Sustained Activation of mTORC1 in Skeletal Muscle Inhibits Constitutive and Starvation-Induced Autophagy and Causes a Severe, Late-Onset Myopathy
Open accessAbstract
Autophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a growing number of myopathological conditions. Although FoxO3 was shown to promote the expression of autophagy-related genes in skeletal muscle, the mechanisms triggering autophagy are unclear. We show that TSC1-deficient mice (TSCmKO), characterized by sustained activation of mTORC1, develop a late-onset myopathy related to impaired autophagy. In young TSCmKO mice, constitutive and starvation-induced autophagy is blocked at the induction steps via mTORC1-mediated inhibition of Ulk1, despite FoxO3 activation. Rapamycin is sufficient to restore autophagy in TSCmKO mice and improves the muscle phenotype of old mutant mice. Inversely, abrogation of mTORC1 signaling by depletion of raptor induces autophagy regardless of FoxO inhibition. Thus, mTORC1 is the dominant regulator of autophagy induction in skeletal muscle and ensures a tight coordination of metabolic pathways. These findings may open interesting avenues for therapeutic strategies directed toward autophagy-related muscle diseases.
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A slow and progressive myopathic phenotype was described in mice with chronic mTORC1 activation by TSC1 inhibition, and the autophagy system was blocked and contributed to the phenotype.
“A slow and progressive myopathic phenotype was also described in mice that displayed a chronic mTORC1 activation by TSC1 inhibition15. Consistent with mTOR hyperactivation, the autophagy system was blocked and this impairment contributed to the phenotype of TSC1 knockout15.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [15]
Specific deletion of Atg7 or overexpression of TSC2 recapitulates the pathological features of aging sarcopenia, such as increased oxidative stress, accumulation of dysfunctional mitochondria, myofiber denervation, atrophy, weakness, and premature death.
“Importantly, specific deletion of Atg7 or overexpression of TSC2 recapitulates the pathological features of aging sarcopenia, such as increased oxidative stress, accumulation of dysfunctional mitochondria, myofiber denervation, atrophy, weakness, and premature death15,51.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [15]
Autophagy is critical for maintaining normal homeostasis of muscle mass in physiological and pathological conditions.
“autophagy is critical for maintaining normal homeostasis of muscle mass in physiological and pathological conditions30,47–49.”
From Disuse-associated loss of the protease Lonp1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength (2022) · cites this paper as [48]
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References 37 · Cited by 302
- Authors
- Castets, P., Lin, S., Rion, N., Di Fulvio, S., Romanino, K., Guridi, M., Frank, S., Tintignac, L. A., Sinnreich, M., & Rüegg, M. A.
- Affiliations
- University of Basel (CH)
- University Hospital of Basel (CH)
- Corresponding author
- Sinnreich, Michael
- Rüegg, Markus A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 17
- Issue
- 5
- Pages
- 731-744
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2060129186
- Cited by
- 302
- References
- 37
- Citations by year
- 2026: 25 · 2025: 28 · 2024: 30 · 2023: 19 · 2022: 21 · 2021: 26 · 2020: 20 · 2019: 30 · 2018: 19 · 2017: 13 · 2016: 22 · 2015: 25 · 2014: 17 · 2013: 7
- FWCI
- 17.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- edoc (University of Basel) (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- HAL (submittedVersion)
- edoc (University of Basel)
- Funders
- National Science Foundation
- Universität Basel
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (145505)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- 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
- Keywords
- mTORC1, autophagy, skeletal muscle, myopathy, ULK1, FOXO3, raptors, rapamycin, starvation-induced autophagy, late-onset myopathy, muscle metabolism
- MeSH terms
- Forkhead Box Protein O3, Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 1 Protein, Animals, Autophagy, Muscular Diseases, Starvation, Muscle, Skeletal, Tumor Suppressor Proteins, Multiprotein Complexes, Mice, Forkhead Transcription Factors, TOR Serine-Threonine Kinases
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