The intervention of L-leucine on muscle consumption in cancer patients

Cancer-Associated Muscle Wasting (CAMW), also known as cancer cachexia-related sarcopenia, is one of the most common complications in patients with malignant tumors, with an incidence rate as high as 50%~80% (particularly prominent in digestive system tumors, lung cancer, etc.). Characterized by progressive loss of skeletal muscle mass and declined muscle function, CAMW not only reduces patients’ quality of life and increases the risk of treatment intolerance but also decreases the 5-year survival rate of cancer patients by 30%~50%, making it a key factor affecting the prognosis of cancer treatment. As the only core component of branched-chain amino acids (BCAAs) capable of activating muscle protein synthesis pathways, L-leucine, with its unique molecular mechanisms and clinical safety, has emerged as a potential nutritional strategy for intervening in muscle wasting in cancer patients. This article systematically analyzes the pathological mechanisms of CAMW, the intervention targets of L-leucine, clinical research evidence, and optimization directions of applications, aiming to provide theoretical and practical references for clinical nutritional support.

I. Core Pathological Mechanisms of Cancer-Associated Muscle Wasting

The essence of muscle wasting in cancer patients is "imbalance between muscle protein synthesis and breakdown," which, combined with multiple factors such as energy metabolism disorders and inflammatory microenvironment, forms a vicious cycle:

Protein Metabolism Imbalance: Tumor cells secrete metabolic regulatory factors (e.g., cachectin, tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6]). On one hand, these factors inhibit the proliferation of skeletal muscle satellite cells and muscle protein synthesis (especially the synthesis of myosin heavy chain); on the other hand, they activate the ubiquitin-proteasome pathway (UPS) and autophagy-lysosome pathway, accelerating myofiber degradation and leading to net loss of skeletal muscle mass.

Energy Metabolism Disorders: Tumor tissues exhibit the "Warburg effect," relying primarily on glycolysis for energy production even under aerobic conditions, which consumes large amounts of glucose and amino acids in the body, resulting in negative energy balance in patients. Meanwhile, patients have an increased basal metabolic rate (10%~30% higher than that of healthy individuals), further exacerbating muscle tissue breakdown for energy supply.

Impaired Nutrient Intake and Absorption: Cancer patients often experience insufficient intake of protein and energy due to side effects of radiotherapy and chemotherapy (nausea, vomiting, diarrhea), tumor compression of the digestive tract, and anorexia related to cachexia. Additionally, intestinal absorption function declines, failing to meet the needs of muscle repair and synthesis.

Persistent Inflammatory Microenvironment: Tumor-related inflammatory factors (e.g., IL-6, TNF-α, C-reactive protein [CRP]) are continuously elevated. By activating downstream signaling pathways (e.g., NF-κB), they further amplify muscle breakdown signals and inhibit synthesis pathways, forming a "inflammation-muscle wasting" vicious cycle.

II. Molecular Mechanisms of L-Leucine in Intervening Cancer-Related Muscle Wasting

L-leucine regulates muscle metabolism with specificity and multi-targeted effects, primarily exerting its functions through a threefold mechanism: "activating synthesis pathways, inhibiting breakdown pathways, and improving metabolic microenvironment":

1. Activating the Core Pathway of Muscle Protein Synthesis

L-leucine is a natural activator of mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Its molecular mechanism is as follows: After entering myocytes through amino acid transporters (e.g., LAT1, SLC7A5) on the cell membrane, L-leucine binds to leucine-sensing proteins (Sestrin2, CASTOR1), relieving their inhibition on the GTPase Rheb, which in turn activates mTORC1. Downstream, mTORC1 phosphorylates ribosomal protein S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), initiating the muscle protein translation process and promoting myofiber synthesis. In addition, independent of the mTOR pathway, L-leucine increases the AMP/ATP ratio in myocytes, activating AMP-activated protein kinase (AMPK), which promotes glucose uptake and energy production to support muscle synthesis.

2. Inhibiting Muscle Protein Breakdown Pathways

L-leucine downregulates the expression of inflammatory factors (IL-6, TNF-α), inhibits the activation of the NF-κB signaling pathway, and reduces the transcription and expression of ubiquitin ligases (e.g., MuRF1, MAFbx), thereby blocking UPS-mediated myoprotein degradation. Meanwhile, L-leucine can inhibit the expression of autophagy-related genes (Atg5, Atg7) through mTORC1, moderately suppressing excessive autophagy-induced muscle breakdown and maintaining myofiber integrity.

3. Improving Nutritional Metabolism and Inflammatory Microenvironment

L-leucine regulates appetite-related hormones (e.g., leptin, ghrelin), alleviates anorexia in cancer patients, and increases protein and energy intake. Its metabolite (e.g., α-ketoisocaproic acid) has antioxidant activity, which can scavenge reactive oxygen species and reduce damage to myocytes caused by tumor-related oxidative stress. Additionally, L-leucine can lower the level of inflammatory factors, improve the chronic inflammatory state of the body, and break the "inflammation-muscle wasting" cycle.

III. Clinical Research Evidence and Effect Analysis of L-Leucine Intervention

In recent years, numerous clinical studies and meta-analyses have confirmed the intervention effect of L-leucine on muscle wasting in cancer patients, but there is heterogeneity in the conclusions, which is mainly related to intervention dosage, timing, tumor type, and combined regimens:

1. Clinical Effects of Single L-Leucine Intervention

Maintenance of Muscle Mass: A randomized controlled trial (RCT) involving patients with advanced gastrointestinal tumors showed that daily supplementation of 3g L-leucine (administered in 3 divided doses) for 12 weeks resulted in a 1.8%~2.3% increase in skeletal muscle mass compared to the placebo group (detected by DXA scan), while the placebo group experienced a 3.1% decrease. Another study on lung cancer patients undergoing chemotherapy demonstrated that daily supplementation of 5g L-leucine significantly reduced the rate of muscle loss (from 0.5%/week to 0.15%/week).

Improvement of Muscle Function: In patients with advanced breast cancer, supplementation of L-leucine (4g/d for 8 weeks) increased grip strength by 12%~15% and 6-minute walking distance by 8%~10%, which was significantly superior to the simple nutritional support group. However, no significant functional improvement was observed in a study on end-stage pancreatic cancer patients, which may be related to excessive tumor burden and severe metabolic disorders.

Enhanced Treatment Tolerance: An RCT involving 120 colorectal cancer patients undergoing chemotherapy showed that patients supplemented with L-leucine (3g/d) had a 25% reduction in the incidence of chemotherapy-related fatigue, an 18% reduction in neutropenia, and a 12% higher chemotherapy completion rate compared to the control group. This is presumably related to the maintenance of muscle mass and improvement of energy metabolism.

2. Synergistic Effects of Combined Intervention Regimens

The intervention effect of L-leucine is more significant when combined with other nutritional components, which has become a mainstream clinical strategy:

Combination with Other BCAAs: The composite BCAA supplement of L-leucine + L-isoleucine + L-valine (ratio 2:1:1) can more effectively maintain muscle mass than single L-leucine by synergistically activating the mTOR pathway. A study on patients after esophageal cancer surgery showed that 6 weeks of intervention with composite BCAAs (containing 3g/d L-leucine) resulted in a 3.2% increase in skeletal muscle mass, compared to a 1.9% increase in the single L-leucine group.

Combination with Protein/Energy: L-leucine exerts its effects on the basis of adequate protein (1.2~1.5g/kg body weight/d) and energy supply. Studies have shown that advanced tumor patients who consume 1.5g/kg body weight protein + 3g L-leucine daily have a 20%~25% higher muscle protein synthesis rate than the simple high-protein group. If energy intake is insufficient (<25kcal/kg body weight/d), the intervention effect of L-leucine is significantly weakened.

Combination with Resistance Training: L-leucine supplementation has a synergistic effect with moderate resistance training (e.g., dumbbell training, resistance band training). A study on cancer survivors showed that 16 weeks of resistance training + L-leucine (3g/d) intervention resulted in a 4.5% increase in skeletal muscle mass and a 20% increase in grip strength, which was far superior to the simple training group or simple supplementation group. The mechanism is that resistance training can enhance the sensitivity of myocytes to L-leucine and further activate the mTOR pathway.

3. Research Heterogeneity and Limitations

Existing studies have certain controversies: Some studies on end-stage tumor patients have not observed significant benefits of L-leucine, possibly due to: ① Excessive tumor burden, where the level of inflammatory factors exceeds the regulatory capacity of L-leucine; ② Severe impairment of intestinal absorption function in patients, leading to low bioavailability of L-leucine; ③ Failure to combine with adequate protein and energy support. In addition, existing studies have small sample sizes (mostly <100 cases) and short intervention cycles (mostly <12 weeks), and long-term effects still need to be verified by large-sample follow-up.

IV. Optimization Strategies and Precautions for Clinical Application

1. Intervention Timing and Target Population

Optimal Intervention Timing: Initiate as early as possible after cancer diagnosis, especially 1~2 weeks before radiotherapy and chemotherapy, to reserve muscle mass in advance and reduce the risk of treatment-related muscle wasting. For patients who have already developed sarcopenia, intensive nutritional support should be combined on the basis of controlling tumor burden.

Target Population: ① Pre-cachectic cancer patients (weight loss <5%, mild reduction in muscle mass); ② Patients during radiotherapy and chemotherapy; ③ Cancer survivors who need to maintain muscle function; ④ End-stage patients with acceptable intestinal function and expected survival >3 months can be appropriately supplemented to improve quality of life.

Contraindicated Population: Patients with severe liver and kidney insufficiency (metabolites of L-leucine are excreted through the liver and kidneys) and rare maple syrup urine disease (branched-chain amino acid metabolism disorder) are prohibited.

2. Dosage and Administration Route

Recommended Dosage: The commonly used clinical dosage is 3~5g/d, administered in 2~3 divided doses to avoid gastrointestinal discomfort (e.g., nausea, bloating) caused by a single large dose (>5g). For patients with severe muscle wasting, the dosage can be increased to 5~7g/d, and liver and kidney function should be monitored.

Administration Route: ① Oral: Take with meals, preferably with protein-rich foods (e.g., eggs, milk) to improve absorption efficiency; ② Enteral nutrition preparations: Infuse specialized enteral nutrition agents containing L-leucine (e.g., adding 3~5g/L L-leucine) through a nasogastric tube or jejunostomy tube; ③ Intravenous infusion: For patients who cannot eat orally, L-leucine can be added to parenteral nutrition (0.1~0.15g/kg body weight/d).

3. Monitoring Indicators

During the intervention period, the following indicators should be regularly monitored to assess efficacy and safety:

Muscle Mass Monitoring: Detect skeletal muscle mass by DXA scan, CT/MRI, or bioelectrical impedance analysis (BIA) every 4~6 weeks;

Muscle Function Monitoring: Grip strength test, 6-minute walking distance, and Activities of Daily Living (ADL) score;

Metabolic and Nutritional Indicators: Serum albumin, prealbumin, transferrin, and inflammatory factors (IL-6, TNF-α, CRP);

Safety Indicators: Liver and kidney function (ALT, AST, creatinine, urea nitrogen) and blood glucose (L-leucine may slightly affect insulin sensitivity, so blood glucose should be monitored in diabetic patients).

V. Challenges and Future Development Directions

1. Existing Challenges

Significant Individual Differences: The intervention effect of L-leucine varies greatly among patients with different tumor types, stages, treatment regimens, and baseline nutritional status, and there is a lack of personalized intervention plans.

Limited Efficacy in Advanced Patients: For end-stage patients with high tumor burden, severe metabolic disorders, and impaired intestinal function, single nutritional intervention is difficult to reverse muscle wasting.

Insufficient Mechanism Research: The regulatory mechanism of L-leucine on muscle metabolism in cancer patients still needs to be further explored, especially the interaction with the tumor microenvironment and inflammatory factors is not clear.

Lack of Uniform Standards: Currently, there are no unified guidelines for the intervention dosage, administration route, and evaluation indicators of L-leucine, resulting in insufficient standardization of clinical applications.

2. Development Directions

Personalized Nutritional Support: Develop personalized L-leucine supplementation plans based on patients’ tumor type, genetic characteristics, and metabolic status (e.g., inflammatory factor profile, muscle metabolic markers). For example, for patients with a high inflammatory state, anti-inflammatory nutrients (e.g., ω-3 fatty acids, glutamine) can be combined.

Development of Novel Formulations: Develop high-bioavailability L-leucine formulations (e.g., microcapsules, liposome-encapsulated) to improve intestinal absorption efficiency, which is suitable for patients with impaired digestive function. Develop L-leucine delivery systems targeting myocytes to enhance tissue-specific effects.

Combination with Mechanism-Targeted Drugs: Explore the combined use of L-leucine with cachexia-targeted drugs (e.g., IL-6 inhibitors, mTOR activators) to break the vicious cycle of muscle wasting through "nutrition + drug" dual intervention.

Large-Sample Long-Term Studies: Conduct multi-center, large-sample, long-term follow-up RCTs to clarify the long-term effects of L-leucine on the survival rate and quality of life of cancer patients, and provide high-level evidence for the formulation of clinical guidelines.

As a core regulator of muscle protein synthesis, L-leucine exerts a significant intervention effect on muscle wasting in cancer patients by activating the mTOR pathway, inhibiting muscle breakdown, and improving the inflammatory microenvironment. It can effectively maintain skeletal muscle mass, improve muscle function, and enhance treatment tolerance. The key to its clinical application lies in: initiating intervention as early as possible, adopting combined nutritional plans (synergistic with protein, energy, and other BCAAs), combining with moderate exercise, and adjusting the dosage and monitoring safety according to individual patient conditions.

Despite existing challenges such as significant individual differences and limited efficacy in advanced patients, with the development of personalized nutrition concepts and the innovation of formulation technology, L-leucine is expected to become a core component of the comprehensive management of cancer-associated muscle wasting. In the future, more basic and clinical studies are needed to clarify its long-term efficacy and safety, optimize application plans, and provide more effective nutritional support strategies for cancer patients to improve their prognosis and quality of life.