During skeletal muscle hypertrophy, Akt activation is increased when examined in vivo Bodine et al. In addition, a genetically altered, constitutively active Akt was able to induce muscle hypertrophy independent of additional treatments Bodine et al. Akt acts through mTORC1 pathways to initiate and enhance protein synthesis.

In addition, Akt can enhance protein synthesis through inhibition of proteins that impede protein synthesis such as GSK-3β and PRAS As mentioned previously, GSK3β is an inhibitor of protein synthesis through phosphorylation and inhibition of eIF2.

Akt phosphorylates GSK3β at Ser9 and inactivates its kinase activity, thus allowing the initiation of protein synthesis. Administration of IGF-1 resulted in myotube hypertrophy, associated with hyperphosphorylation of both Akt and GSK3β Rommel et al. Figure 2.

The binding of growth factors such as IGF-1 and insulin activates receptor tyrosine kinases RTKs , which recruits and activates IRS IRS-1 then activates phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K , which consists of a regulator subunit p85 and a catalytic subunit p PI3K generates phosphoinositide 3,4, 5-phosphate PIP 3.

PIP3 recruits and activates PDK1 and Akt. In addition to PIP3 signaling, mTORC2 can also phosphorylate and activate Akt.

From there, Akt can signal through both mTORC1 and eIF2 pathways to increase protein synthesis. Akt can phosphorylate and inactivate GSK-3β, which is an inhibitor of the eIF2 complex.

mTOR assembles into two distinct complexes, mTORC1 and mTORC2. mTORC1 consists of raptor regulated associated protein of mTOR , mLST8, DEPTOR, PRAS40, and mTOR. mTORC2 consists of rictor rapamycin insensitive companion of mTOR , mSIN1, mLST8, DEPTOR, and mTOR. Akt can phosphorylate several proteins that regulate mTORC1 activity including mTORC1 itself, PRAS40 and tuberous sclerosis complex 2 TSC2 Sancak et al.

Currently, the signaling mechanism for Akt through TSC2 is the most well described pathway. Akt phosphorylates TSC2 on multiple residues leading to its inactivation. TSC2 is a GTPase activating protein for Rheb. Therefore, inactivation of TSC2 by Akt increases the amount of GTP:Rheb complex bound to mTOR and leads to its activation.

The second mechanism by which Akt can activate mTORC1 is through phosphorylation of the mTORC1 inhibitor PRAS Phosphorylated PRAS40 will disassociate from mTORC1, release its inhibition and increase mTOR kinase activity Wang et al. In relation to mTORC1, there is a limited understanding of the role of mTORC2 in muscle protein synthesis and growth Bentzinger et al.

Initial studies have shown mTORC2 to be involved in organization of actin cytoskeleton and possibly phosphorylate Akt at Ser Jacinto et al.

In addition, there may be a coordinated effort for both mTOR complexes to work together for maximizing muscle protein synthesis under anabolic conditions Ogasawara et al.

The mTORC1 complex has several related protein-protein complexes which regulate signaling activity. Each protein has a unique function in the complex.

Raptor acts as a scaffolding protein to recruit downstream targets of mTOR, p70S6K, and 4E-BP1 Hara et al. It is also the anchoring protein used by the Rag GTPases to recruit mTORC1 to the lysosome Sancak et al.

In skeletal muscle, raptor KO mice have a marked reduction in phosphorylation of both p70S6K and 4E-BP1 Bentzinger et al. In addition, p70S6K and 4E-BP1 proteins have common mTORC1 signaling TOS motifs, which are essential for mTORC1-targeted phosphorylation Dunlop et al.

The raptor protein can also be modified at multiple phosphorylation sites. Phosphorylation of raptor appears to happen in a sequential manner Foster et al. The phosphorylation events must be in the presence of adequate amino acid concentrations.

In HEK cells, insulin-stimulated phosphorylation of raptor was not evident in amino acid depleted serum showing amino acid availability is critical for mTORC1 activity despite the availability of other growth factors Foster et al.

Skeletal muscle raptor phosphorylation at the AMPK targeted Ser is associated with body weight loss during cancer-associated muscle wasting White et al. The protein PRAS40 is another member of the TORC1 complex. PRAS40 has been shown to be an inhibitor of mTOR activity Sancak et al.

PRAS40 is bound to the inactive mTORC1 complex and directly inhibits substrate binding to raptor preventing downstream phosphorylation Wang et al. Akt has been shown to phosphorylate and inhibit PRAS40 binding to raptor Vander Haar et al.

Upon activation from insulin or amino acids, activated mTOR can phosphorylate PRAS40 which facilitated its disassociation from the complex Foster et al. Once PRAS40 is off the complex, raptor can bind p70S6K and 4E-BP1 for eventual phosphorylation. In male mice, muscle PRAS40 phosphorylation is responsive to circulating testosterone and muscle mass White et al.

Castration decreases phospho PRAS40, which is rescued with androgen add-back White et al. DEP domain-containing mTOR-interacting protein is a relatively recent addition to the mTORC1 complex, having an inhibitory function on mTORC1 activity Peterson et al.

mTORC1 and DEPTOR negatively regulate each other, depending on nutrient availability. In a low nutrient state, the PZD domain of DEPTOR binds to the C-terminal portion of mTOR and inhibits downstream signaling to p70S6K and 4E-BP1. During nutrient availably and subsequent mTORC1 activity, DEPTOR is phosphorylated and released from the mTORC1 complex.

The reduction in protein expression is also accompanied with a suppression of DEPTOR mRNA expression Peterson et al. In C2C12 myotubes, the knockdown of DEPTOR increased protein synthesis and associated mTORC1 signaling Kazi et al.

DEPTOR knockdown, in vivo , resulted in an attenuation of immobilization-induced muscle atrophy associated with increased muscle protein synthesis Kazi et al. The sensitivity of DEPTOR to atrophy conditions has been replicated by others showing DEPTOR expression increases with limb immobilization Shimkus et al.

However, further investigation is needed to determine how DEPTOR is regulated under different nutrients and availability of amino acids.

There are several negative regulators of mTORC1 activity existing outside the mTORC1 complex. Two well documented inhibitors are AMPK and the protein regulated in DNA damage and development 1 REDD1, also referred to as Rtp and DDIT4.

AMPK and mTOR are key energy sensors in the cell, and function to regulate processes to either inhibit or enhance ATP production depending on nutrient availability. AMPK will be discussed in more detail later in this review.

REDD1 is thought to inhibit mTORC1 signaling through activation of upstream TSC2 Brugarolas et al. In addition, REDD1 protein and mRNA expression are increased with cellular stress events including ATP depletion Sofer et al.

Furthermore, treatment with the synthetic glucocorticoid dexamethasone has shown to increase REDD1 mRNA and protein in skeletal muscle as well as L6 myotubes Wang et al. Glucocorticoids such as cortisone are elevated during fasting states which, in part through REDD1, may play a role in the inhibition of mTORC1 signaling and the subsequent reduction in protein synthesis.

REDD1 protein and mRNA expression was increased with 18 h of starvation in rats which coincided with a reduction in mTORC1 signaling McGhee et al.

Upon refeeding, REDD1 protein and mRNA expression was returned to baseline and mTORC1 signaling was increased. Interestingly, fasting-induced glucocorticoid concentrations directly correlated with REDD1 expression showing evidence of cross talk between energy-sensitive hormones and energy-sensitive signaling within muscle McGhee et al.

Finally, the loss of REDD1 during a mechanical-overload hypertrophy stimuli enhanced the rate of muscle protein synthesis Gordon et al. Figure 3. Translation pathways with or without amino acid availability. This renders both S6 and 4E-BP1 unphosphorylated, shutting off translation.

In addition, the inactive mTORC1 with be further suppressed by inhibitors DEPTOR, REDD1 and PRAS. On the eIF2 pathway, the absence of amino acids maintains GCN2 and PERK activity, which phosphorylates eIF2, inhibiting guanine nucleotide exchange of eIF2 by eIF2B.

With eIF2 bound to GDP, it will release from the ribosome and stop translation. Once at the lysosome, mTOR kinase activity is activated by GTP-bound Rheb and will phosphorylate p70S6K and 4E-BP1 to initiate translation.

mTORC1 activation will also disassociate inhibitors DEPTOR and PRAS Once dissociated, DEPTROR is quickly degraded. In relation to eIF2, the availability of amino acids will inhibit GCN2 and PERK, reversing phosphorylation on eIF2 and allowing guanine nucleotide exchange of eIF2 back to GTP.

This will bind the eIF2 complex to the 40S ribosomal subunit and initiate protein translation. AMPK is activated through the buildup of low energy phosphate group, AMP or by phosphorylation by one or more upstream kinases at a threonine residue within the activation loop of the α subunit Hawley et al.

The multiple targets that AMP can activate will induce a large activation in the activity of AMPK with relatively small changes in AMP. The energy state of the cell is not solely monitored by AMP concentrations. High ATP concentrations will oppose activation of AMP-induced pathways.

Thus, the AMP:ATP ratio appears to the critical readout of cellular energy status and regulator of AMPK activity. During physiological conditions, AMPK can be regulated by chemical mediators of metabolism in addition to ATP:AMP levels.

Cellular levels of phosphocreatine can allosterically inhibit AMPK activity Ponticos et al. In addition, glycogen content of the cell can affect AMPK activity Hudson et al. The β-subunits of AMPK contain a glycogen binding domain.

Reports in human and rodent muscle show high glycogen stores can inhibit AMPK activation Wojtaszewski et al. Over expression of AMPK in culture has shown AMPK to localize in large glycogen granules Hudson et al. Glycogen will not only bind AMPK, but also contain in close proximity glycogen synthase, a substrate of AMPK.

Considering AMPK is allosterically regulated by phosphocreatine and glycogen stores, it has been speculated that AMPK is regulated by both short and long term energy stores Hardie, AMPK has been shown to inhibit protein synthesis in skeletal muscle Rolfe and Brown, ; Bolster et al.

The potency of AMPK signaling was described by Pruznak et al. In contrast, deletion of the AMPKα1 gene in primary myotubes resulted in cell hypertrophy Mounier et al. The mechanism by which AMPK inhibits muscle protein synthesis is through the inhibition of the mTORC1 complex Bolster et al.

There are currently three proposed mechanisms by which AMPK can inhibit mTORC1 signaling. The first is through phosphorylation of mTOR on Thr Cheng et al. This process does not directly inhibit mTOR activity, however, phosphorylation at Ser prevents phosphorylation of Ser which has been shown to increase mTOR activity Bolster et al.

The second method, and perhaps the best described mechanism, is through AMPK-mediated phosphorylation of the tuberous sclerosis complex 2 TSC2 gene product Tuberin on Thr and Ser Inoki et al. TSC2 combines with TSC1 to form a GTPase activator protein GAP for the Ras homolog enriched in brain Rheb , causing an increase in GDP bound to Rheb Zhang et al.

The binding of the GDP:Rheb complex to mTORC1 inhibitors mTOR. The third mechanism, as discussed earlier in the review, is the phosphorylation of raptor Gwinn et al.

This promotes binding of the protein and inhibition of raptor to signal downstream to p70S6K and 4E-BP1. The AMPK pathways has been heavily investigated in muscle in regards to other aspects of mTORC1 signaling. In C2C12 cells, AICAR-induced AMPK activation showed a reduction in protein synthesis, polysome aggregation and downstream mTORC1 signaling proteins 4E-BP1, p70S6K and eEF2 Williamson et al.

Although Akt, upstream of mTORC1, remained unaffected with AICAR treatment, downstream AMPK targets raptor and TSC2 were effected with AMPK activation. In addition, AICAR increased the amount of TSC1 bound to TSC2 Williamson et al.

A study by Du et al. Tong et al. AICAR treatment without IGF-1 resulted in cell atrophy caused by a reduction in signaling related to protein synthesis and an increase in markers of protein degradation. The addition of IGF-1 did not rescue the inhibition of AICAR treatment despite a significant increase in Akt, supporting the proposed mechanism of potent mTORC1 inhibition by AMPK.

AMPK has been examined in rodent models of muscle hypertrophy to determine its role in growth suppression. This occurred in conjunction with an increase in phosphorylation of downstream targets of mTORC1 signaling p70S6K and 4E-BP1 Mounier et al.

In contrast, AICAR treatment resulted in a reduction in the percentage of plantaris muscle mass gained after 1 week of over load Gordon et al.

In the same study, there was a significant negative correlation between the percentage of plantaris hypertrophy and AMPK phosphorylation status in the plantaris muscle. In addition, there were also negative correlations between phosphorylation status of AMPK and p70S6K, eEF2 and 4E-BP1.

Catabolic signaling through AMPK can override amino acid-induced mTORC1 activation. AICAR treatment prevented leucine-stimulated protein synthesis in the mouse gastrocnemius muscle Pruznak et al. The prevention of synthesis was accompanied with the prevention of mTOR activation.

AMPK can phosphorylate and activate TSC-2, which subsequently inactivates mTOR. However, AICAR treatment did increase phosphorylation of raptor independent of leucine treatment.

The activation of downstream signaling proteins p70S6K1, 4E-BP1, and eIF4F were increased with leucine administration and prevented when leucine was given with AICAR treatment. This data is in agreement with the results from Du et al.

Du et al. In support of these data, myoblasts expressing a dominant negative AMPKα subunit were administered AICAR.

Without AMPK activation, leucine was able to increase protein synthesis even with AICAR treatment. Once again, suggesting AMPK-induced inhibition of protein synthesis was through the reduction in mTORC1.

These results support the hypothesis that cellular energy demands can supersede the anabolic potential of amino acid availability. Branched-chain amino acids BCAAs , especially leucine, are potent regulators of mTORC1 activity and increase rates of protein synthesis Goberdhan et al.

Infusion of an amino acid mixture into resting human subjects increased protein synthesis as early as 30 min after infusion and remained elevated for 90 min Bohe et al. Amino acid infusion has been shown to increase phosphorylation of downstream targets of mTORC1, p70S6K, and 4E-BP1 Greiwe et al.

In the rodent, mTORC1 activity is necessary for BCAAs to induce anabolic signaling, as rapamycin prevented leucine-induced increased phosphorylation of p70S6K and 4E-BP1 Anthony et al. Despite strong evidence suggesting BCAAs activate mTORC1 signaling, the direct mechanism for mTORC1 activation remains unclear, especially in skeletal muscle.

In mammals, there are four RAG GTPases A-D shown to have a role in amino acid signaling to mTORC1 Schurmann et al. Rheb activates mTORC1 by direct associated and activation of the mTOR catalytic domain Long et al.

The regulation of mTORC1 activation with and without amino acid availability is illustrated in Figure 3. Amino acid metabolism has been well described, especially in the context of insulin resistant and obesity White and Newgard, In skeletal muscle, the balance between amino acid catabolism and anabolism is complex, due to both metabolic and anabolic flux of the myofiber.

Although the majority of amino acid metabolism occurs in the liver, skeletal muscle has high expression of the branched-chain aminotransferase BCAT. Interestingly, despite its metabolic nature, the liver does not express BCAT, rendering a unique pathway of BCAA metabolism to skeletal muscle Hutson, ; White et al.

BCAT-mediated transamination of leucine generates α-ketoisocaproate, the first step of BCAA catabolism in muscle. The second step of leucine catabolism is an irreversible oxidative decarboxylation of α-ketoisocaproate, which is catalyzed by the branched-chain α-keto acid dehydrogenase BCKDH.

This reaction is a rate-limiting step in leucine metabolism Harris et al. Branched-chain α-keto acid dehydrogenase is a highly regulated dehydrogenase enzyme responsible for metabolizing branched-chain keto acids BCKA into branched-chain acyl CoAs.

The branched-chain CoAs are further metabolized into acetyl CoA or Succinyl CoA and used as TCA intermediates for energy Walejko et al. The multi-subunit BCKDH complex consists of three components including the e1, e2, and e3 subunits. Each subunit carries out different reactions to convert BCKAs into branched-chain acyl CoAs.

There are two opposing regulators of BCKDH activity, the BCKDH kinase BDK and the PPM1K phosphatase also referred to as PP2Cm White et al. Both enzymes perform phosphorylation and dephosphorylation, respectively, of serine of the e1a subunit.

In the liver, increased phosphorylation of BCKDH on serine occurs secondary to elevated expression of BDK, and decreased expression of PPM1K She et al. Murine knockout models of either BDK or PPM1K Joshi et al. Currently, there is limited understanding of this pathway in skeletal muscle, especially in regards to anabolic and catabolic conditions.

BCAA fate and the antagonist relationship between BCKDH and PPM1K is shown in Figure 4. Figure 4. Molecular mechanisms of amino acid trafficking. Amino acids, especially BCAAs, enter the cell via their respective transporters. Once in the cell, depending on metabolic need, they can be metabolized for energy or used for other biochemical processes like protein synthesis.

If needed for energy, the enzyme BCAT metabolizes the BCAA into branched-chain keto acids, which undergo a series of catabolic reactions to produce C3 and C5 CoAs by BCKDH. Phosphorylation of BCKDH by BDK inhibits BCKDH activity while dephosphorylation by PPM1K activates BCKDH and increases generation of BCAA-derived CoAs for energy production.

If BDK is able to phosphorylate BCKDH, or PPM1K is inhibited, amino acids would be available to active mTORC1 and initiate protein translation. AMPK can regulate BCAA metabolism by increasing PPM1K and lowering BDK expression, which will activate BCKDH and increase BCAA flux to the TCA cycle.

As AMPK is a potent inhibitor of mTORC1 activity, it would also make sense that AMPK would regulate muscle amino acid metabolism. AICAR-induced AMPK activation can increase BCKDH activity in skeletal muscle through a reduction in BDK protein Lian et al.

Although AICAR increased PPM1K in liver and adipose tissue, muscle PPM1K was not effected by AICAR treatment Lian et al. Skeletal muscle PGC-1α over-expression increases gene expression of branched-chain amino transferase BCAT 2 and BCKDH, while BDK was not changed.

BCAAs levels in the PGC-1α mice were decreased in both muscle and blood Hatazawa et al. These outcomes show the coupled relationship between two potent metabolic regulators, i.

The extent of BCAA metabolism can have an impact on global muscle metabolism, as excess BCAAs or branched-chain ketoacids can inhibit insulin signaling in muscle in vitro Moghei et al. Interestingly, this result is dependent on certain BCAAs or a mixture of BCAAs as valine does seem to interfere with myotube insulin signaling in vitro Rivera et al.

Nutrient availability may also regulate metabolic fate of leucine. In C2C12 myotubes, leucine is used preferentially for protein synthesis rather than oxidation for energy production Estrada-Alcalde et al. However, in the setting of high palmate, leucine oxidation increases and its incorporation into proteins decreases Estrada-Alcalde et al.

Moreover, high fat feeding increase BCKDH activity in muscle promoting amino acid catabolism White et al. This again, points to the complexity of muscle metabolism and substrate availability altering BCAA trafficking.

The proposed BCAA trafficking and related AMPK signaling pathways are shown in Figure 4. In the context of muscle mass regulation, muscle BDK knockout mice have no overt muscle mass phenotype under a typical chow diet, despite a lower BCAA concentration in blood and muscle Ishikawa et al.

However, under a low protein diet, the lack of BDK magnifies myofibrillar protein loss associated with a reduction in mTORC1 signaling activity.

Of note, protein restriction resulted in a reduction of myofibrillar protein synthesis, but not total soluble protein, indicating a preferential degradation of myofibrillar proteins to compensate for the low protein diet.

A natural hypothesis would point to autophagy as a mechanism to provide amino acids during the restricted feeding. This study highlights the interaction between BCAA metabolism and protein synthesis pathways, supporting an interactive crosstalk between the two processes.

More work is needed to gain a better understanding of the molecular network between BCAA trafficking and mTORC1 signaling. Together, muscle protein synthesis is an interactive process, taking input from numerous anabolic and catabolic pathways. The unique plasticity of skeletal muscle adds more layers of regulation, incorporating both metabolic demands and mechanical stimuli into these already intricate pathways.

Moreover, there must be an adequate combination of mechanical stimuli and nutritional availability to maintain or hypertrophy myofiber size. In relation to other tissues, especially tumor biology, the molecular mechanisms involved in skeletal muscle protein synthesis are less developed.

This concept is supported by the fact that the majority of citations in this review investigating amino acid metabolism and regulation of mTORC1 are not in muscle tissue. This is interesting, considering the extensive protein content of skeletal muscle and the potential utility of skeletal muscle as a model to investigate the complexities of protein synthesis.

A better understanding of the interface between muscle amino acid metabolism and synthesis pathways could uncover additional regulators of muscle protein synthesis. The high expression of BCAT in skeletal muscle supports the preference of branched-chain amino acids as a bioenergetic substrate.

There is a gap in our understanding of fate decisions of BCAAs and anabolic signaling in muscle. This could be a result of the temporal nature of muscle energetics, having diverse metabolism with changes in nutrient availability and contractile activity.

However, it would not be surprising to identify additional regulators of BCAA metabolism having an impact on both catabolic and anabolic processes.

The potency of these pathways to regulate muscle mass is supported by strong in vivo studies using preclinical models discussed throughout his review. Manipulation of key regulatory proteins within the mTORC1 signaling pathway can accelerate Ishikawa et al.

Since we now have a general understanding of these pathways, why are there no available drugs to offset muscle wasting? The challenge is to identify key targets within these complex pathways and manipulate them in a muscle-specific manner.

The mTORC1 pathway is tightly controlled and ubiquitous across many cell types. Promoting muscle anabolism by manipulating global mTORC1 activity will most likely alter the delicate balance of non-muscle cells and promote unchecked growth and malignancies.

Finding key regulators within the mTORC1 pathway, specific to muscle would be ideal for drug development.

This warrants continued investigation of anabolic pathways, especially within skeletal muscle. The author confirms being the sole contributor of this work and has approved it for publication.

This work was supported by grants from the National Institutes of Health grants K01AG and R21AG The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author would like to thank Phillip White for his valuable discussion and insight pertaining to this review. Alessi, D. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha.

doi: CrossRef Full Text Google Scholar. Andjelkovic, M. Role of translocation in the activation and function of protein kinase B. Google Scholar. Anthony, J. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. PubMed Abstract CrossRef Full Text Google Scholar.

Bentzinger, C. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy.

Cell Metab. Biswas, D. Branched-chain ketoacid overload inhibits insulin action in the muscle. Bodine, S. Cell Biol. Bohe, J. Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids.

Bolster, D. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin mTOR signaling. Brugarolas, J. Genes Dev. Chan, A. Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte.

Cheng, S. Thr is a novel mammalian target of rapamycin mTOR phosphorylation site regulated by nutrient status. Chiang, G. Phosphorylation of mammalian target of rapamycin mTOR at Ser is mediated by p70S6 kinase. Crosby, J. Regulation of hemoglobin synthesis and proliferation of differentiating erythroid cells by heme-regulated eIF-2alpha kinase.

Blood 96, — Demetriades, C. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2.

Cell , — Deshmukh, A. Dever, T. Gene-specific regulation by general translation factors. Du, M. Leucine stimulates mammalian target of rapamycin signaling in C2C12 myoblasts in part through inhibition of adenosine monophosphate-activated protein kinase. Dunlop, E. Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition.

Cell Signal. Estrada-Alcalde, I. Metabolic fate of branched-chain amino acids during adipogenesis, in adipocytes from obese mice and C2C12 Myotubes. Cell Biochem. Foster, K. Regulation of mTOR complex 1 mTORC1 by raptor Ser and multisite phosphorylation. Frost, R. Gao, X. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling.

Glass, D. Recent studies have shown that amino acids, including BCAA, have individual physiological actions, in addition to being the constituents of body proteins. As a result, demand for amino acid supplements that can be taken when exercising has increased.

However, there has been almost no research published that demonstrates the positive impact of amino acids upon exercise abilities. With this in mind, Otsuka Pharmaceutical Saga Nutraceuticals Research Institute and partners studied the influence of BCAA on exercise performance, proving that it is effective during long distance and intense exercise routines.

A study showing that at least 2,mg of BCAA are required to benefit the most from the effects of BCAA. A study highlighting the positive effects of BCAA on muscle damage, muscle fatigue and muscle pain.

A study on how a regular intake of BCAA can be used to maintain peak performance during endurance exercises. BCAA Helps Maintain Exercise Performance. BCAA is an energy source for muscles. Potential effects of taking BCAA during exercise. Promotion of muscle protein synthesis Suppression of muscle protein degradation Muscle damage reduction.

Nesta breve revisão, apresentamos a compreensão fisiológica e bioquímica de como a ingestão de uma fonte completa de proteína e de aminoácidos de cadeia ramificada afeta o crescimento do músculo esquelético no estado pós-absortivo e pós-exercício. Mostramos também as evidências que suportam ou não a afirmação dos potenciais efeitos anabólicos na síntese de proteína muscular dos aminoácidos de cadeia ramificada quando consumidos isoladamente em humanos.

These aids are thought to boost energy production and use, support recovery from exercise, improve body composition and increase resistance to peripheral and central fatigue. Beck KL, Thomson JS, Swift RJ, von Hurst PR.

Role of nutrition in performance enhancement and postexercise recovery. Open Access J Sports Med. According to the International Society of Sports Nutrition ISSN , ergogenic supplement claims must be backed up by plausible data and supported by solid evidence of efficacy; these supplements must also be legal and safe.

Kerksick CM, Wilborn CD, Roberts MD, Smith-Ryan A, Kleiner SM, Jäger R, et al. J Int Soc Sports Nutr. Branched-chain amino acids BCAA enjoy great popularity among allegedly ergogenic supplements. The marketing appeal of these products derives from claims that isolated BCAA intake combined with resistance physical exercise stimulates muscle protein synthesis.

This long-standing over 35 years claim is based on cellular and animal model studies reporting enhanced anabolic intracellular signaling in response to BCAA intake. Wolfe RR. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality?

However, evidence supporting the efficacy of isolated BCAA intake for muscle hypertrophy in humans is equivocal. This study set out to review muscle protein synthesis in the postabsorptive state and after resistance physical exercise from a basic biochemistry perspective, and to examine existing evidence in favor of or against claims of potential anabolic effects of isolated BCAA intake on muscle protein synthesis in humans.

A secondary search was conducted based on the references listed in selected articles. Proteins consist of 20 amino acids AA linked by peptide bonds and arranged in different combinations and amounts. Nine out of these 20 AA are thought to be essential EAA - essential amino acids , i.

The remaining 11 EAA are classified as nonessential NEAA, nonessential amino acids , as they can be synthesized in the body. Moran LA, Horton HR, Scrimgeour KG, Perry MD. Amino acids and the primary structure of proteins.

In: Moran LA, Horton HR, Scrimgeour KG, Perry MD, editores. Biochemistry São Paulo: Pearson Education of Brazil; Nelson DL, Cox MM. Amino acids, peptides and proteins.

In: Nelson DL, Cox MM, editores. Principles of Biochemistry 6 ed. Porto Alegre: Artmed Publisher; In healthy individuals with normal mobility, dynamic balance between protein degradation and synthesis orchestrates skeletal muscle protein maintenance. In the postabsortive i.

In the postprandial state, synthesis exceeds degradation, since intake of some nutrients, such as proteins and carbohydrates, stimulates muscle protein synthesis and insulin release, suppressing degradation.

Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW. Control of the size of the human muscle mass. Annu Rev Physiol. Therefore, muscle hypertrophy requires a positive net protein balance i. Physical exercise and nutrient availability are the major drivers of muscle protein synthesis in adult individuals.

Atherton PJ, Smith K. Muscle protein synthesis in response to nutrition and exercise. J Physiol. McGlory C, Van Vliet S, Stokes T, Mittendorfer B, Phillips SM. The impact of exercise and nutrition on the regulation of skeletal muscle mass.

The anabolic effects of nutrients are boosted primarily by transfer and incorporation of AA obtained through the diet into skeletal muscle proteins.

These effects are particularly associated with EAA. Smith K, Barua JM, Watt PW, Scrimgeour CM, Rennie MJ. Flooding with L-[C]leucine stimulates human muscle protein incorporation of continuously infused L-[C] valine. Am J Physiol. The full range of EAA and the 11 NEAA must be present in proper amounts for muscle protein synthesis.

Therefore, muscle protein synthesis is limited by lack or low availability of any of the EAA, whereas lack of NEAA can be offset by increased de novo synthesis. In the postprandial state, within approximately 30 to 45 minutes of consumption of a protein-rich meal average time required for digestion, absorption and transport of AA to the systemic circulation , EAA availability increases and muscle protein synthesis rates exceed muscle protein degradation rates, inducing an anabolic state that peaks between 1.

Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby A, Rankin D, et al. Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling.

Am J Clin Nutr. Aminoacidemia-induced muscle protein synthesis is transient. In the postabsortive state i. In these circumstances, plasma EAA level maintenance and hence protein turnover relies on protein breakdown in skeletal muscles, the major body protein reservoir. Cahill GF Jr, Aoki TT.

Starvation and body nitrogen. Trans Am Clin Climatol Assoc. The impact of factors such as protein amount and quality, protein intake distribution throughout day and physical exercise on the balance between protein degradation and synthesis must be emphasized. BCAA supplements may improve the health outcomes of people with liver disease, while also possibly protecting against liver cancer.

BCAAs are found in foods and whole protein supplements. Getting BCAAs from complete protein sources is more beneficial, as they contain all the essential amino acids. Fortunately, BCAAs are available in a variety of food sources. This makes BCAA supplements unnecessary for most, especially if you consume enough protein in your diet already Consuming protein-rich foods will also provide you with other important nutrients that BCAA supplements lack.

The best food sources of BCAAs include 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 :. Many protein-rich foods contain high amounts of BCAAs. If you consume enough protein in your diet, BCAA supplements are unlikely to provide additional benefits.

The branched-chain amino acids BCAAs are a group of three essential amino acids: leucine, isoleucine, and valine. BCAA supplements have been shown to build muscle, decrease muscle fatigue , and alleviate muscle soreness.

They have also successfully been used in a hospital setting to prevent or slow muscle loss and to improve symptoms of liver disease. However, because most people get plenty of BCAAs through their diet, supplementing with BCAA is unlikely to provide additional benefits.

Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. BCAA stands for branched-chain amino acids. These are essential amino acids with several benefits for muscle growth and performance.

While pre-workout supplements may boost your exercise performance, you may be worried about side effects. Here are 5 side effects of pre-workout….

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Let's look at benefits, limitations, and more. A new study found that healthy lifestyle choices — including being physically active, eating well, avoiding smoking and limiting alcohol consumption —…. To conclude, the ingestion of BCAAs alone, without the concurrent ingestion of other EAA, intact protein or other macronutrients, increases the stimulation of mTORC1 activity and myofibrillar-MPS following exercise in resistance-trained young men.

Our data support the notion that BCAA ingestion alone does not maximally stimulate myofibrillar-MPS following exercise despite stimulation of translation initiation pathways. The lack of sufficient EAA appears to limit the response of myofibrillar-MPS following exercise.

Thus, whereas our data clearly show that BCAA ingestion activates cell-signaling pathways that result in increased myofibrillar-MPS, ingestion of BCAAs alone may not be the optimal nutritional regimen to stimulate a maximal MPS response to resistance exercise training.

SRJ, OCW, GAW, and KDT designed the research project and conducted the research; SRJ, OCW, and KDT had primary responsibility for the final content of the manuscript and wrote the manuscript; SRJ, OCW, AP, and KB analyzed data or performed statistical analysis and all authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Anthony, J. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation.

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Keywords: amino acid ingestion, fractional synthesis rate, intracellular signaling proteins, leucine, muscle anabolism.