Journal Article

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

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

2013

Overview

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.

• Publisher: Springer Netherlands,Springer Nature B.V,Springer Verlag
• Subject: Adolescent / Adult / Age differences / Aged / Aged, 80 and over / Aging / Aging - physiology / Animals / Autophagy-Related Protein 7 / Biochemistry, Molecular Biology / Biomedical and Life Sciences / Caloric intake / Cell Biology / Clinical Neurophysiology / Degradation / Delayed / Developmental Biology / Disorders / Female / Forkhead Box Protein O1 / Forkhead Transcription Factors / Forkhead Transcription Factors - physiology / Genetics / Geriatrics / Geriatrics/Gerontology / Gerontology / Humans / Insulin / Insulin-Like Growth Factor I / Insulin-Like Growth Factor I - physiology / Insulin-like growth factors / Intervention / Kinases / Klinisk neurofysiologi / Life Sciences / Male / Medicine / Mice / Mice, Inbred C57BL / Mice, Inbred DBA / Mice, Knockout / Mice, Transgenic / Microtubule-Associated Proteins / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - physiology / Models, Animal / Muscle Proteins / Muscle Proteins - genetics / Muscle Proteins - physiology / Muscle, Skeletal / Muscle, Skeletal - physiology / Muscles / Musculoskeletal system / Neurosciences / Pathology / Protein synthesis / Proteins / Proto-Oncogene Proteins c-akt / Proto-Oncogene Proteins c-akt - physiology / Research Article / Sarcopenia / Sarcopenia - physiopathology / Sedentary / Serpin E2 / Serpin E2 - genetics / Serpin E2 - physiology / Signal Transduction / Signal Transduction - physiology / SKP Cullin F-Box Protein Ligases / SKP Cullin F-Box Protein Ligases - genetics / SKP Cullin F-Box Protein Ligases - physiology / Strength / TOR Serine-Threonine Kinases / TOR Serine-Threonine Kinases - physiology / Transcription factors / Tripartite Motif Proteins / Ubiquitin-Protein Ligases / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - physiology / Young Adult