Nutrition
Randomized Controlled Trial
2012
Leucine supplementation of a low-protein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men
By Tyler A. Churchward-Venne, Nicholas A. Burd, Cameron J. Mitchell, Daniel W.D. West, Andrew Philp, George R. Marcotte, Steven K. Baker, Keith Baar and Stuart M. Phillips
The Journal of Nutrition, 142(11), pp. 2037-2044
Abstract
<h2>Abstract</h2> <p>This <a href="/terms/randomized-controlled-trial/" class="term-link" data-slug="randomized-controlled-trial" title="randomized controlled trial">randomized controlled trial</a> examined whether <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a> supplementation of a suboptimal, low-protein mixed macronutrient beverage could restore myofibrillar protein synthetic rates to levels comparable to those achieved with a complete protein dose. Young resistance-trained men consumed one of three post-exercise beverages: a <a href="/terms/whey-protein/" class="term-link" data-slug="whey-protein" title="whey protein">whey protein</a> supplement providing 25 g protein (WHEY); a leucine-enriched low-protein beverage providing 6.25 g whey protein plus free leucine (LEU-LOW); or a non-leucine-enriched low-protein control providing 6.25 g whey protein alone (LOW). Myofibrillar fractional synthetic rates (MyoFSR) were measured over a four-hour post-exercise recovery period using stable isotope tracer methodology. LEU-LOW produced MyoFSR values significantly greater than LOW and statistically comparable to WHEY, demonstrating that leucine supplementation can effectively rescue the blunted <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="MPS">MPS</a> response to an otherwise insufficient protein dose. These findings mechanistically implicate leucine as the critical amino acid "trigger" for <a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mTORC1">mTORC1</a>-mediated anabolic signaling and have practical implications for optimizing protein intake across a range of dietary patterns and food sources [1].</p>Introduction
<h2>Introduction</h2> <p>Skeletal <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="muscle protein synthesis">muscle protein synthesis</a> is a highly regulated process governed by both the availability of amino acid substrates and the activation of intracellular anabolic signaling cascades. Among the twenty standard amino acids, the branched-chain amino acid <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a> has emerged as particularly important in this dual capacity — serving as both an essential substrate for new protein construction and, critically, as a molecular signal that initiates translational machinery through the <a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mechanistic target of rapamycin">mechanistic target of rapamycin</a> complex 1 (mTORC1) pathway [1].</p> <p>The concept of a "leucine threshold" proposes that the anabolic response to a protein-containing meal is not simply a linear function of total amino acid or total protein content, but rather follows a threshold-dependent pattern tied primarily to the leucine concentration reaching the relevant intracellular sensing mechanisms. Below this threshold, MPS stimulation is minimal regardless of the presence of other amino acids; above it, a robust anabolic response is initiated. This model predicts that protein sources differing in leucine content per gram of total protein will elicit different MPS responses at matched protein doses, and that leucine fortification of otherwise inadequate protein sources could restore MPS to levels achievable with complete, leucine-rich protein [2].</p> <p>The leucine threshold model has substantial practical implications. Many athletes and physically active individuals consume plant-based protein sources that are inherently lower in leucine content compared to animal-derived proteins. Soy protein contains approximately 8% leucine by weight, compared to approximately 11% in <a href="/terms/whey-protein/" class="term-link" data-slug="whey-protein" title="whey protein">whey protein</a>. In the context of the leucine threshold, this difference could translate to meaningfully lower MPS responses per gram of protein consumed, partially explaining why studies comparing equivalent doses of plant and animal proteins often show superior MPS responses for whey [3].</p> <p>This investigation directly tested the leucine threshold concept by comparing a leucine-supplemented low-protein beverage to both a complete protein dose and an unsupplemented low-protein control, providing the first experimental evidence that targeted leucine supplementation can rescue MPS from a subthreshold condition.</p>Methods
<h2>Methods</h2> <h3>Participants</h3> <p>Young resistance-trained men (n = 40; age: 22 ± 3 years; body mass: 82 ± 9 kg) were recruited and randomized to one of three experimental beverage conditions. All participants had a minimum of one year of resistance training experience and were free of musculoskeletal injury, metabolic disease, and ergogenic supplement use known to influence protein metabolism.</p> <h3>Experimental Beverages</h3> <p>Three isonitrogenous (for LOW and LEU-LOW) or higher-protein (<a href="/terms/whey-protein/" class="term-link" data-slug="whey-protein" title="WHEY">WHEY</a>) beverage conditions were designed [1]:</p> <ul> <li><strong>WHEY:</strong> 25 g whey protein concentrate (providing approximately 3.0 g <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a>)</li> <li><strong>LEU-LOW:</strong> 6.25 g whey protein concentrate plus 3.0 g free L-leucine (matched leucine content to WHEY; total protein equivalent: ~9.25 g)</li> <li><strong>LOW:</strong> 6.25 g whey protein concentrate only (providing approximately 0.75 g leucine)</li> </ul> <p>All beverages were equated for total energy content through the addition of maltodextrin and were matched for flavor using non-nutritive flavoring agents to maintain participant blinding.</p> <h3>Exercise Protocol</h3> <p>Participants performed a standardized unilateral leg resistance exercise protocol consisting of four sets of leg press and four sets of leg extension at 80% of <a href="/terms/one-repetition-maximum/" class="term-link" data-slug="one-repetition-maximum" title="1RM">1RM</a>. This unilateral design enabled the non-exercised contralateral leg to serve as a resting control limb within the same participant, isolating the interactive effects of exercise and nutrition [2].</p> <h3>Measurement of Myofibrillar <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="Protein Synthesis">Protein Synthesis</a></h3> <p>Stable isotope tracer methodology was employed using L-[ring-^13C_6]phenylalanine as the tracer amino acid, infused continuously via intravenous catheter. Muscle biopsies were obtained from the vastus lateralis of both legs at 1 hour and 4 hours post-exercise. Myofibrillar proteins were isolated by differential centrifugation, and fractional synthetic rate (MyoFSR) was calculated from the incorporation of tracer phenylalanine into the myofibrillar fraction relative to plasma enrichment [1].</p> <h3>Statistical Analysis</h3> <p>One-way analysis of variance (ANOVA) with post-hoc Bonferroni correction was used to compare MyoFSR values among the three beverage conditions. Significance threshold was p 0.05.</p>Results
<h2>Results</h2> <h3>Myofibrillar Fractional Synthetic Rate</h3> <p>Post-exercise myofibrillar fractional synthetic rates (MyoFSR) differed significantly among the three beverage conditions (p 0.05 for overall ANOVA). Pairwise comparisons revealed the following pattern [1]:</p> <ul> <li><strong><a href="/terms/whey-protein/" class="term-link" data-slug="whey-protein" title="WHEY">WHEY</a></strong> produced the numerically highest MyoFSR in the exercised leg</li> <li><strong>LEU-LOW</strong> produced MyoFSR values statistically comparable to WHEY (p 0.05 for WHEY vs. LEU-LOW) and significantly greater than LOW (p 0.05)</li> <li><strong>LOW</strong> produced the lowest MyoFSR, significantly below both WHEY and LEU-LOW</li> </ul> <p>These results confirm the central hypothesis: <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a> supplementation of an otherwise suboptimal protein dose can rescue MyoFSR to levels comparable to a complete, higher-dose <a href="/terms/protein-supplementation/" class="term-link" data-slug="protein-supplementation" title="protein supplement">protein supplement</a>.</p> <h3>Exercise vs. Rest Limb Comparison</h3> <p>In all three conditions, MyoFSR was significantly higher in the exercised leg compared to the rested contralateral leg, confirming that post-exercise sensitization of the muscle to dietary protein was operative. The leucine manipulation was most impactful in the exercised leg, where anabolic signaling was primed by the preceding contractile activity [2].</p> <h3>Plasma Leucine Kinetics</h3> <p>Plasma leucine concentrations following beverage ingestion tracked predictably with beverage leucine content. WHEY and LEU-LOW produced comparable peak plasma leucine concentrations and areas under the leucine-time curve, while LOW produced substantially lower plasma leucine. The temporal pattern of plasma leucine availability aligned mechanistically with the observed MyoFSR data, supporting the role of leucine as the primary stimulus for <a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mTORC1">mTORC1</a> activation and subsequent <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="MPS">MPS</a> [1].</p> <h3>Signaling Protein Phosphorylation</h3> <p>Although not the primary outcome, Western blot analysis of biopsy samples revealed that phosphorylation of key mTORC1 downstream targets — specifically p70 ribosomal S6 kinase (p70S6K) and 4E-binding protein 1 (4E-BP1) — was significantly greater in WHEY and LEU-LOW conditions compared to LOW, corroborating the tracer-based MPS findings at the molecular signaling level [2].</p>Discussion
<h2>Discussion</h2> <p>The results of this investigation provide direct experimental evidence for the <a href="/terms/leucine/" class="term-link" data-slug="leucine" title="leucine">leucine</a> threshold model of <a href="/terms/muscle-protein-synthesis/" class="term-link" data-slug="muscle-protein-synthesis" title="MPS">MPS</a> regulation, demonstrating that leucine — rather than total protein quantity per se — is the primary nutritional trigger for post-exercise myofibrillar anabolism. The ability of leucine supplementation to rescue MPS from a suboptimal protein dose to levels comparable with a complete, higher-dose <a href="/terms/whey-protein/" class="term-link" data-slug="whey-protein" title="whey protein">whey protein</a> supplement is a finding of considerable mechanistic and practical significance.</p> <h3>Mechanistic Significance of Leucine</h3> <p>The data are consistent with the model in which leucine acts at multiple levels of the <a href="/terms/mtor/" class="term-link" data-slug="mtor" title="mTORC1">mTORC1</a> signaling cascade. Leucine is a direct activator of the leucine sensor Sestrin2, which under leucine-replete conditions disinhibits the GATOR complex, allowing mTORC1 to localize to the lysosomal membrane where it is activated by RagGTPases [1]. Once active, mTORC1 phosphorylates p70S6K and releases 4E-BP1, stimulating ribosomal biogenesis and translational initiation — the rate-limiting steps in MPS. The <a href="/terms/squat-depth/" class="term-link" data-slug="squat-depth" title="parallel">parallel</a> between plasma leucine kinetics, downstream signaling phosphorylation, and MyoFSR observed in this study is mechanistically internally consistent [2].</p> <h3>Practical Implications for Dietary Protein Selection</h3> <p>From a practical nutritional standpoint, these findings suggest that when dietary protein intake is limited — whether due to overall lower protein intake, reliance on lower-leucine plant protein sources, or practical constraints on meal size — leucine supplementation represents a targeted strategy to maintain anabolic signaling. This is particularly relevant for plant-based athletes who rely on legume, grain, and soy proteins, all of which provide substantially less leucine per gram of total protein than whey or egg white [3].</p> <p>A protein food containing approximately 2.5-3.0 g of leucine — achievable with 20-25 g of whey protein, 3 large eggs, or approximately 100 g of chicken breast — appears to reliably exceed the leucine threshold in young adults. When food choices fall below this threshold, supplemental leucine (typically 2-3 g as a standalone supplement or via a <a href="/terms/branched-chain-amino-acids/" class="term-link" data-slug="branched-chain-amino-acids" title="BCAA">BCAA</a> product) can serve as a practical solution.</p> <h3>Limitations</h3> <p>This study examined only acute MPS responses over a four-hour window. Whether the observed differences in MyoFSR translate to differential <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="muscle hypertrophy">muscle hypertrophy</a> over weeks to months of training with contrasting leucine intake patterns remains to be directly tested in long-term trials [1].</p>관련 논문
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