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Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway

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Abstract

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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Notes

  1. The following MYOAGE groups have contributed to the studies reported here: LL has been responsible for mouse samples, ABM (together with AYB and CGMM) for human subjects and biopsies from Leiden, PM-C (together with ALS) for PAI-1/IGF1, AM (together with LB) for IGF1 isoforms, MP (together with MR and DP) for Akt-mTOR, CR (together with AP and LT) for myostatin, MS (together with GM and VR) for FoxO targets, and SS (together with KD and BB) for Akt overexpression.

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Acknowledgments

Supported by the EC FP7 Project MYOAGE (to LL, ABM, PM-C, AM, MP, CR, MS, and SS), Fondation Thierry Latran, MIUR and AFM (to AM), the Swedish Research Council (8651 to LL), MDA, Ministerio de Ciencia e Innovación of Spain SAF2012-38547, FIS-PS09/01267, PLE2009-0124, Marató/TV3 and AFM (to PM-C and ALS), EU interregio project PANGEA (to CR), King Gustaf V and Queen Victoria’s Foundation, and the National Institute of Health Grants (AG-14731, AR-45627 and AR-47318 to LL).

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Authors and Affiliations

  1. Dulbecco Telethon Institute at Venetian Institute of Molecular Medicine, Padua, Italy

    M. Sandri

  2. Department of Biomedical Sciences, University of Padova, Padua, Italy

    M. Sandri, B. Blaauw, C. Mammucari, G. Pallafacchina, A. Paoli, L. Toniolo, C. Reggiani & R. Rizzuto

  3. Institute Pasteur Cenci Bolognetti, Istituto Italiano di Tecnologia, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, Rome, Italy

    L. Barberi & A. Musarò

  4. Section of Gerontology and Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands

    A. Y. Bijlsma & A. B. Maier

  5. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

    A. Y. Bijlsma

  6. Venetian Institute of Molecular Medicine (VIMM), Padua, Italy

    B. Blaauw, K. A. Dyar, G. Milan, V. Romanello & S. Schiaffino

  7. Department of Rehabilitation Medicine, Leiden University Medical Center, Leiden, The Netherlands

    C. G. M. Meskers

  8. Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Padua, Italy

    M. Sandri, G. Pallafacchina, C. Reggiani, R. Rizzuto & S. Schiaffino

  9. Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden

    L. Larsson

  10. Department of Biobehavioral Health, The Pennsylvania State University, University Park, TX, USA

    L. Larsson

  11. Cell Biology Group, Department of Experimental and Health Sciences, CIBERNED and ICREA, Pompeu Fabra University, Barcelona, Spain

    A. L. Serrano & P. Muñoz-Cánoves

  12. Faculté de Médecine, UMRS-845, INSERM U845, Université Paris Descartes, Paris, France

    D. Pion, M. Roceri & M. Pende

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  1. M. Sandri
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  2. L. Barberi
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  6. G. Milan
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  8. C. G. M. Meskers
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  9. G. Pallafacchina
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  10. A. Paoli
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  13. V. Romanello
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  14. A. L. Serrano
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Correspondence to S. Schiaffino.

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Sandri, M., Barberi, L., Bijlsma, A.Y. et al. Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 14, 303–323 (2013). https://doi.org/10.1007/s10522-013-9432-9

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