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Frontiers | Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans | Physiology
Discussion
The present study demonstrated that ingesting of all three BCAAs alone, without concurrent ingestion of other EAA, protein, or macronutrients, stimulated a 22% greater response of myofibrillar-MPS following resistance exercise compared with a placebo. The magnitude of this increased response of myofibrillar-MPS was ~50% less than the previously reported myofibrillar-MPS response to a dose of whey protein containing similar amounts of BCAAs (Churchward-Venne et al., 2012; Witard et al., 2014). Taken together, these results demonstrate that BCAAs exhibit the capacity to stimulate myofibrillar-MPS, however a full complement of EAA could be necessary to stimulate a maximal response of myofibrillar-MPS following resistance exercise. This information potentially has important nutritional implications for selecting amino acid supplements to facilitate skeletal muscle hypertrophy in response to resistance exercise training and the maintenance of muscle mass during aging, unloading, or disease.
The most likely physiological explanation for the apparent attenuation of the post-exercise response of myofibrillar-MPS to BCAA ingestion in comparison to an intact protein source relates to the limited availability of amino acids as substrate for MPS. It is well-established that BCAA ingestion stimulates the activation of mTORC1 signaling pathways that regulate the translational activity of MPS (Karlsson et al., 2004; Apro and Blomstrand, 2010; Moberg et al., 2016).
Moreover, recent results demonstrate that the presence of the valine and isoleucine enhances the response of mTORC1 to leucine (Moberg et al., 2016). However, results from the present study suggest that ingesting BCAAs alone, without the other EAA, provides limited substrate for protein synthesis in exercised muscles. Thus, the overall response of MPS is not maximized. Instead, the limited availability of EAA likely explains the qualitative difference in magnitude of the MPS response to ingestion of BCAAs alone and ingestion of similar amounts of BCAAs as part of intact whey protein (Churchward-Venne et al., 2012, 2014; Witard et al., 2014). Moreover, in the present study, we observed a decline in arterialized phenylalanine concentrations 3 h after drink ingestion in the BCAA trial. This finding is consistent with previous research that observed decreased EAA concentrations following leucine ingestion (Hagenfeldt and Wahren, 1980; Nair et al., 1992; Tipton et al., 2009; Borgenvik et al., 2012).
Taken together, these data support the notion that EAA availability is the rate-limiting factor for stimulating a maximal MPS response to resistance exercise with BCAA ingestion.
The decline in EAA availability that we observed with BCAA ingestion also provides a potential physiological explanation for the differential response of MPS to ingesting a BCAA source at rest and following resistance exercise. Previously, Wilkinson and colleagues reported an ~100% increase in myofibrillar-MPS in response to ingestion of leucine alone at rest (Wilkinson et al., 2013). Furthermore, a study from Churchward-Venne and colleagues reported that adding leucine to a “suboptimal” dose (6.25 g) of whey protein resulted in rates of myofibrillar-MPS similar to those after ingestion of 25 g of whey protein at rest. However, consistent with the results reported in the present study, the addition of leucine to 6.25 g of whey protein was not as effective as higher doses of whey protein ingested after resistance exercise (Churchward-Venne et al., 2012). Thus, exercise has been shown to alter the relationship of the MPS response to ingested leucine and intact protein. It is likely that the enhanced ability of muscle to utilize ingested protein following exercise (Pennings et al., 2011; Witard et al., 2014) leads to a greater demand for EAA, thus resulting in limited EAA availability at the greater rates of MPS. In another study, Churchward-Venne et al. (2014) also reported that BCAA added to a suboptimal dose of whey protein resulted in less stimulation of MPS than when the same amount of leucine alone was added to suboptimal whey protein. These data suggest that leucine alone may be sufficient to stimulate MPS following exercise provided a minimal amount of EAA is included. However, Churchward-Venne et al. (2014) included ingestion of leucine with 6.25 g of whey protein and a mixed macronutrient beverage making direct comparisons with our results difficult. Leucine seems to be the most important BCAA for stimulation of the translation initiation pathways (Anthony et al., 2000; Crozier et al., 2005) and leucine alone stimulates MPS at rest (Wilkinson et al., 2013). Thus, it is possible that leucine is solely responsible for the stimulation in MPS we report here.
On the other hand, recent data suggest that there is a greater stimulatory effect on mTORC1 when valine and isoleucine are consumed alongside leucine (Moberg et al., 2016). Nevertheless, taken together, these past and present data suggest that the availability of EAA may be a critical factor for the optimal response of MPS following resistance exercise. Since the ingestion of BCAAs alone stimulates myofibrillar-MPS, but does not increase the supply of all EAA, the overall response of myofibrillar-MPS following resistance exercise is limited.
The influence of exogenous BCAAs on the stimulation of MPS following exercise is mediated by an increased activation of the mTORC1-S6K1 signaling pathway. In the present study, the stimulation of PRAS40Thr246, and S6K1Thr389 phosphorylation 1 h following drink ingestion was higher in BCAA than PLA. Thus, our results are consistent with earlier work demonstrating an upregulation of translational activity with BCAA ingestion (Karlsson et al., 2004; Apro and Blomstrand, 2010). The present study is the first to demonstrate the upregulation of mTORC1 signaling with BCAA ingestion translates into an increased response of myofibrillar-MPS following resistance exercise.
BCAAs has been shown to influence muscle protein metabolism through MPB as well as MPS (Buse and Reid, 1975; Louard et al., 1990; Wilkinson et al., 2013). Early studies demonstrated that BCAAs reduce whole-body protein breakdown (Ferrando et al., 1995) and MPB (Louard et al., 1990; Nair et al., 1992). Recent evidence suggests the impact of BCAAs on MPB may be mediated by the leucine metabolite, β-hydroxy-β-methylbutyrate (Wilkinson et al., 2013). However, to date no study has investigated the impact of BCAA supplementation on MPB following exercise. Unfortunately, it was not possible to directly measure MPB in the present study, however our data suggest that whole-body protein breakdown was reduced by BCAA ingestion. Whereas, urea production rates were similar between trials, phenylalanine Ra, and phenylalanine oxidation rates—both indicators of whole body protein catabolism—were lower in BCAA than PLA during the 4 h period after drink ingestion. These data are consistent with previously reported results following ingestion of intact protein with similar amounts of BCAAs (Witard et al., 2014). It has been reported that MPB is reduced by insulin following resistance exercise (Biolo et al., 1999). However, the insulin response to BCAA and PLA was similar, so it is unlikely that insulin explains the decline in whole-body protein breakdown following BCAA ingestion. Thus, it seems clear that whole-body protein breakdown is decreased, albeit minimally, with ingestion of BCAAs following resistance exercise. However, these results do not necessarily mean that MPB is decreased with BCAA ingestion.
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.
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