Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis
Open accessAbstract
Background: The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age‐related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown. Methods: We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle‐specific mTOR knockout (mTORmKO) littermates. Results: In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice (P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% (P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down‐regulation of glycogen phosphorylase expression (0.16‐fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V. Conclusions: Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole‐body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole‐body homeostasis.
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Autophagy is not hyperactivated in conditional mTOR knockout and mTOR catalytically inactive mice, but instead is impaired, and this inhibition contributes to the pathological features of these animals.
“Surprisingly, autophagy is not hyperactivated in these mice, as might be expected to occur following inhibition of the mTORC1 complex (Fig. 1), but instead is impaired and this inhibition greatly contributes to the pathological features of these animals12,14.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [14]
Both conditional mTOR knockout and mTOR catalytically inactive transgenic mice show myofiber degeneration and a myopathic phenotype, suggesting an important pro-survival role of mTOR.
“However, both conditional mTOR knockout and mTOR catalytical inactive transgenic mice show myofiber degeneration and myopathic phenotype, suggesting an important pro-survival role of mTOR.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [14]
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- Authors
- Zhang, Q., Duplany, A., Moncollin, V., Mouradian, S., Goillot, E., Mazelin, L., Gauthier, K., Streichenberger, N., Angleraux, C., Chen, J., Ding, S., Schaeffer, L., & Gangloff, Y.
- Affiliations
- Lyon 1 Université (FR)
- Institut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon France
- École Normale Supérieure de Lyon (FR)
- University of Illinois Urbana-Champaign (US)
- East China Normal University (CN)
- Corresponding author
- Gangloff, Yann‐Gaël
- ORCID
- Venue
- Journal of Cachexia, Sarcopenia and Muscle
- Publisher
- Wiley
- Published
- 2018-11-21
- Volume
- 10
- Issue
- 1
- Pages
- 35-53
- ISSN
- 2190-5991 (ISSN-L)
- 2190-6009
- PMC
- PMC6438346
- OpenAlex
- W2901740372
- Cited by
- 31
- References
- 91
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 5 · 2019: 6
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Cachexia Sarcopenia and Muscle (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Association Française contre les Myopathies
- National Institutes of Health (R01 AR048914)
- Suzhou Municipal Science and Technology Bureau (SYS201711)
- National Natural Science Foundation of China (31171142)
- China Scholarship Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- skeletal muscle, myopathy, mTORC1 signaling, muscle growth, body composition, muscle atrophy, muscular dystrophy, glycogen phosphorylase, glycogen storage disease type V, autophagy, oxidative metabolism, protein synthesis, rapamycin
- MeSH terms
- Animals, Disease Models, Animal, Homeostasis, Humans, Male, Mice, Transgenic, Muscular Diseases, Muscle, Skeletal, TOR Serine-Threonine Kinases
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