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 & 3 others C Reggiani, R Rizzuto, S Schiaffino

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)303-23
Number of pages21
JournalBiogerontology
Volume14
Issue number3
DOIs
Publication statusPublished - Jun 2013

Fingerprint

Sarcopenia
Somatomedins
Sirolimus
Skeletal Muscle
Muscles
Ribosomal Protein S6
Caloric Restriction
Gene Expression Profiling
Ligases
Ubiquitin
Hypertrophy
Proteolysis
Proteins
Transcription Factors
Phosphotransferases
Up-Regulation
Down-Regulation
Phosphorylation
Pathology

Keywords

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging/physiology
  • Animals
  • Autophagy-Related Protein 7
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors/physiology
  • Humans
  • Insulin-Like Growth Factor I/physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mice, Transgenic
  • Microtubule-Associated Proteins/genetics
  • Models, Animal
  • Muscle Proteins/genetics
  • Muscle, Skeletal/physiology
  • Proto-Oncogene Proteins c-akt/physiology
  • SKP Cullin F-Box Protein Ligases/genetics
  • Sarcopenia/physiopathology
  • Serpin E2/genetics
  • Signal Transduction/physiology
  • TOR Serine-Threonine Kinases/physiology
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases/genetics
  • Young Adult

Cite this

Sandri, M., Barberi, L., Bijlsma, A. Y., Blaauw, B., Dyar, K. A., Milan, G., ... Schiaffino, S. (2013). Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology, 14(3), 303-23. https://doi.org/10.1007/s10522-013-9432-9
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. / Signalling pathways regulating muscle mass in ageing skeletal muscle : the role of the IGF1-Akt-mTOR-FoxO pathway. In: Biogerontology. 2013 ; Vol. 14, No. 3. pp. 303-23.
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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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Sandri, M, Barberi, L, Bijlsma, AY, Blaauw, B, Dyar, KA, Milan, G, Mammucari, C, Meskers, CGM, Pallafacchina, G, Paoli, A, Pion, D, Roceri, M, Romanello, V, Serrano, AL, Toniolo, L, Larsson, L, Maier, AB, Muñoz-Cánoves, P, Musarò, A, Pende, M, Reggiani, C, Rizzuto, R & Schiaffino, S 2013, 'Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway' Biogerontology, vol. 14, no. 3, pp. 303-23. https://doi.org/10.1007/s10522-013-9432-9

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

In: Biogerontology, Vol. 14, No. 3, 06.2013, p. 303-23.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Signalling pathways regulating muscle mass in ageing skeletal muscle

T2 - the role of the IGF1-Akt-mTOR-FoxO pathway

AU - Sandri, M

AU - Barberi, L

AU - Bijlsma, A Y

AU - Blaauw, B

AU - Dyar, K A

AU - Milan, G

AU - Mammucari, C

AU - Meskers, C G M

AU - Pallafacchina, G

AU - Paoli, A

AU - Pion, D

AU - Roceri, M

AU - Romanello, V

AU - Serrano, A L

AU - Toniolo, L

AU - Larsson, L

AU - Maier, A B

AU - Muñoz-Cánoves, P

AU - Musarò, A

AU - Pende, M

AU - Reggiani, C

AU - Rizzuto, R

AU - Schiaffino, S

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Aging/physiology

KW - Animals

KW - Autophagy-Related Protein 7

KW - Female

KW - Forkhead Box Protein O1

KW - Forkhead Transcription Factors/physiology

KW - Humans

KW - Insulin-Like Growth Factor I/physiology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred DBA

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Microtubule-Associated Proteins/genetics

KW - Models, Animal

KW - Muscle Proteins/genetics

KW - Muscle, Skeletal/physiology

KW - Proto-Oncogene Proteins c-akt/physiology

KW - SKP Cullin F-Box Protein Ligases/genetics

KW - Sarcopenia/physiopathology

KW - Serpin E2/genetics

KW - Signal Transduction/physiology

KW - TOR Serine-Threonine Kinases/physiology

KW - Tripartite Motif Proteins

KW - Ubiquitin-Protein Ligases/genetics

KW - Young Adult

U2 - 10.1007/s10522-013-9432-9

DO - 10.1007/s10522-013-9432-9

M3 - Article

VL - 14

SP - 303

EP - 323

JO - Biogerontology

JF - Biogerontology

SN - 1389-5729

IS - 3

ER -