The regulatory role of L-leucine in protein turnover in skeletal muscle

L-leucine is a key signaling molecule that regulates skeletal muscle protein turnover. It exerts bidirectional regulation by activating synthetic pathways and inhibiting catabolic pathways, playing a critical role in muscle growth, post-exercise repair, and anti-sarcopenia. The specific regulatory mechanisms and effects are as follows:

I. Core Regulatory Mechanism: Bidirectional Regulation of Protein Synthesis and Degradation

Skeletal muscle protein turnover is a dynamic balance between "synthesis" and "degradation." L-leucine disrupts this balance toward "synthesis dominance" by precisely targeting two core pathways, enabling muscle mass maintenance or growth.

1. Activating Skeletal Muscle Protein Synthesis Pathway: Targeting mTORC1 as the Core

The most critical role of L-leucine is activating mTORC1 (mammalian target of rapamycin complex 1)—the "switch" regulating protein synthesis. The specific activation process occurs in two steps:

Step 1: Relieving mTORC1 Inhibition

Under normal conditions, mTORC1 binds to inhibitory proteins (e.g., TSC2) and remains dormant. After L-leucine is recognized by "amino acid sensors" (e.g., Sestrin2, CASTOR1) on the cell membrane, it promotes the binding of these inhibitory proteins to L-leucine, causing them to dissociate from mTORC1 and relieve inhibition.

Step 2: Promoting mTORC1 Phosphorylation and Activation

The de-inhibited mTORC1 is further phosphorylated (e.g., at the Ser2448 site). Once activated, it directly acts on two key downstream factors:

4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1): Phosphorylated 4E-BP1 dissociates from eIF4E (translation initiation factor), allowing eIF4E to normally initiate mRNA translation.

p70S6K (ribosomal S6 protein kinase 1): Phosphorylated p70S6K promotes the synthesis of ribosomal proteins (e.g., S6 protein), increasing ribosome quantity. Ribosomes are the "factories" for protein synthesis, so more ribosomes directly enhance synthesis efficiency.

Experimental data: After humans ingest 2–3 g of L-leucine, mTORC1 activity in skeletal muscle increases 2–3 times within 30 minutes, p70S6K phosphorylation levels rise by 50%–80%, and protein synthesis rate increases significantly—with the effect lasting 2–3 hours.

2. Inhibiting Skeletal Muscle Protein Degradation Pathway: Reducing Muscle Protein Breakdown

L-leucine also reduces muscle protein loss by inhibiting two major protein degradation pathways:

Inhibiting the Ubiquitin-Proteasome Pathway

This is the primary pathway for muscle protein degradation (accounting for ~60% of total degradation), with the core process being "ubiquitin labeling of proteins to be degraded → proteasome degradation." L-leucine decreases the expression of ubiquitin ligases (e.g., MuRF1, MAFbx)—muscle-specific ubiquitin ligases that specifically label myofibrillar proteins (e.g., actin, myosin). Studies show that L-leucine supplementation reduces MuRF1 mRNA levels in post-exercise muscle by 35%–45%, lowering the probability of muscle proteins being labeled for degradation.

Inhibiting the Autophagy-Lysosome Pathway

The autophagy pathway mainly degrades damaged organelles and long-lived proteins, and is activated during starvation or post-exercise overfatigue. L-leucine indirectly inhibits the activity of autophagy initiators (e.g., ULK1) by activating mTORC1, reducing autophagosome formation and thus preventing excessive muscle protein degradation. This effect is particularly important during energy deficiency (e.g., fat loss periods) to reduce "compensatory muscle breakdown."

II. Regulatory Effects in Different Physiological Scenarios: Targeted Regulation of Muscle Turnover

L-leucine’s regulation of skeletal muscle protein turnover adjusts dynamically based on physiological states (e.g., exercise, starvation, aging), showing scenario-specificity.

1. Post-Exercise Muscle Repair: Accelerating Synthesis and Reducing Degradation

Exercise (especially resistance training) causes "micro-tears" in skeletal muscle fibers. Meanwhile, increased energy consumption leads to a temporary rise in protein degradation. L-leucine regulates this process to restore balance:

During exercise: Muscles consume amino acids for energy, L-leucine concentration decreases, mTORC1 activity is inhibited, and catabolic pathways become relatively active.

Post-exercise L-leucine supplementation:

Rapidly increases intramuscular L-leucine concentration, activates mTORC1, and promotes the synthesis of repair-related proteins (e.g., myoglobin, collagen) to accelerate myofibril repair.

Inhibits the expression of catabolic enzymes (e.g., MuRF1) to prevent further degradation of damaged muscle.

Practical effect: Supplementing 3–5 g of L-leucine within 30 minutes after resistance training shifts muscle protein net synthesis rate (synthesis - degradation) from "negative" (degradation > synthesis) post-exercise to "positive," increasing repair efficiency by 20%–25% and shortening muscle strength recovery time by 12–24 hours.

2. Starvation/Energy Restriction Periods: Inhibiting Degradation and Protecting Muscle

During starvation or fat loss periods (insufficient energy intake), the body breaks down muscle protein for energy, leading to muscle loss. L-leucine reduces this loss through "signal deception":

During starvation, blood glucose and insulin levels drop, activating catabolic pathways (e.g., ubiquitin-proteasome pathway). After L-leucine supplementation, even with low insulin levels, it can independently activate mTORC1 to initiate synthetic pathways while inhibiting the expression of catabolic enzymes.

Research evidence: Supplementing 1.5 g of L-leucine three times daily during fat loss reduces muscle loss by 30%–40% without affecting fat breakdown, achieving "fat loss while preserving muscle."

3. Age-Related Sarcopenia: Improving Synthesis Resistance

Older adults often experience "muscle synthesis resistance"—even with amino acid intake, mTORC1’s response to signals weakens, leading to reduced synthesis efficiency and annual muscle loss (approximately 1%–2%). L-leucine improves this resistance through "high-concentration signaling":

The sensitivity of amino acid sensors (e.g., Sestrin2) in older adults’ muscles decreases, requiring higher L-leucine concentrations to activate mTORC1. Supplementing 4–6 g of L-leucine daily (in 2–3 divided doses) increases mTORC1 activity in older adults’ skeletal muscle to 70%–80% of that in young adults, raises protein synthesis rate by 15%–20%, and delays sarcopenia.

III. Factors Influencing Regulatory Effects: Dosage, Synergy, and Individual Differences

The regulatory effect of L-leucine on skeletal muscle protein turnover is not determined by a single factor; key variables require attention:

1. Dose Dependence

The minimum effective dose for adults is 2 g per serving (single intake below this dose fails to significantly activate mTORC1).

The optimal effective dose is 3–5 g per serving (can be increased to 5 g for post-exercise or older adults).

Excess intake (e.g., >10 g per serving) provides no additional benefits; instead, it may cause branched-chain amino acid (BCAA) imbalance, inhibit the absorption of other essential amino acids (e.g., tryptophan), and indirectly affect protein synthesis.

2. Synergy with Other Nutrients

Synergy with carbohydrates: Carbohydrates increase insulin levels, and insulin enhances mTORC1 activity—forming "synergistic activation" with L-leucine, which improves synthesis efficiency by 30%–40% (e.g., post-exercise supplementation of "L-leucine + glucose" is more effective than L-leucine alone).

Synergy with other BCAAs (isoleucine, valine): Supplementing the three in a 2:1:1 ratio (highest proportion of L-leucine) avoids BCAA imbalance caused by excessive single leucine intake. Meanwhile, isoleucine and valine help maintain the stability of intramuscular amino acid pools, extending the regulatory effect.

3. Individual Differences

Muscle mass: More muscle mass requires higher L-leucine doses (e.g., 5 g per serving for a 70 kg athlete vs. 3 g per serving for a 50 kg older adult).

Insulin sensitivity: Individuals with insulin resistance (e.g., diabetic patients) require higher L-leucine doses to activate mTORC1, with regulatory effects potentially reduced by 15%–20%.

By "activating the mTORC1 synthetic pathway + inhibiting the ubiquitin-proteasome catabolic pathway," L-leucine becomes a core regulator of skeletal muscle protein turnover, playing a key role in post-exercise repair, muscle preservation during starvation, and anti-sarcopenia in aging. In practical applications, doses should be adjusted based on physiological scenarios, and L-leucine should be used synergistically with carbohydrates and other BCAAs to maximize its regulatory value for muscle turnover.