Resistance exercise enhances long-term mTORC1 sensitivity to leucine
Open accessAbstract
Objective Exercise enhances the sensitivity of mammalian target of rapamycin complex 1 (mTORC1) to amino acids, in particular leucine. How long this enhanced sensitivity lasts, and which mechanisms control enhanced leucine-mediated mTORC1 activation following exercise is currently unknown. Methods C57BL/6J mice were exercised for one night in a resistance-braked running wheel after a 12-day acclimatization period. Mice were gavaged with a submaximal dose of l -leucine or saline acutely or 48 h after exercise cessation, following 3 h food withdrawal. Muscles were excised 30 min after leucine administration. To study the contribution of mTORC1, we repeated those experiments but blocked mTORC1 activation using rapamycin immediately before the overnight running bout and one hour before the first dose of leucine. mTORC1 signaling, muscle protein synthesis and amino acid sensing machinery were assessed using immunoblot and qPCR. Leucine uptake was measured using L-[ 14 C(U)]-leucine tracer labeling. Results When compared to sedentary conditions, leucine supplementation more potently activated mTORC1 and protein synthesis in acutely exercised muscle. This effect was observed in m. soleus but not in m. tibialis anterio r nor m. plantaris . The synergistic effect in m. soleus was long-lasting as key downstream markers of mTORC1 as well as protein synthesis remained higher when leucine was administered 48 h after exercise. We found that exercise enhanced the expression of amino acid transporters and promoted uptake of leucine into the muscle, leading to higher free intramuscular leucine levels. This coincided with increased expression of activating transcription factor 4 (ATF4), a main transcriptional regulator of amino acid uptake and metabolism, and downstream activation of amino acid genes as well as leucyl-tRNA synthetase (LARS), a putative leucine sensor. Finally, blocking mTORC1 using rapamycin did not reduce expression and activation of ATF4, suggesting that the latter does not act downstream of mTORC1. Rather, we found a robust increase in eukaryotic initiation factor 2α (eIF2α) phosphorylation, suggesting that the integrated stress response pathway, rather than exercise-induced mTORC1 activation, drives long-term ATF4 expression in skeletal muscle after exercise. Conclusions The enhanced sensitivity of mTORC1 to leucine is maintained at least 48 h after exercise. This shows that the anabolic window of opportunity for protein ingestion is not restricted to the first hours immediately following exercise. Increased mTORC1 sensitivity to leucine coincided with enhanced leucine influx into muscle and higher expression of genes involved in leucine sensing and amino acid metabolism. Also, exercise induced an increase in ATF4 protein expression. Altogether, these data suggest that muscular contractions switch on a coordinated program to enhance amino acid uptake as well as intramuscular sensing of key amino acids involved in mTORC1 activation and the stimulation of muscle protein synthesis.
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In mice, increased sensitivity of mTORC1 to leucine persists for at least 48 h after exercise, indicating the anabolic window for protein intake extends beyond the initial hours following exercise.
“According to a mechanistic study in mice, the increased sensitivity of mTORC1 to leucine persists for at least 48 h after exercise, indicating that the “anabolic window” for protein intake extends beyond the initial hours following exercise [65].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [65]
High-volume resistance training induces greater activation of the PI3K-AKT-mTOR pathway, increasing MPS rates and amplifying caloric surplus effects.
“High-volume resistance training induces a greater activation of the PI3K–AKT–mTOR pathway, increasing MPS rates and amplifying caloric surplus effects.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [65]
Resistance training enhances anabolic signaling and increases muscle hypertrophy when combined with overfeeding.
“Resistance training enhances anabolic signaling and increases muscle hypertrophy when combined with overfeeding.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [65]
High protein intake supports muscle preservation by providing essential amino acids, particularly leucine, which stimulates the mTOR pathway.
“High protein intake further supports muscle preservation by providing essential amino acids, particularly leucine, which is a powerful stimulator of the mTOR pathway.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [65]
Leucine directly activates mTORC1 at the cellular level, enhancing translation and assembly of muscle proteins.
“Leucine’s role is crucial, as it directly activates mTORC1 at the cellular level, enhancing the translation and assembly of muscle proteins, leading to more effective muscle maintenance or growth even during periods of reduced calorie intake [65].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [65]
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- Authors
- D'Hulst, G., Masschelein, E., & De Bock, K.
- Affiliations
- ETH Zurich (CH)
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 66
- Pages
- 101615
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC9626937
- OpenAlex
- W4306250546
- Cited by
- 42
- References
- 70
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 12 · 2023: 6
- FWCI
- 4.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- resistance training, mTORC1, skeletal muscle, muscle protein synthesis, amino acid transporters, leucine uptake, ATF4, eIF2α phosphorylation, integrated stress response, rapamycin, soleus muscle, leucyl-tRNA synthetase, food withdrawal, amino acid sensing, leucine supplementation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acids, Animals, Leucine, Mice, Inbred C57BL, Muscle Proteins, Physical Conditioning, Animal, Sirolimus, Mice, Activating Transcription Factor 4
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