Dang 2014, Changes in Akt MTOR Signaling Pathway in Response to Concurrent Exercise a Review

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  Review   Changes in Akt/mTOR signaling pathway in response to concurrent exercise: A review Carl-Erik Dang  Department of Physical Education and Health, Örebro University, Örebro, Sweden Dang CE.  Changes in mTOR signaling pathway in response to resistance, endurance and concurrent exercise: A review.  —   Exercise is known to cause morphological, architectural (Seynnes, 2007) and biochemical changes in human skeletal muscle (Zoll, 2002). However, different exercise modes cause different adaptations in the human body. Resistance training has proven to cause increases in muscle fiber size and strength (Seynnes, 2007), whereas endurance exercise adaptations leads to increases in maximal oxygen uptake, formation of capillaries and mitochondrial biogenesis (Ingjer, 1979). A combination of exercise modes are widely used to gain  benefits from both resistance and endurance exercise, known as concurrent training. Concurrent training is used to induce adaptations that occur with both endurance and resistance training. However, there has been a debate whether the adaptations of these exercises may interfere with one another, known as the interference effect (Hickson, 1980). In 1980 this phenomenon was investigated by Hickson (1980) who in fact revealed that strength gains were compromised with 10 weeks of concurrent training. However, maximal oxygen uptake improvements were not diminished when compared to endurance training alone. This pioneering work of Hickson (1980) has led to several investigations of concurrent training. A more recent study (Silva, 2014) investigated the effects of concurrent training on leg strength compared to resistance training alone. Forty-eight physically active females were randomly divided into four groups with resistance training combined with continuous running, interval running, continuous cycle ergometer training or resistance training only. Interestingly, the study reported that leg strength was not inferior with 11 weeks of concurrent training when compared to resistance training alone.  Akt/mTOR signaling pathway. The up regulation of protein synthesis has been proven to be regulated by the mammalian target of rapamycin (mTOR). There are quite many different factors that affect the Akt/mTOR signaling pathway, one of them being phosphorylation of eukaryotic translation factors (eukaryotic initiation, elongation and release factors). It has  been demonstrated that leucine administers the activity of S6K1 by increasing the availability of eIF4E for formation with active eIF4G and eIF4E complex, all which partakes in up regulation of protein synthesis (Anthony 2000). Furthermore, it appea rs that it’s possible to inhibit hypertrophy by blocking phosphorylation of p70 S6K   without altering the phosphorylation of Akt or mTOR. Conversely, Anthony et al. (2000) demonstrated an increase in  phosphorylation of downstream targets of mTOR, specifically 4E-BP1 and S6K1, but with lack of increases in the rate of protein synthesis. The downstream targets of mTOR proven to regulate hypertrophy in skeletal muscle are GSK-3 β , p70 S6K   and PHAS-1/4E-BP1. Blockage of mTOR signaling and its downstream targets inhibits hypertrophy (Bodine, 2001). The mTOR signaling pathway is therefore crucial in order to achieve skeletal muscle hypertrophy. Atherton et al (2005) found in mice that low frequency stimulation (LFS) caused increases in phosphorylated AMPK and that mTOR and protein synthesis was increased following high frequency stimulation (HFS). Furthermore, AMPK has been proven to attenuate phosphorylation of S6K1, 4E-BP1 and activity of eEF2 signaling responses in rats (Thomson, 2008). HFS increased phosphorylation of Akt/TSC2/mTOR signaling, GSK-3 β  and activated translation initiation regulators p70 S6K  , 4E-BP1, eIF2B and elongation factor eEF2. All of which has an important role in anabolic processes in skeletal muscle. However, some of these anabolic responses, specifically the downstream targets of TSC2, were inhibited following LFS. Findings also suggest that TSC2 mediates anabolic responses to HFS via Akt/TSC2/mTOR pathway and inhibits protein synthesis during LFS. Inhibition of inactivity of AMPK occurs with accumulated high concentrations of AMP (Hawley, 1995) and inhibits phosphorylation of mTOR and some of its downstream targets (Bolster, 2002). It has been suggested that short contractions, similar to high frequency stimulation, does not accumulate as high concentration of AMP as seen in longer and continuous stimulation (Atherton, 2005). It has also been proposed that resistance and endurance exercise combined attenuates desired molecular adaptations when compared to each exercise alone (Lundberg, 2012, Apro 2013, Donges 2012). There appears to be many physiological factors that may influence and interfere with the adaptations of concurrent training. The purpose of this brief review is to focus on the molecular response to concurrent training, more specifically the Akt/mTOR signaling pathway. ROLE OF MTOR IN ENDURANCE EXERCISE  Animal studies. As previously mentioned, 3 h low frequency stimulation done on mice did not induce significant increases in phosphorylated Akt, mTOR via Ser2448 or its downstream targets, p70 S6K  , 4-BP1 and eIF2B post stimulation or 3 h after. However, a slight increase was found in GSK-3 β . In contrast, a study (Edgett, 2013) performed on mice found quite the opposite. 3 h treadmill exercise induced expression of mRNA translation initiation by significantly increasing  phosphorylated Akt, mTOR, rpS6 and eIF2B ε . Interestingly, another study (Souza, 2013) done on rats revealed no increases directly after exercise or 2 h post-exercise in  phosphorylation of Akt, AMPK, mTOR or p70 S6K1  following 60 minutes of running at 60% of V max .  Human skeletal muscle.  Mascher et al. (2007) studied the effects of 1 h cycling exercise on changes in signaling  pathways. Six male subjects performing endurance exercise less than twice a week participated. Phosphorylated GSK-3 β      was constantly increased during a time course of 3 h post-exercise. Interestingly, there was an acute increase of  phosphorylated Akt 1 h and 2 h post-exercise, but not after 3 h. Phosphorylated mTOR revealed an increase directly after, 30 min and 2 h post-exercise, but not after 3 h. mTOR and Akt were partially greater during different time points, it suggests that there are alternate pathways in which mTOR can be activated. In support of this notion, Mascher et al. (2010) revealed an increase of phosphorylated Akt 3 h post-exercise, whereas mTOR and p70 S6K   was immediately greater in the working and resting leg following 60 minutes of one-legged cycling. Interestingly, despite an acute increase in mTOR post-exercise, a significant increase in the mTOR inhibitor AMPK was reported. Moreover, the fractional  protein synthesis was higher in the exercising leg. The evidence suggests that increases in phosphorylated AMPK and mTOR can occur concomitantly. Mascher et al. (2006) did not only prove that endurance exercise induces acute mRNA translation initiation, but also that gene expression fluctuates during a time course of 3 h post-exercise. Studies examining at one time point may therefore miss out on valuable information concerning changes in gene expression. ROLE OF MTOR IN RESISTANCE EXERCISE Changes in mTOR signaling pathway in response to resistance exercise has been studied well more than changes that occurs with endurance exercise. Several studies done on human subjects support the notion that resistance exercise induces acute increases in mTOR phosphorylation (insert studies). In addition to this notion, intake of BCAA or whey  protein isolate can further elevate mTOR signaling (Apro, 2010, Farnfield 2009). Resistance exercise with subjects performing 4 sets of 10 repetitions at 80% of 1RM on leg press for a total of 20 minutes induced increases in phosphorylated mTOR, p70 S6K  , rpS6 and decrease in eEF2 15 min, 1 h and 2 h post-exercise (Mascher, 2008). In accordance with previously mentioned studies (insert), increases in phosphorylated mTOR were established with absence of elevated phosphorylated Akt after resistance exercise (Apro, 2010, Mascher 2008). However, the elevation of phosphorylated mTOR did not differ between the BCAA and the placebo group (Apro, 2010). Moreover,  phosphorylated p70 S6K   were significantly higher than before exercise and the placebo group, whereas placebo group did not elevate p70 S6K  . Increases in the downstream target of  p70 S6K  , rpS6 and eEF2, were found, but with no differences  between groups. Interestingly, Apró et al. (2010) failed to elevate phosphorylated p70 S6K   while elevations of rpS6 were reported. Roux et al. (2007) showed that RAS/ERK (Extracellular signal-regulated kinase) signaling pathway can  promote phosphorylation of rpS6 at Ser  235/236  independently of the mTOR pathway. It appears that four sets of 10 repetitions of 80% of 1RM followed by four sets of 15 repetitions of 65% of 1RM in leg  press with 5 minutes rest between sets did not elevate levels of phosphorylated AMPK (Apro, 2010). However, a study with a slightly different exercise protocol (10 sets of 10 repetitions leg extension at 70% of 1RM, 3 minute rest  between sets) reported elevated activity levels of AMPK  α 2,  but not AMPK  α 1, during and 1 h post-exercise (Dreyer, 2006). EFFECTS OF CONCURRENT TRAINING ON MTOR SIGNALING PATHWAY Coffey (2009) studied the effect of exercise order on gene expression. Subjects with more than one year experience in aerobic and resistance training underwent two trials consisting of cycling before resistance training, and a reverse order. Biopsies were taken 15 minutes following each exercise and 3 h post-exercise. Phosphorylation of AMPK was higher if cycling was performed subsequently to resistance exercise (RE). There was a slight increase 3 h post-exercise in the mTOR inhibitor, TSC2, if cycling was  performed after RE. Interestingly, p70 S6K   and rpS6 were acutely elevated following the first exercise irrespectively of exercise mode, with no different between the groups. Collectively, the study indicates that cycling preceding RE attenuates anabolic response, whereas RE following cycling may worsen the inflammatory response and protein degradation. Donges et al. (2012) compared the effects RE, endurance and concurrent training on molecular adaptations on sedentary subjects. The RE exercise protocol consisted of eight sets of eight repetitions leg-extensions at 70% of 1RM, whereas endurance exercise consisted of 40 min ergometer cycling at 55% of peak aerobic power output and concurrent trial did 50% of the work of RE and endurance trial. Measurements of gene expression were done 1 h and 4 h post-exercise. Interestingly, none of the trials induced increases in  phosphorylated mTOR, but RE and concurrent training revealed increases in Akt 1 h post-exercise. In addition, concurrent and resistance exercise induced an equally high amount of myofibrillar protein fractional synthesis rate (FSR), whereas aerobic exercise remained unchanged. Moreover, mitochondrial FSR was increased with all three trials, with no difference between trials. Both concurrent and endurance exercise failed to elevate phosphorylation of rpS6,  but the RE trial received a ten-fold increase 1 h post-exercise. Surprisingly, this extreme increase did not elevate FSR more so than the concurrent trial, with concurrent performing half of the RE work. No changes in AMPK were reported in any trial, which may be due to subjects getting fed immediately after exercise. It appears that these particular exercise  protocols (Concurrent and RE) can both induce increases in equivalent rate of myofibrillar protein synthesis in sedentary subjects in fed state. It should also be noted that transcription factors MyoD and MyoG mRNA were only elevated with RE. Modest increases in mTOR and p70 S6K   phosphorylation were reported in subjects performing RE 6 h after endurance exercise when compared to RE alone (Tommy, 2012). Subjects had standardized meals before aerobic and resistance exercise. The RE protocol consisted of leg press and leg-extensions, two sets of seven repetitions for each exercise. One-legged cycling was executed 6 h prior to RE. Biopsies were taken prior to RE, 15 min and 3 h post-exercise. Acute molecular changes subsequently to endurance trial were not measured. RE alone failed to elevate mTOR,  p70 S6K  , rpS6 and eEF2 phosphorylation, which may indicate that the RE protocol was not optimal to induce molecular changes or that elevations occurred between 15 min and 3 h  post-exercise. Moreover, the purpose of one-legged cycling    was not to maximize cardiovascular stress, but to provide an aerobic stimulus. A study comparing endurance and RE to RE alone reported an increase in phosphorylated Akt with RE and endurance exercise when compared to rest values and RE trial alone, but increases in mTOR, p70 S6K1  and eEF2 phosphorylation with  both exercise trials, but no difference between the trials (Apro, 2013). Interestingly, both trials revealed a reduction of AMPK 3 h post-exercise. Collectively, the findings indicate that RE with subsequent endurance training does not impair gene expression when compared to RE alone in moderately trained subjects. Moreover, the authors suggested, based on the results, that prior activation of mTORC1 inhibits elevated activity of AMPK.    REFERENCES 1.   Apró W, Blomstrand E. Influence of supplementation with branched-chain amino acids in combination with resistance exercise on p70 S6  kinase phosphorylation in resting and exercising human skeletal muscle.  Acta  Physiol  . 2010;200(3):237-248 2.   Apró W, Wang Li, Pontén M, Blomstrand E, Sahlin K.  Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle.  Am J Physiol Endocrinol Metab . 2013 Jul 1;305(1):E22-E32 3.   Atherton PJ, Babraj JA, Smith K, Singh J, Rennie MJ, Wackerhage H. 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