Analysis of the biological activity of L-leucine

The bioactivity of L-leucine centers on its core identity as an "essential human branched-chain amino acid (BCAA)". It is primarily exerted through three key pathways: regulating protein metabolism, participating in energy supply, and modulating cellular signaling pathways. Its bioactivity exhibits tissue specificity and dose dependence, with detailed analysis as follows:

I. Core Bioactivity: Three Key Mechanisms of Action

(I) Regulating Protein Metabolism: Core Function for Maintaining Muscle Homeostasis

The most critical bioactivity of L-leucine is regulating protein metabolism. Through the dual effects of "promoting synthesis + inhibiting decomposition", it maintains stable muscle mass, relying primarily on the activation of the mammalian target of rapamycin (mTOR) signaling pathway.

In skeletal muscle, L-leucine directly binds to regulatory proteins (e.g., Rag GTPases) of the mTOR complex (mTORC1) to activate the pathway. As the core switch for "nutrient sensing-protein synthesis" in cells, activated mTOR promotes ribosome assembly (e.g., phosphorylation of 4E-BP1, activation of S6K1), accelerates amino acid chain synthesis, and ultimately increases protein synthesis rate. For example, supplementing with 1–2 g of L-leucine after exercise can boost muscle protein synthesis rate by 30%–50%. This activity is strongest in skeletal muscle, far exceeding that of other BCAAs (L-valine, L-isoleucine).

Meanwhile, L-leucine inhibits protein decomposition by reducing the activity of the "ubiquitin-proteasome system" (the main pathway for intracellular protein degradation), thereby minimizing muscle protein loss. Particularly in energy-deficient scenarios such as starvation or post-exercise recovery, it can inhibit the expression of "muscle atrophy-related genes (e.g., MAFbx, MuRF1)" and reduce the activity of proteases like calpain, preventing muscle breakdown.

(II) Participating in Energy Metabolism: Muscle-Preferred Efficient Energy Supply

Unlike most amino acids that are mainly metabolized in the liver, L-leucine metabolism exhibits "muscle preference"—it can be directly oxidized for energy in skeletal muscle, serving as an important energy source during exercise or starvation. Its metabolic pathway involves two steps:

First, it undergoes "transamination" in muscle cells to generate α-ketoisocaproic acid (KIC).

Then, KIC undergoes "oxidative decarboxylation" to produce acetyl-CoA and acetoacetate. The former enters the "tricarboxylic acid cycle" for direct energy supply, while the latter can be converted into β-hydroxybutyrate (a ketone body) to provide energy for organs such as the brain and heart (ketone bodies can meet 50% of the brain’s energy needs during prolonged starvation).

This energy supply mode has two key characteristics:

High efficiency: Complete oxidation of 1 mol of L-leucine produces 32 mol of ATP, with an energy density close to that of glucose (36 mol of ATP/mol). Its metabolism is insulin-independent, making it suitable for diabetics or individuals with insulin resistance.

Glucose sparing: Supplementing with L-leucine during exercise reduces muscle glucose uptake by approximately 15%–20%. By using its own oxidation for energy, it spares glycogen and extends exercise endurance—for example, long-distance runners may experience a 10%–15% extension in time to exhaustion after supplementation.

(III) Modulating Cellular Signaling Pathways: Involvement in Metabolic Balance and Cell Repair

Beyond the mTOR pathway, L-leucine also regulates other key cellular signaling pathways, influencing metabolic homeostasis, cell proliferation, and repair—with notable effects in stress states such as infection or trauma.

Regulating insulin secretion: As an "incretin secretagogue", L-leucine activates "glutamate dehydrogenase (GDH)" in pancreatic β-cells, promoting ATP production. This closes potassium channels and triggers calcium influx, ultimately stimulating insulin release. This effect is only activated when blood glucose rises (avoiding hypoglycemia risk). For example, supplementing with 2–3 g of L-leucine after meals can increase insulin secretion by 20%–30%, helping transport blood glucose to muscle cells and reducing postprandial blood glucose fluctuations.

Promoting cell proliferation and repair: In rapidly proliferating cells (e.g., intestinal mucosal cells, T lymphocytes), L-leucine activates the mTOR pathway and the "mitogen-activated protein kinase (MAPK) pathway", promoting the cell cycle transition from G1 phase to S phase and accelerating cell proliferation. For instance, during intestinal injury (e.g., inflammatory bowel disease), L-leucine supplementation can increase intestinal villus height by 15%–20% and improve intestinal absorption function; in post-surgical immunosuppressive states, it promotes T cell proliferation and enhances immunity.

II. Tissue Specificity of Bioactivity: Functional Differences Across Organs

The bioactivity of L-leucine is not uniform throughout the body but exhibits significant differences based on the metabolic characteristics of different organs, focusing primarily on four key organs:

Skeletal muscle: Bioactivity concentrates on protein metabolism and energy supply. It is critical for maintaining muscle mass, improving exercise recovery, and preventing muscle atrophy, making it suitable for scenarios such as post-exercise recovery and age-related muscle loss in the elderly.

Liver: It is mainly involved in minor BCAA metabolism and albumin synthesis. It maintains liver synthetic function and reduces protein loss after liver injury, applicable to hepatitis recovery and adjuvant treatment of liver cirrhosis.

Brain: It acts as a neurotransmitter precursor (e.g., for γ-aminobutyric acid, GABA) and improves neural excitability, relieves fatigue, and stabilizes mood through ketone body energy supply. It is suitable for scenarios involving prolonged mental work or fatigue caused by sleep deprivation.

Intestines: Bioactivity focuses on promoting mucosal cell proliferation and enhancing intestinal barrier function. It prevents intestinal mucosal atrophy and reduces intestinal flora translocation, applicable to post-surgical intestinal function recovery and adjuvant treatment of inflammatory bowel disease.

III. Key Factors Influencing Bioactivity

The bioactivity of L-leucine is significantly affected by supplementation dose, nutrient combination, and human physiological status, requiring targeted adjustments to maximize efficacy:

(I) Dose Dependence

The physiological requirement dose (2–3 g/day in adult diets) only meets basic protein synthesis needs.

A supplementation dose of 1–3 g per serving activates the mTOR pathway and promotes muscle synthesis.

When a single dose exceeds 5 g, the excess is mainly used for oxidative energy supply, and the effect on protein synthesis no longer increases significantly (due to saturation).

(II) Nutrient Combination

Combining with other BCAAs at a ratio of 2:1:1 (L-leucine:L-valine:L-isoleucine) reduces L-leucine decomposition in the liver (BCAAs compete for the same transporter), improving its utilization in muscle and enhancing protein synthesis by 15%–20%.

Co-supplementation with carbohydrates (e.g., glucose) leverages "insulin synergy" (carbohydrates promote insulin secretion, while L-leucine enhances insulin sensitivity), further promoting muscle amino acid uptake and accelerating repair.

(III) Physiological Status

During "peak repair demand" periods (e.g., post-exercise, post-trauma), muscle and tissue sensitivity to L-leucine increases, making supplementation most effective.

Elderly individuals exhibit reduced sensitivity of muscle cells to L-leucine ("anabolic resistance"). Higher doses (3–4 g per serving) or combination with creatine are required to achieve the same protein synthesis effect as young adults.

Diabetics have weakened L-leucine-induced insulin secretion. Doses must be adjusted under medical guidance to avoid hypoglycemia caused by synergy with hypoglycemic drugs.

The bioactivity of L-leucine centers on "regulating skeletal muscle protein metabolism", with additional functions in energy supply and cellular signal modulation. It exhibits tissue specificity based on organ metabolic characteristics, and its efficacy is significantly influenced by dose, combination, and physiological status. These bioactive traits make it irreplaceable in sports nutrition, elderly health, clinical rehabilitation, and metabolic regulation. Targeted utilization of its bioactive mechanisms can maximize its physiological value.