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1Åstrand Laboratory, University College of Physical Education and Sports; and 2Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Submitted 23 March 2006 ; accepted in final form 5 July 2006
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ABSTRACT |
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mode of contraction; protein synthesis; translation initiation
Changes in the rate of protein synthesis are likely to be mediated through activation of enzymes controlling protein translation in muscle, including protein kinase B (or Akt), the mammalian target of rapamycin (mTOR), and p70 S6 kinase (p70S6k) (29). Activation of p70S6k increases the phosphorylation of the ribosomal protein S6 and thereby enhances the translation of 5'TOP mRNAs, i.e., mRNAs that encode for ribosomal proteins and elongation factors (23). A role for the Akt/mTOR/p70S6k pathway in controlling muscle growth was first reported by Bodine et al. (5), who showed that activation of this pathway was necessary for adaptive hypertrophy and recovery after atrophy in rat muscle. In two recent studies, resistance exercise in rats or high-frequency stimulation of rat muscle in vitro was also reported to activate this pathway, supporting the view that the Akt/mTOR/p70S6k pathway is involved in contraction-induced muscle growth (2, 6). Furthermore, results in experimental animals suggest that the mode of contraction is crucial for activating p70S6k phosphorylation in muscle. Stimulation of the muscle via the sciatic nerve led to maximal phosphorylation of p70S6k in muscles performing high-resistance lengthening contractions, whereas in muscles performing shortening contractions a smaller increase or no change was found (3). In addition, high-frequency electrical stimulation of the muscle in vitro led to increases in p70S6k phosphorylation, whereas low-frequency stimulation did not stimulate the kinase (2). In human subjects, Cuthbertson et al. (10) found the same increase in phosphorylation of Akt and p70S6k after dynamic lengthening and shortening exercise when nutrition was supplied to optimize the anabolic response. However, the effect of lengthening and shortening contractions on phosphorylation of Akt, mTOR, and p70S6k in human muscle without nutritional supply is not known.
The purpose of the present study was to compare 1) maximal concentric and maximal eccentric contractions and 2) maximal concentric and submaximal eccentric contractions (of equal force to that of the maximal concentric contractions) regarding the stimulatory effect on signaling proteins in skeletal muscle in the absence of a nutritional intake. The subjects performed one-leg concentric and eccentric exercise with alternating legs. Skeletal muscle biopsies were taken before and repeatedly during the recovery period, and the phosphorylation of Akt, mTOR, p70S6k, and S6 was determined by immunoblot analyses using phosphospecific antibodies.
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METHODS |
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Sixteen healthy male subjects participated in the study after being fully informed orally and in writing of its purpose and the possible risks involved before providing informed consent. The subjects did not perform endurance or resistance exercise on a regular basis. The mean age (±SE) was 26 (±1) yr, height 181 (±1) cm, weight 75 (±2) kg, and maximal oxygen uptake (
O2 max) 3.92 (±0.15) l/min. The investigation was performed according to the principles outlined in the Declaration of Helsinki. The Ethics Committee of the Karolinska Institute approved the study protocol.
Preparatory Tests
Prior to the experiment, subjects participated in two preparatory tests. The tests were carried out on a modified leg press machine equipped with a force transducer (Nobel Elektronik KPG-4 T10; Vishay Nobel, Karlskoga, Sweden). Force was sampled and amplified using an analog device (Nobel Elektronik BKI-5; Vishay Nobel). Force data were A/D converted, transferred to a computer, and analyzed regarding peak force amplitude. The preparatory tests were designed to determine each subject's one-leg maximum force and to familiarize the subjects with the exercise procedure. The individual settings of the machine were documented for each subject. Specific attention was given to preventing the subjects from performing the movement at a knee angle of <90° and to avoiding extension at a knee angle >180°.
Electromyographic activity (EMG) was recorded from the right limb (vastus lateralis, 
15 cm proximal to the patella and on the mid-muscle belly of the hamstrings) in four subjects. The skin above the recorded muscles was shaved and cleansed with alcohol. Disposable bipolar surface electrodes (Blue Sensor M-00-S; Medicotest, Oelstykke, Denmark) with a 35-mm inter-electrode distance were used. The recording surface of each electrode was 6 x 3 mm. The electrodes were aligned longitudinally in the muscle fiber direction. Raw EMG signals were preamplified 600 times and filtered through a band-pass filter with low and high cutoff frequencies of 6 and 1,500 Hz, respectively. The filtered signal was converted to a root mean square signal using an AD536 circuit (Analog Devices, Norwood, MA) with an average constant of 100 ms. The converted signal, the root mean square of the raw signal, was then sampled at 100 Hz using a MuscleLab system (Model 4000e; Ergotest Technology, Langesund, Norway). The maximal isometric voluntary contractions (MVC) in the vastus lateralis and hamstrings were performed with the hip and knee joint of the right limb in a fixed position. The mean EMG activity in the vastus lateralis and hamstring muscles during the concentric and eccentric force production phases and MVC were calculated. The angular displacement of the right knee joint was recorded by means of a lightweight electrogoniometer taped over the joint. The angular velocity at the right knee joint was calculated to be 40°/s–1 (or 0.8 rad/s–1) during the shortening and lengthening contractions.
O2 max was determined by use of an online system (Amis 2001 Automated Metabolic Cart; Innovision, Odense, Denmark) while running on a treadmill. The speed and incline of the treadmill was gradually increased until exhaustion (1).
Experimental Protocol
Part 1: maximal concentric vs. maximal eccentric contractions. Ten subjects participated in this first part of the study. They were told not to engage in any intensive physical activity for 2 days prior to the experiment. On the day of the experiment, the subjects arrived at the laboratory in the morning after fasting overnight. A catheter was inserted in the antecubital vein, and the subjects rested for 30 min in a supine position. A resting blood sample was taken and after local anesthesia had been induced; a muscle biopsy sample was taken from the lateral part of the quadriceps muscle (vastus lateralis) of the leg selected for exercise. The subject was seated on the leg press machine and warmed up with 10 eccentric or concentric contractions (same contraction type as the following exercise) at 50% of the one-leg maximum, rested for 2 min, and then the subject performed four sets of six maximal eccentric or concentric contractions with a 5-min rest between sets. After 1 h of rest in a supine position, the subject repeated the same procedure with the opposite leg and the other contraction type, i.e., maximal concentric contractions when maximal eccentric contractions were performed with the previous leg and vice versa. Each repetition was done at a set pace so that each eccentric and concentric movement phase took 2.4 s. The eccentric movement was performed from straight leg (180° knee angle) to bent leg (90°), and the concentric movement was performed from bent leg (90°) to straight leg (180°). Six of 10 subjects started the exercise protocol with maximal one-leg eccentric exercise followed by maximal concentric exercise with the opposite leg, and four subjects started with concentric exercise followed by eccentric exercise. Figure 1 shows a schematic presentation of the experimental protocol.
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15 cm above the patella and the following samples 3 cm above the previous biopsy point. The muscle biopsy samples were taken at rest and immediately after the exercise as well as during recovery at 1 and 2 h after exercise. All biopsy samples were immediately (within 10 s) frozen in liquid nitrogen and stored at –80°C for later analysis. The choice of time points for biopsy sampling was based on our previous data in human subjects (26) and on observations in experimental animals (6) showing a rapid and sometimes temporary increase in kinase phosphorylation after resistance exercise. Part 2: maximal concentric vs. submaximal eccentric contractions Six additional subjects participated in the second part of the study. The same experimental protocol as described above was applied except that, instead of maximal eccentric contractions, the subjects performed four sets of six submaximal eccentric contractions with the same force as for the maximal shortening contractions. Three of the subjects started the exercise test with maximal concentric exercise followed by submaximal eccentric exercise, and three subjects started with the eccentric exercise followed by the concentric exercise.
Blood Analyses
Blood samples were drawn in heparinized tubes and centrifuged at 9,000 g for 3 min, and the plasma was stored at –80°C. Plasma glucose and lactate concentrations were analyzed according to Bergmeyer (4). Plasma creatine kinase activity was measured using a Reflotron reflectance photometer (Roche Diagnostics, Basel, Switzerland).
Tissue Processing
Muscle biopsy specimens were freeze-dried, dissected free from blood and connective tissue, and homogenized in ice-cold buffer (2 mM HEPES, pH 7.4, 1 mM EDTA, 5 mM EGTA, 10 mM MgCl2, 50 mM 
-glycerophosphate, 1 mM Na3VO4, 2 mM DTT, 1% Triton X-100, 2 µg/ml leupeptin, 5 µg/ml aprotinin, 40 µg/ml PMSF) at a dilution of 80 µl/mg of dry weight muscle. The inclusion of an additional phosphatase inhibitor cocktail (P 2850; Sigma) to the homogenizing buffer did not affect Ser/Thr phosphorylation of the measured kinases. Homogenates were rotated for 60 min at 4°C, centrifuged at 10,000 g for 10 min at 4°C to remove cell debris, and stored at –80°C. Protein was determined in aliquots of the supernatant diluted 1:10 in distilled water using a bicinchoninic acid protein assay (Pierce Biotechnology, Rockford, IL).
Western Immunoblot Analyses
Aliquots of muscle lysate were solubilized in Laemmli sample buffer and heated to denaturate proteins. Samples containing 30 (mTOR, p70S6k, and S6) or 40 µg (Akt) total protein were separated by SDS-PAGE for 90 min (Akt) or 120 min (mTOR, p70S6k, and S6) at 100 V using 4–20% gels on Criterion electrophoresis cell (Bio-Rad Laboratories, Richmond, CA). All eight samples from one subject were run on the same gel. After electrophoresis, gels were incubated in transfer buffer (25 mM Tris·HCl, 192 mM glycine, and 20% methanol) for 30 min to equilibrate gels for optimal transfer. Proteins were then transferred to polyvinylidine fluoride membranes (Bio-Rad Laboratories) at 100 mA constant current for 1.5 h (Akt) or 3 h (mTOR, p70S6k, and S6) on ice in a cold room at 4°C. Membranes were blocked in Tris-buffered saline (TBS; 10 mM Tris, pH 7.6, 100 mM NaCl) containing 5% nonfat dry milk (mTOR, p70S6k on Ser424/Thr421, and S6) or StartingBlock blocking buffer (Akt and p70S6k on Thr389; Pierce Biotechnology) for 1 h and then incubated overnight at 4°C with commercially available primary phosphospecific polyclonal antibodies. Antibodies recognized phosphorylated Akt on Ser473, mTOR on Ser2448 and Ser2481, p70S6k on Ser424/Thr421, and S6 on Ser235/Ser236 (Cell Signaling Technology, Beverly, MA) or p70S6k on Thr389 (Santa Cruz Biotechnology, Santa Cruz, CA). Antibodies were diluted 1:1,000 (Akt, mTOR, p70S6k on Ser424/Thr421, and S6) or 1:2,000 (p70S6k on Thr389) either in TBS with 0.1% Tween-20 (TBS-T) containing 2.5% nonfat dry milk (mTOR, p70S6k on Ser424/Thr421, and S6) or StartingBlock blocking buffer containing 0.1% TBS-T (Akt and p70S6k on Thr389). Membranes were then washed in TBS-T or TBS-T containing 2.5% nonfat dry milk, incubated with secondary antibody (horseradish peroxidase-linked anti-rabbit IgG; Cell Signaling Technology), and diluted 1:10,000 (Akt, p70S6k, and S6) or 1:5,000 (mTOR) in their respective primary antibody solutions for 1 h followed by washing in TBS-T (Akt and p70S6k on Thr389) or TBS-T containing 2.5% nonfat dry milk (mTOR, p70S6k on Ser424/Thr421 and S6). Phosphorylated proteins were visualized by enhanced chemiluminescence reagents according to the manufacturer's protocol (SuperSignal west femto maximum sensitivity substrate; Pierce Biotechnology) and quantified by densitometric scanning using a Gel Doc 2000 in combination with Quantity One version 4.4.0 (Bio-Rad Laboratories).
The membranes described above were incubated in Restore Western blot stripping buffer (Pierce Biotechnology) for 30 min at 37°C and reprobed with appropriate polyclonal antibodies for detection of the total expression levels of each protein. Protein expression of Akt, mTOR, p70S6k, and S6 was determined by immunoblot analysis as described above, using the respective polyclonal antibodies recognizing all forms of Akt, p70S6k, and S6 (Cell Signaling Technology) and mTOR (Santa Cruz Biotechnology).
Statistics
Data are presented as means ± SE of the mean. A two-factorial (time, mode of contraction) repeated-measures ANOVA was employed to analyze changes in the phosphorylation state of the different kinases in muscle after exercise and for changes in plasma concentration of glucose and lactate. When a significant overall effect was indicated, a Fisher least significant difference post hoc test was performed. Student's t-test for paired observations was employed to compare plasma creatine kinase activities before and 1 h after exercise. Significance was accepted at P < 0.05.
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RESULTS |
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DISCUSSION |
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In experimental animals, Baar and Esser (3) reported a different response in p70S6k phosphorylation in muscles after lengthening vs. shortening contractions, similar to the present results in human muscle. The increase in p70S6k was maximal (similar to insulin-stimulated increase) in the muscles performing lengthening contractions, whereas a smaller or no increase was found in muscles after shortening contractions (3). Nader and Esser (28) reported that a prolonged increase in p70S6k phosphorylation in the tibialis anterior muscle was observed only in response to high-frequency electrical stimulation, causing eccentric contractions of the muscle, suggesting that the lengthening contractions were more effective in activating p70S6k. The prolonged effect on p70S6k differs from the present results, where p70S6k phosphorylation peaked at 1 h after exercise and already tended to decrease again at 2 h recovery (Fig. 3). This difference may be explained, at least in part, by the elctrical stimulation protocol, leading to an activation of all fibers in the rat muscle, which may not be the case during maximal voluntary contraction by human subjects. Furthermore, the animals were allowed free access of food in the period after contraction, which may also have contributed to prolong the effect on p70S6k. In contrast, Parkington et al. (30) reported that both concentric and eccentric contractions caused elevated phosphorylation of p70S6k in the fast-twitch muscles of the rat but no effect in the slow-twitch soleus muscle, suggesting a fiber-type specific effect rather than an effect of the contraction mode. Future studies that investigate whether the observed effect of lengthening contractions on p70S6k activity in human skeletal muscle (Fig. 3, A and B) also involves a fiber type-specific effect are necessary.
The rate of protein synthesis was not measured in the present study, but recent data demonstrate increases in both p70S6k phosphorylation and rates of protein synthesis in young subjects after infusion of insulin and amino acids or after exercise (10, 15), supporting the notion that an increase in p70S6k activity is important for stimulating protein synthesis. In the exercise study (10), similar increases in p70S6k phosphorylation were reported after dynamic shortening and lengthening contractions (stepping up with one leg onto a knee-high box and stepping down with the other carrying 25% of body weight), suggesting no effect of the mode of contraction, in contrast to the present results. However, in the present study, exercise was performed in the absence of nutritional intake, whereas in the study by Cuthbertson et al. (10), essential amino acids and sucrose were supplied to the subjects after exercise. The anabolic response may therefore be caused by a combination of nutritional supply and the actual exercises and possibly with a large contribution from nutrition (11). In contrast, a more rapid increase in the rate of protein synthesis was reported during 4 h of recovery after maximal lengthening compared with shortening contractions, suggesting that protein accretion was larger after the lengthening exercise (27). However, also in this study, nutrition was supplied to the subjects after exercise.
In the present study, Akt phosphorylation was not affected by either eccentric or concentric exercise, suggesting that p70S6k is phosphorylated via an alternative signaling pathway that is independent of Akt in human muscle. This conforms with results in two recently published studies (8, 12) where Akt phosphorylation was unaffected by maximal leg extension exercise in endurance-trained subjects. In the latter study, both Ser473 and Thr308 phosphorylation of Akt were assessed and reported to be unchanged after resistance exercise (12). Furthermore, in the study by Coffey et al. (8), Akt was unaltered in both endurance- and strength-trained subjects 3 h after exercise, and p70S6k phosphorylation was increased immediately after exercise in the endurance-trained but not in the strength-trained subjects. Results from another study (9) indicate that changes in Akt phosphorylation are dependent on the preexercise muscle glycogen content. Akt phosphorylation was increased 10 min after resistance exercise (3 x 10 repetitions of knee extension exercise at 70% of 1 repetition maximum) in the glycogen-loaded muscle but unaffected after exercise with reduced muscle glycogen concentration (9). Elevation of p70S6k without changes in Akt phosphorylation was also reported in rat muscle after nerve stimulation (30), but not after resistance exercise and in isolated rat muscle stimulated to contract (2, 6). Akt kinase exists in three isoforms (Akt1–3) that are all expressed in skeletal muscle. Akt1 is important for regulation of muscle growth, and Akt2 is essential for insulin-stimulated glucose transport (24). However, whether these isoforms respond differently to the stimuli of resistance exercise has not yet been examined.
The tendency for an increase in mTOR phosphorylation on Ser2448 after the maximal eccentric exercise in the present study (P < 0.1 for main effect of time and for mode of contraction, respectively) may suggest that mTOR can activate p70S6k in human muscle or that p70S6k through a feedback mechanism phosphorylates mTOR, which was recently reported to occur in cell cultures (7, 19). However, the two- to threefold increase in p70S6k phosphorylation after lengthening contractions would have been expected to induce a clearer effect on mTOR than was found (Fig. 3), assuming there is the same feedback effect of p70S6k on mTOR in human muscle as there is in the investigated cell cultures.
Plasma creatine kinase activity was measured in the present study as a marker for skeletal muscle injury. The maximal eccentric contractions induced an increase in creatine kinase activity in five of six subjects, suggesting some degree of muscle damage. However, it should be pointed out that measurements of creatine kinase activity were made 1 h after exercise, and the activity is likely to increase further during recovery. This makes comparisons with earlier studies difficult, since assessments of muscle damage have often been made several hours or days after high-intensity eccentric resistance exercise (13, 35).
The higher force produced in the maximal eccentric vs. maximal concentric exercise, as well as the lower electrical activity, is consistent with earlier findings in human subjects (1, 33). During eccentric exercise there is an elongation and thus stretching of the muscle, which may have induced the observed increase in p70S6k phosphorylation. Force generation and stretch are factors, which can both activate protein synthesis, and they seem to have an additive effect on protein synthesis in rabbit muscle (14). An increase in p70S6k activation may thus be caused by a combined effect of muscle force/tension and mode of contraction. An effect of the eccentric muscle action per se would have induced an effect during the submaximal eccentric exercise as well, which was not noted. A higher neural activation level, expressed as the EMG amplitude, can also be ruled out as a possible stimulator of the kinases, as EMG recordings showed a lower activation level during maximal eccentric muscle action than during maximal concentric contractions.
Results in experimental animals have recently demonstrated that mechanical stimulation by passive stretching of the muscle in vitro increased phosphorylation of p70S6k on Ser424/Thr421 as well as Thr389 in an Akt-independent way (20). The changes in p70S6k phosphorylation on Ser424/Thr421 occurred in parallel with increases in p38 mitogen-activated protein kinase (MAPK) phosphorylation, and neither of these was blocked by rapamycin, suggesting no involvement of mTOR in phosphorylating p70S6k on these sites (20). In a previous study, a transient increase in p38 MAPK phosphorylation was found in the muscle after resistance exercise; however, the increase was completely suppressed 1 h after exercise when phosphorylation of p70S6k on Ser424/Thr421 was still elevated, making a role for p38 MAPK in phosphorylating p70S6k less likely (26).
In summary, maximal eccentric but not maximal concentric or submaximal eccentric contractions led to increases in the Thr389 phosphorylation of p70S6k and phosphorylation of the ribosomal protein S6 via an Akt-independent pathway. This suggests that maximal eccentric exercise can fully activate p70S6k in human muscle and thus stimulate translation of specific proteins in the absence of an immediate nutritional intake, an effect that may be mediated through greater muscle tension and stretching of the muscle during the eccentric muscle action. These results can have important implications for training recommendations after muscle injury and for recreational athletes.
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ACKNOWLEDGMENTS |
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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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REFERENCES |
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or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. FASEB J 19: 786–788, 2005.This article has been cited by other articles:
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