The metabolic mechanism of L-leucine in branched-chain amino acids

As a key member of branched-chain amino acids (BCAAs), L-leucine is characterized by "skeletal muscle-prioritized catabolism + limited hepatic metabolism." It exerts critical physiological effects such as muscle growth promotion, anti-fatigue, and metabolic regulation by modulating pathways related to protein synthesis and energy metabolism.

I. Core Metabolic Mechanisms

1. Absorption and Transport

After oral administration, L-leucine is rapidly absorbed in the small intestine via sodium-dependent amino acid transporters (e.g., B⁰AT1, LAT1) and preferentially transported to skeletal muscle. Approximately 60%–70% of its metabolism occurs in skeletal muscle, with the liver only participating in minor subsequent metabolism.

It competes with L-isoleucine and L-valine for transporters during absorption; the highest transport efficiency is achieved when the three amino acids are in a balanced ratio (approximately 2:1:1).

2. Key Metabolic Steps

Step 1: In skeletal muscle cells, L-leucine undergoes transamination catalyzed by branched-chain amino acid transaminase (BCAT) to form α-ketoisocaproate (KIC), releasing amino groups for the synthesis of glutamate or alanine.

Step 2: KIC undergoes oxidative decarboxylation catalyzed by the branched-chain α-ketoacid dehydrogenase (BCKDH) complex to generate isovaleryl-CoA. This is the rate-limiting step of metabolism, regulated by phosphorylation (dephosphorylation activates the complex).

Final Products: Through β-oxidation, it produces acetyl-CoA and acetoacetate, which can enter the tricarboxylic acid (TCA) cycle for energy supply, be converted to ketone bodies in the liver, or be used for fatty acid synthesis.

3. Metabolic Regulation Characteristics

Skeletal Muscle Specificity: The BCKDH complex exhibits the highest activity in skeletal muscle, ensuring L-leucine is prioritized for muscle energy supply or protein synthesis.

Feedback Regulation: The metabolic product acetyl-CoA inhibits BCKDH activity to prevent excessive catabolism; insulin promotes BCKDH dephosphorylation, enhancing metabolic efficiency.

II. Core Physiological Functions

1. Regulation of Protein Metabolism (Most Critical Function)

Promotes Protein Synthesis: Activates the mammalian target of rapamycin (mTOR) signaling pathway, phosphorylating ribosomal protein S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) to initiate protein synthesis.

Inhibits Protein Degradation: Suppresses the activity of the ubiquitin-proteasome system, reducing skeletal muscle protein breakdown—particularly effective during energy restriction or post-exercise recovery.

Application Scenarios: Post-exercise supplementation accelerates muscle repair; supplementation in the elderly delays sarcopenia (muscle loss).

2. Energy Metabolism and Anti-Fatigue

Energy Supply Advantage: Under conditions of prolonged exercise, starvation, or low sugar, it can be rapidly catabolized for energy, accounting for 10%–15% of skeletal muscle energy sources—superior to other amino acids.

Reduces Fatigue Accumulation: Its metabolism lowers post-exercise lactic acid production, maintains stable blood glucose, extends exercise endurance, and shortens recovery time.

3. Regulation of Glucose and Lipid Metabolism

Improves Insulin Sensitivity: Promotes the expression of glucose transporter 4 (GLUT4) in skeletal muscle cells, enhancing glucose uptake and utilization, lowering blood glucose—suitable for individuals with type 2 diabetes.

Regulates Lipid Metabolism: Inhibits the activity of hepatic fatty acid synthase, reducing triglyceride deposition; promotes fatty acid oxidation, lowering body fat percentage, especially abdominal fat accumulation.

4. Other Physiological Functions

Immunomodulation: Provides energy and synthetic substrates for immune cells (e.g., lymphocytes), enhances immune cell activity, and improves the body’s resistance.

Neuroprotection: Can cross the blood-brain barrier, metabolize to form γ-aminobutyric acid (GABA) precursors, relieve neural excitability, improve sleep quality, and reduce oxidative damage to nerve cells.

III. Key Factors Influencing Metabolism and Efficacy

1. Supplementation Dosage and Method

Effective Dosage: 2–5 g/day for daily health maintenance, 5–10 g/day for post-exercise recovery, 3–7 g/day for anti-sarcopenia in the elderly. Excess intake (>15 g/day) may cause metabolic burden.

Supplementation Timing: Optimal protein synthesis occurs when supplemented within 30 minutes after exercise (when mTOR pathway activity is high); co-administration with carbohydrates improves absorption efficiency.

2. Individual Physiological Status

Athletic Populations: Skeletal muscle metabolism is active, resulting in higher L-leucine utilization and more significant anti-fatigue and muscle-building effects.

Elderly Individuals: BCKDH activity declines, reducing metabolic efficiency. Appropriate dosage increases and combination with other BCAAs yield better results.

Patients with Metabolic Diseases: Supplementation can improve metabolism in individuals with diabetes or obesity but requires dose control under medical guidance to avoid blood glucose fluctuations.

3. Nutritional Synergistic Effects

Synergy with Other BCAAs: Supplementation of L-leucine, L-isoleucine, and L-valine in a 2:1:1 ratio avoids transport competition and improves overall metabolic efficiency.

Synergy with Protein: Combining with high-quality proteins (e.g., whey protein, egg protein) provides complete amino acids for protein synthesis, enhancing muscle-building effects.

Synergy with B Vitamins: Vitamins B1, B2, and B6 participate in the activation of L-leucine metabolic enzymes; adequate intake promotes metabolic conversion.

IV. Safety and Precautions

1. Safety Profile

Low Acute Toxicity: The oral LD₅₀ in rats exceeds 5000 mg/kg, with no obvious side effects at normal doses.

Long-Term Safety: Daily supplementation of ≤5 g for 12 months causes no liver or kidney damage, complying with international food additive standards.

2. Precautions

Avoid Excessive Isolated Supplementation: Long-term isolated supplementation of L-leucine (>10 g/day) may disrupt the balance of BCAAs and affect the absorption of other amino acids.

Contraindications for Special Populations: Individuals with severe liver or kidney dysfunction should avoid supplementation due to impaired metabolic capacity and potential metabolite accumulation; caution is advised for patients with phenylketonuria.

Drug Interactions: Co-administration with hypoglycemic drugs (e.g., metformin) may enhance hypoglycemic effects; blood glucose monitoring is required to prevent hypoglycemia.