Biogerontology

, Volume 14, Issue 3, pp 303–323

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

  • M. Sandri
  • L. Barberi
  • A. Y. Bijlsma
  • B. Blaauw
  • K. A. Dyar
  • G. Milan
  • C. Mammucari
  • C. G. M. Meskers
  • G. Pallafacchina
  • A. Paoli
  • D. Pion
  • M. Roceri
  • V. Romanello
  • A. L. Serrano
  • L. Toniolo
  • L. Larsson
  • A. B. Maier
  • P. Muñoz-Cánoves
  • A. Musarò
  • M. Pende
  • C. Reggiani
  • R. Rizzuto
  • S. Schiaffino
Research article

DOI: 10.1007/s10522-013-9432-9

Cite this article as:
Sandri, M., Barberi, L., Bijlsma, A.Y. et al. Biogerontology (2013) 14: 303. doi:10.1007/s10522-013-9432-9

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.

Keywords

SarcopeniaAgeingIGF1AktmTORFoxO

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • M. Sandri
    • 1
    • 2
    • 8
  • L. Barberi
    • 3
  • A. Y. Bijlsma
    • 4
    • 5
  • B. Blaauw
    • 2
    • 6
  • K. A. Dyar
    • 6
  • G. Milan
    • 6
  • C. Mammucari
    • 2
  • C. G. M. Meskers
    • 7
  • G. Pallafacchina
    • 2
    • 8
  • A. Paoli
    • 2
  • D. Pion
    • 12
  • M. Roceri
    • 12
  • V. Romanello
    • 6
  • A. L. Serrano
    • 11
  • L. Toniolo
    • 2
  • L. Larsson
    • 9
    • 10
  • A. B. Maier
    • 4
  • P. Muñoz-Cánoves
    • 11
  • A. Musarò
    • 3
  • M. Pende
    • 12
  • C. Reggiani
    • 2
    • 8
  • R. Rizzuto
    • 2
    • 8
  • S. Schiaffino
    • 6
    • 8
  1. 1.Dulbecco Telethon Institute at Venetian Institute of Molecular MedicinePaduaItaly
  2. 2.Department of Biomedical SciencesUniversity of PadovaPaduaItaly
  3. 3.Institute Pasteur Cenci Bolognetti, Istituto Italiano di Tecnologia, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University of RomeRomeItaly
  4. 4.Section of Gerontology and Geriatrics, Department of Internal MedicineVU University Medical CenterAmsterdamThe Netherlands
  5. 5.Department of Gerontology and GeriatricsLeiden University Medical CenterLeidenThe Netherlands
  6. 6.Venetian Institute of Molecular Medicine (VIMM)PaduaItaly
  7. 7.Department of Rehabilitation MedicineLeiden University Medical CenterLeidenThe Netherlands
  8. 8.Institute of Neuroscience, Consiglio Nazionale delle RicerchePaduaItaly
  9. 9.Department of Neuroscience, Clinical NeurophysiologyUppsala UniversityUppsalaSweden
  10. 10.Department of Biobehavioral HealthThe Pennsylvania State UniversityUniversity ParkUSA
  11. 11.Cell Biology Group, Department of Experimental and Health SciencesCIBERNED and ICREA, Pompeu Fabra UniversityBarcelonaSpain
  12. 12.Faculté de Médecine, UMRS-845, INSERM U845, Université Paris DescartesParisFrance