title: Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway.
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.
authors.affiliation: Dulbecco Telethon Institute at Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sandri
authors.forename: L
authors.initials: L
authors.lastname: Barberi
authors.forename: A Y
authors.initials: AY
authors.lastname: Bijlsma
authors.forename: B
authors.initials: B
authors.lastname: Blaauw
authors.forename: K A
authors.initials: KA
authors.lastname: Dyar
authors.forename: G
authors.initials: G
authors.lastname: Milan
authors.forename: C
authors.initials: C
authors.lastname: Mammucari
authors.forename: C G M
authors.initials: CG
authors.lastname: Meskers
authors.forename: G
authors.initials: G
authors.lastname: Pallafacchina
authors.forename: A
authors.initials: A
authors.lastname: Paoli
authors.forename: D
authors.initials: D
authors.lastname: Pion
authors.forename: M
authors.initials: M
authors.lastname: Roceri
authors.forename: V
authors.initials: V
authors.lastname: Romanello
authors.forename: A L
authors.initials: AL
authors.lastname: Serrano
authors.forename: L
authors.initials: L
authors.lastname: Toniolo
authors.forename: L
authors.initials: L
authors.lastname: Larsson
authors.forename: A B
authors.initials: AB
authors.lastname: Maier
authors.forename: P
authors.initials: P
authors.lastname: Muñoz-Cánoves
authors.forename: A
authors.initials: A
authors.lastname: Musarò
authors.forename: M
authors.initials: M
authors.lastname: Pende
authors.forename: C
authors.initials: C
authors.lastname: Reggiani
authors.forename: R
authors.initials: R
authors.lastname: Rizzuto
authors.forename: S
authors.initials: S
authors.lastname: Schiaffino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D000818:Animals; D000071193:Autophagy-Related Protein 7; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D023421:Models, Animal; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000502:physiology; D055948:Sarcopenia / Q000503:physiopathology; D058258:Serpin E2 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology; D055815:Young Adult
chemical_list: C502661:Atg7 protein, mouse; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D008869:Microtubule-Associated Proteins; D009124:Muscle Proteins; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D000070584:Tripartite Motif Proteins; D007334:Insulin-Like Growth Factor I; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000071193:Autophagy-Related Protein 7