BCAAs (leucine, isoleucine, and valine), particularly leucine, have anabolic effects on protein metabolism by increasing the rate of protein synthesis and decreasing the rate of protein degradation in resting human muscle. Also, during recovery from endurance exercise, BCAAs were found to have anabolic effects in human muscle. These effects are likely to be mediated through changes in signaling pathways controlling protein synthesis. This involves phosphorylation of the mammalian target of rapamycin (mTOR) and sequential activation of 70-kD S6 protein kinase (p70 S6 kinase) and the eukaryotic initiation factor 4E-binding protein 1. Activation of p70 S6 kinase, and subsequent phopsphorylation of the ribosomal protein S6, is associated with enhanced translation of specific mRNAs. When BCAAs were supplied to subjects during and after one session of quadriceps muscle resistance exercise, an increase in mTOR, p70 S6 kinase, and S6 phosphorylation was found in the recovery period after the exercise with no effect of BCAAs on Akt or glycogen synthase kinase 3 (GSK-3) phosphorylation. Exercise without BCAA intake led to a partial phosphorylation of p70 S6 kinase without activating the enzyme, a decrease in Akt phosphorylation, and no change in GSK-3. It has previously been shown that leucine infusion increases p70 S6 kinase phosphorylation in an Akt-independent manner in resting subjects; however, a relation between mTOR and p70 S6 kinase has not been reported previously. The results suggest that BCAAs activate mTOR and p70 S6 kinase in human muscle in the recovery period after exercise and that GSK-3 is not involved in the anabolic action of BCAAs on human muscle.

Several factors have been identified to cause peripheral fatigue during exercise, whereas the mechanisms behind central fatigue are less well known. Changes in the brain 5-hydroxytryptamine (5-HT) level is one factor that has been suggested to cause fatigue. The rate-limiting step in the synthesis of 5-HT is the transport of tryptophan across the blood–brain barrier. This transport is influenced by the fraction of tryptophan available for transport into the brain and the concentration of the other large neutral amino acids, including the BCAAs (leucine, isoleucine, and valine), which are transported via the same carrier system. Studies in human subjects have shown that the plasma ratio of free tryptophan (unbound to albumin)/BCAAs increases and that tryptophan is taken up by the brain during endurance exercise, suggesting that this may increase the synthesis of 5-HT in the brain. Ingestion of BCAAs increases their concentration in plasma. This may reduce the uptake of tryptophan by the brain and also 5-HT synthesis and thereby delay fatigue. Accordingly, when BCAAs were supplied to human subjects during a standardized cycle ergometer exercise their ratings of perceived exertion and mental fatigue were reduced, and, during a competitive 30-km cross-country race, their performance on different cognitive tests was improved after the race. In some situations the intake of BCAAs also improves physical performance. The results also suggest that ingestion of carbohydrates during exercise delays a possible effect of BCAAs on fatigue since the brain's uptake of tryptophan is reduced.

The aim of this study was to compare the training stimuli of eccentric (lengthening) and concentric (shortening) contractions regarding the effect on signaling enzymes involved in protein synthesis. Ten male subjects performed 4 × 6 maximal eccentric contractions on one leg followed by 4 × 6 maximal concentric contractions on the other. Six additional subjects performed the same protocol, but with maximal concentric and submaximal eccentric exercise of equal force to that of the maximal concentric contractions. Muscle biopsy samples were taken from the vastus lateralis before, immediately after, and 1 and 2 h after exercise in both legs. The average peak force produced during the maximal eccentric exercise was 31% higher than during the maximal concentric exercise, 2,490 (±100) vs. 1,894 (±108) N ( P < 0.05). The maximal eccentric contractions led to two- to eightfold increases in the phosphorylation of p70 S6 kinase (p70^S6k) and the ribosomal protein S6 that persisted for 2 h into recovery but no significant changes in phosphorylation of Akt or mammalian target of rapamycin (mTOR). Maximal concentric and submaximal eccentric contractions did not induce any significant changes in Akt, mTOR, p70^S6k, or S6 phosphorylation up to 2 h after the exercise. The results indicate that one session of maximal eccentric contractions activates p70^S6k in human muscle via an Akt-independent pathway and suggest that maximal eccentric contractions are more effective than maximal concentric contractions in stimulating protein synthesis in the absence of a nutritional intake, an effect that may be mediated through a combination of greater tension and stretching of the muscle.

An account of the tryptophan (Trp)–5-hydroxytryptamine (5-HT)–central fatigue theory is provided and an explanation of how oral administration of BCAAs can decrease fatigue on the basis of this theory is given. The rate-limiting step in the synthesis of 5-HT is the transport of Trp across the blood–brain barrier. This transport is influenced by the fraction of Trp available for transport into the brain and the concentration of the other large neutral amino acids, including the BCAAs, which are transported via the same carrier system. During endurance exercise, there is an uptake of Trp by the brain, suggesting that this may increase the synthesis and release of 5-HT in the brain. Oral intake of BCAAs may reduce this uptake and also brain 5-HT synthesis and release, thereby delaying fatigue. Other hypotheses for the effect of BCAAs on central fatigue are included.

Key points: For individuals showing suboptimal adaptations to resistance training, manipulation of training volume is a potential measure to facilitate responses. This remains unexplored. Here, 34 untrained individuals performed contralateral resistance training with moderate and low volume for 12 weeks. Moderate volume led to larger increases in muscle cross‐sectional area, strength and type II fibre‐type transitions. These changes coincided with greater activation of signalling pathways controlling muscle growth and greater induction of ribosome synthesis. Out of 34 participants, thirteen displayed clear benefit of MOD on muscle hypertrophy and sixteen showed clear benefit of MOD on muscle strength gains. This coincided with greater total RNA accumulation in the early phase of the training period, suggesting that ribosomal biogenesis regulates the dose–response relationship between training volume and muscle hypertrophy. These results demonstrate that there is a dose‐dependent relationship between training volume and outcomes. On the individual level, benefits of higher training volume were associated with increased ribosomal biogenesis. Resistance‐exercise volume is a determinant of training outcomes. However not all individuals respond in a dose‐dependent fashion. In this study, 34 healthy individuals (males n = 16, 23.6 (4.1) years; females n = 18, 22.0 (1.3) years) performed moderate‐ (3 sets per exercise, MOD) and low‐volume (1 set, LOW) resistance training in a contralateral fashion for 12 weeks (2–3 sessions per week). Muscle cross‐sectional area (CSA) and strength were assessed at Weeks 0 and 12, along with biopsy sampling (m. vastus lateralis). Muscle biopsies were also sampled before and 1 h after the fifth session (Week 2). MOD resulted in larger increases in muscle CSA (5.2 (3.8)% versus 3.7 (3.7)%, P < 0.001) and strength (3.4–7.7% difference, all P < 0.05. This coincided with greater reductions in type IIX fibres from Week 0 to Week 12 (MOD, −4.6 percentage points; LOW −3.2 percentage points), greater phosphorylation of S6‐kinase 1 (p85 S6K1^Thr412, 19%; p70 S6K1^Thr389, 58%) and ribosomal protein S6^Ser235/236 (37%), greater rested‐state total RNA (8.8%) and greater exercise‐induced c‐Myc mRNA expression (25%; Week 2, all P < 0.05). Thirteen and sixteen participants, respectively, displayed clear benefits in response to MOD on muscle hypertrophy and strength. Benefits were associated with greater accumulation of total RNA at Week 2 in the MOD leg, with every 1% difference increasing the odds of MOD benefit by 7.0% (P = 0.005) and 9.8% (P = 0.002). In conclusion, MOD led to greater functional and biological adaptations than LOW. Associations between dose‐dependent total RNA accumulation and increases in muscle mass and strength point to ribosome biogenesis as a determinant of dose‐dependent training responses.

Resistance exercise and amino acids are two major factors that influence muscle protein turnover. Here, we examined the effects of resistance exercise and branched-chain amino acids (BCAA), individually and in combination, on the expression of anabolic and catabolic genes in human skeletal muscle. Seven subjects performed two sessions of unilateral leg press exercise with randomized supplementation with BCAA or flavored water. Biopsies were collected from the vastus lateralis muscle of both the resting and exercising legs before and repeatedly after exercise to determine levels of mRNA, protein phosphorylation, and amino acid concentrations. Intake of BCAA reduced ( P < 0.05) MAFbx mRNA by 30 and 50% in the resting and exercising legs, respectively. The level of MuRF-1 mRNA was elevated ( P < 0.05) in the exercising leg two- and threefold under the placebo and BCAA conditions, respectively, whereas MuRF-1 total protein increased by 20% ( P < 0.05) only in the placebo condition. Phosphorylation of p70^S6k increased to a larger extent (∼2-fold; P < 0.05) in the early recovery period with BCAA supplementation, whereas the expression of genes regulating mTOR activity was not influenced by BCAA. Muscle levels of phenylalanine and tyrosine were reduced (13–17%) throughout recovery ( P < 0.05) in the placebo condition and to a greater extent (32–43%; P < 0.05) following BCAA supplementation in both resting and exercising muscle. In conclusion, BCAA ingestion reduced MAFbx mRNA and prevented the exercise-induced increase in MuRF-1 total protein in both resting and exercising leg. Further-more, resistance exercise differently influenced MAFbx and MuRF-1 mRNA expression, suggesting both common and divergent regulation of these two ubiquitin ligases.