Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway
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During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well-characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired.
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Inhibition of Atrogin-1 does not block denervation- and glucocorticoid-induced muscle loss and does not protect from aging sarcopenia.
“Inhibition of Atrogin-1 does not block denervation- and glucocorticoids-induced muscle loss19,44 and does not protect from aging sarcopenia46.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [46]
MuRF1 inhibition prevents age-related muscle loss but not the decrease in muscle force.
“Finally, MuRF1 inhibition prevents age-related muscle loss but not the decrease in muscle force45,46.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [46]
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- Authors
- Sandri, M., Barberi, L., Bijlsma, A. Y., Blaauw, B., Dyar, K. A., Milan, G., Mammucari, C., Meskers, C. G. M., Pallafacchina, G., Paoli, A., Pion, D., Roceri, M., Romanello, V., Serrano, A. L., Toniolo, L., Larsson, L., Maier, A. B., Muñoz-Cánoves, P., Musarò, A., Pende, M., Reggiani, C., Rizzuto, R., & Schiaffino, S.
- Affiliations
- Veneto Institute of Molecular Medicine (IT)
- Italian Institute of Technology (IT)
- Leiden University Medical Center (NL)
- University of Padua (IT)
- Inserm (FR)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Uppsala University (SE)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Schiaffino, S.
- ORCID
- Venue
- Biogerontology
- Published
- 2013-05-19
- Volume
- 14
- Issue
- 3
- Pages
- 303-323
- ISSN
- 1389-5729 (ISSN-L)
- 1573-6768
- OpenAlex
- W2087071824
- Cited by
- 340
- References
- 81
- Citations by year
- 2026: 16 · 2025: 12 · 2024: 23 · 2023: 20 · 2022: 32 · 2021: 34 · 2020: 24 · 2019: 25 · 2018: 24 · 2017: 39 · 2016: 28 · 2015: 22 · 2014: 30 · 2013: 10
- FWCI
- 13.45
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Biogerontology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- VU Research Portal (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- National Institute on Aging (P01AG014731, AG14731)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 45627, AR 47318, R01AR047318, R01AR045627)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- sarcopenia, skeletal muscle aging, mTORC1, S6 phosphorylation, protein turnover, muscle protein degradation, atrogin-1, rapamycin, caloric restriction, lifespan, muscle hypertrophy, frailty
- MeSH terms
- Tripartite Motif Proteins, Forkhead Box Protein O1, Autophagy-Related Protein 7, Adolescent, Adult, Aged, Aged, 80 and over, Aging, Animals, Female, Humans, Insulin-Like Growth Factor I, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Microtubule-Associated Proteins, Muscle Proteins, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Models, Animal, Ubiquitin-Protein Ligases, SKP Cullin F-Box Protein Ligases, Proto-Oncogene Proteins c-akt, Mice, Forkhead Transcription Factors, Young Adult, Sarcopenia, Serpin E2, TOR Serine-Threonine Kinases
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