for LPL and the absolute rate of IMCL repletion between hours 1 and 30 after exhaustive exercise (r = 0.62, P = 0.042).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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O2 were characterized in terms of the structural composition of muscle tissue and of the abundance of transcripts coding for main factors involved in FA transport, storage, and oxidation. The results of this study outline a tentative scenario whereby long-term transcriptional adjustments of key steps involved in mobilization of FA from extra- and intracellular stores and oxidative phosphorylation are involved in the enhanced FA turnover in skeletal muscle as a result of endurance training. This indicates that earlier models such as the crossover concept (8) and its possible modifications with endurance training can be investigated at a molecular level.
Limitations.
The temporal difference in the sampling of MR data and muscle biopsies may have been a limiting factor which precluded us from discerning a possible correlation of IMCL utilization with mRNA levels of fat metabolizing pathways. Support for such an explanation is given by the low level of correlation between the IMCL values determined with 1H-MRS and EM morphometry in the biopsies taken 4–8 wk later and used for mRNA quantification (r = 0.35; P = 0.29). Previous studies have shown that IMCL content is markedly influenced by both physical exercise and diet (29, 54).
TA muscle was chosen because of its unique properties with respect to IMCL determination by 1H-MRS. TA is mostly involved in body balance and foot control and is not a major contributor to propulsion. Therefore, all the characteristics detected in the present study must be valued in view of the limited importance of TA in walking and running. Classic markers of improved aerobic capacity as well as of enhanced lipid metabolism on the muscular level (volume density of mitochondria, IMCL content, rates of IMCL utilization and repletion) tended to show the expected adaptations in the group of trained subjects, but the differences compared with the untrained controls did not reach the level of statistical significance (Table 2). This hints that transcriptional markers of fatty acid metabolism are more sensitive than classic markers of aerobic capacity. From this point of view, the biological findings on expressional adaptations in fatty acid metabolism are even more impressive, and it can be assumed that they must be more pronounced in muscles like vastus lateralis which are more strenuously recruited in most types of human exercise. Data published by other authors do confirm that expressional changes in fatty acid metabolism are a hallmark of the plasticity of human skeletal muscle (11, 16, 34).
Correlation analysis permits us to compare the relationship between factors but has limitations with regard to mechanistic conclusions about cause and effect. Nonetheless, the several statistically significant intra-individual intergene correlations observed in the present study indicate that a gradual similarity of certain gene expression levels exists over different individuals.
Regulatory conclusions.
The significantly larger mRNA concentrations of LIPE, FABP3, and COI in trained vs. untrained subjects (Fig. 2) support the hypothesis of transcriptional reprogramming of enzymes involved in oxidative lipid metabolism. This is further supported by the trend for increased mRNA levels of LPL and PPARA, which encode factors involved in liberation of blood-borne FA through lipolysis and in transcriptional regulation of lipid metabolism (13). The latter observation favors the hypothesis that pretranscriptional mechanisms are involved in the regulation of these individual gene products (20, 35, 48). The elevated level of these mRNAs may be the consequence of transient increases in nuclear transcription or of increased sarcoplasmic stabilization of transcripts after each single exercise bout (44, 48), which would lead to an incremental increase in the steady-state mRNA concentrations of these metabolic genes with repetitive training sessions (16).
The observed significant correlations of mRNA levels of LIPE with those of LPL and FABP3 (Fig. 3) argue for a transcriptional coregulation of these key enzymes involved in metabolization of FA from extra- and intracellular stores. At the transcriptional level, the significant correlations between mRNA for PPAR- and those for LIPE and FABP3 (Fig. 4) are of significance. PPAR- plays a major role in expressional control of oxidative metabolism and is activated through lipid products involving unsaturated long-chain FA (13). In particular, FABP3 and LIPE are potential PPAR downstream genes, holding a peroxisomal proliferator response element (PPRE) in their promoter (18, 49). PPAR- content has been demonstrated to increase in skeletal muscle of women after 12–14 wk of endurance training in parallel with increased FA oxidative capacities (28). The role of PPAR- in muscle lipid homeostasis is further corroborated by studies involving skeletal muscle cultures (41). In conjunction with the 86% increase of PPARA mRNA in trained vs. untrained subjects, the correlation analysis is supporting a link of PPARA in the regulation of LPL, FABP3, and COI expression in human TA muscle. The correlation of the mRNA levels of PPARA with that of mitochondrially encoded COI mRNA may likely be related to the role of PPARs in the general control of the expression of genes involved in oxidative metabolism (13). In this regard, the correlation of LIPE mRNA with mitochondrial volume density and IMCL (Fig. 5) could be of importance since in adipocytes the encoded protein, HSL, translocates to the lipid storage droplet upon lipolytic stimulation (14). Genetic and biochemical studies indicate that LIPE is expressed in skeletal muscle cells (37) and that its ablation with knockout technology strongly reduces total lipolytic activity of skeletal muscle tissue (21). The same LIPE transcript is expressed in both human muscle and adipocyte tissue (24). Our present data now emphasize that the number of LIPE transcripts in TA muscle are matched to the pathway oxidizing intramuscular lipids via mitochondria. Together with the correlation of LIPE and PPARA mRNA and the fact that PPAR- activity is regulated by free long-chain FA (13), this suggests that there may be a relation between the flux of FA liberated from IMCL on the one side and expression of the transcript encoding HSL on the other.
Similarly, the correlation between PPARG mRNA and FABP3 and COI transcript levels are of interest. PPARG levels have already been demonstrated to correlate with FABP3 in human skeletal muscle (39); however, the fact that the amount of PPARG mRNA in TA muscle was similar between the trained and the untrained group suggests a minor role of expressional adaptations involving PPAR- in the transcriptional regulation of the former genes in TA muscle of endurance-trained athletes.
In line with our hypothesis, we found no difference in the expression of the DGAT gene at the mRNA level. To the best of our knowledge, our data are the first to document the level of the measured DGAT transcript in human skeletal muscle in relation to the training status.
The finding on similar quantities of mRNAs involved in mitochondrial import (CPT1B) and in ß-oxidation of long-chain fatty acids (ACADL) in TA biopsies of trained and untrained subjects was unexpected. According to other authors, CPT1B mRNA was increased following short-term cycling training in human M. vastus lateralis (44, 50), and activity of the encoded CPT I was shown to be significantly higher in the same muscle from trained vs. inactive subjects (4). Expression of genes encoding the mitochondrial enzymes CPT I and LCAD is controlled by fatty acid availability through the eventual action of PPAR- (7, 23, 38). However, CPT1B mRNA, unlike the other PPAR target genes FABP3 and LIPE, was not correlated with either PPARA or PPARG in the present study. This allows us to argue that differences in the number of training interventions and the different involvement of M. vastus lateralis and TA in contractions during cycling are responsible for the different expressional response of CPT1B in endurance-trained subjects.
Only one of the transcriptional and structural variables of lipid metabolism analyzed, i.e., maximal IMCL content as determined by 1H-MRS, was related to the percent distribution of type I fibers (data not shown). This supports earlier observations made in human vastus lateralis that contractile and metabolic properties of skeletal muscle are to some extent independently controlled in humans (30).
Strikingly, one untrained subject shows up in the cluster of trained athletes in scatter-plot analysis for the mRNA expression of LIPE, FABP3, COI, and PPARA (Figs. 3 and 4), whereas the same subject clearly belonged to the group of untrained controls when functional (O2 max) and ultrastructural parameters (volume density of mitochondria and IMCL) were investigated (Fig. 5). We cannot exclude that this particular subject was consuming a high-fat diet prior to the muscle biopsy, since we did not obtain food records. A high-fat diet could have caused upregulation of genes involved in lipid metabolism (11). Overall, the mRNA profile of this untrained subject supports the close transcriptional coupling of genes encoding enzymes involved in FA metabolism (HSL, H-FABP, COX I) and of their transcriptional regulator PPAR-. Observations in the same subject further stress the importance of standardized prebiopsy conditions (exercise, diet, etc.).
Functional conclusions.
Changes in mRNA levels are thought to be responsible for the structural and related functional adaptations seen with chronic exercise training (16, 44, 48). If the transcriptional adaptations detected in the present study are translated into a codirectional change in the amount of encoded key metabolic factors, as is the case for several of the analyzed genes (2, 16, 22, 45, 48), then a scenario of metabolic adaptations may be expected as a result of endurance training. The increased mRNA level of FABP3 and of LIPE in TA of trained compared with untrained subjects supports the contention that a higher rate of FA mobilization may contribute to the enhanced reliance on lipid utilization in endurance-trained subjects at moderate exercise intensity (12, 27). In particular, the increase in LIPE mRNA is compatible with a larger IMCL utilization demonstrated during exercise at moderate exercise intensity in trained compared with untrained subjects (12). It also supports the conclusion that endurance-trained subjects derive a part of their larger FA utilization during exercise from IMCL (see also Johnson et al., Ref. 32). The increase in COI is in agreement with the generally acknowledged higher capacity for fatty acid oxidation in skeletal muscle of endurance-trained athletes (27).
Moreover, the trend (P < 0.07) of larger mRNA concentrations of LPL, which liberates FA from lipoproteins and chylomicrons in the vasculature (40), suggests that also the capacity for import of blood-borne FA could be increased with endurance training. An increase in LPL activity as a consequence of training has been implicated in the enhanced FA uptake from the bloodstream during exercise (43). Turcotte et al. (51) have shown enhanced FA uptake capacities during prolonged exercise of endurance-trained vs. untrained subjects. The present data on the correlation between the mRNA level for LPL and the rate of IMCL repletion (r = 0.62; P = 0.042) now emphasize that the larger FA uptake capacity does not solely result from an eventually increased LPL activity but seems to be accompanied by enhanced transcription of the LPL gene, thereby altering protein turnover and potentially increasing enzyme concentrations (16). Overall, the present data suggest that human TA muscle responds to endurance training such as running or cycling, although its aerobic load is consistently lower than the one found in other human leg muscles (46) with enhanced potential for oxidative metabolism.
General conclusions.
The significant upregulation of mRNA concentrations of LIPE, FABP3, and COI in TA muscle of trained subjects compared with untrained controls indicates that transcriptional reprogramming of FA metabolization via breakdown from intramyocellular stores and myocellular transport represents the molecular basis for the increased oxidative capacities induced by chronic endurance training.
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ACKNOWLEDGMENTS |
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This study was supported by the Swiss Sports Research Commission (to B. Schmitt), Swiss National Science Foundation Grant SNF-3100.053788.98 (to C. Boesch), and the University of Bern.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Flück, Dept. of Anatomy, Univ. of Bern, Bühlstrasse 26, 3000 Bern 9, Switzerland (E-mail: flueck{at}ana.unibe.ch).
10.1152/physiolgenomics.00089.2003.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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in the metabolic response to training. Am J Physiol Endocrinol Metab 279: E348–E355, 2000.This article has been cited by other articles:
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