Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia

Joanna Brzeszczyńska, Angelika Meyer, Robin McGregor, Alain Schilb, Simone Degen, Valentina Tadini, Neil Johns, Ramon Langen, Annemie Schols, David J. Glass, Ronenn Roubenoff, James A. Ross, Kenneth C.H. Fearon, Carolyn A. Greig, Carsten Jacobi

Research output: Contribution to journalArticle

Abstract

BackgroundSarcopenia is defined as the age‐related loss of skeletal muscle mass and function. While all humans lose muscle with age, 2–5% of elderly adults develop functional consequences (disabilities). The aim of this study was to investigate muscle myogenesis in healthy elderly adults, with or without sarcopenia, compared with middle‐aged controls using both in vivo and in vitro approaches to explore potential biomarker or causative molecular pathways associated with sarcopenic versus non‐sarcopenic skeletal muscle phenotypes during ageing.
MethodsBiomarkers of multiple molecular pathways associated with muscle regeneration were analysed using quantitative polymerase chain reaction in quadriceps muscle samples obtained from healthy elderly sarcopenic (HSE, n = 7) or non‐sarcopenic (HENS, n = 21) and healthy middle‐aged control (HMC, n = 22) groups. An in vitro system of myogenesis (using myoblasts from human donors aged 17–83 years) was used to mimic the environmental challenges of muscle regeneration over time.
ResultsThe muscle biopsies showed evidence of satellite cell activation in HENS (Pax3, P < 0.01, Pax7, P < 0.0001) compared with HMC. Early myogenesis markers Myogenic Differentiation 1 (MyoD1) and Myogenic factor 5 (Myf5) (P < 0.0001) and the late myogenesis marker myogenin (MyoG) (P < 0.01) were increased in HENS. In addition, there was a 30‐fold upregulation of TNF‐α in HENS compared with HMC (P < 0.0001). The in vitro system demonstrated age‐related upregulation of pro‐inflammatory cytokines (2‐fold upregulation of interleukin (IL)‐6, IL‐8 mRNA, increased secretion of tumor necrosis factor‐α (TNF‐α) and IL‐6, all P < 0.05) associated with impaired kinetics of myotube differentiation.The HSE biopsy samples showed satellite cell activation (Pax7, P < 0.05) compared with HMC. However, no significant upregulation of the early myogenesis (MyoD and Myf5) markers was evident; only the late myogenesis marker myogenin was upregulated (P < 0.05).Higher activation of the oxidative stress pathway was found in HENS compared with the HSE group. In contrast, there was 10‐fold higher upregulation of HSPA1A a stress‐induced chaperone acting upon misfolded proteins in HSE compared with the HENS group.
ConclusionsBoth pathological and adaptive processes are active in skeletal muscle during healthy ageing. Muscle regeneration pathways are activated during healthy ageing, but there is evidence of dysregulation in sarcopenia. In addition, increased cellular stress, with an impaired oxidative‐stress and mis‐folded protein response (HSPA1A), may be associated with the development of sarcopenia. The in vitro system of young and old myoblasts replicated some of the differences between young and old muscle.
Original languageEnglish
Pages (from-to)93-105
Number of pages13
JournalJournal of Cachexia, Sarcopenia and Muscle
Volume9
Issue number1
Early online date6 Dec 2017
DOIs
Publication statusE-pub ahead of print - 6 Dec 2017
Externally publishedYes

Fingerprint

Sarcopenia
Muscle Development
Regeneration
Muscles
Up-Regulation
Myogenic Regulatory Factor 5
Myogenin
Skeletal Muscle
Myoblasts
Interleukin-6
MyoD Protein
Tumor Necrosis Factor-alpha
Biopsy
Differentiation Antigens
Skeletal Muscle Fibers
Quadriceps Muscle
Pathologic Processes
In Vitro Techniques
Interleukin-8
Proteins

Keywords

  • Ageing
  • Satellite cells
  • Sarcopenia
  • Muscle regeneration
  • Cellular stress

Cite this

Brzeszczyńska, Joanna ; Meyer, Angelika ; McGregor, Robin ; Schilb, Alain ; Degen, Simone ; Tadini, Valentina ; Johns, Neil ; Langen, Ramon ; Schols, Annemie ; Glass, David J. ; Roubenoff, Ronenn ; Ross, James A. ; Fearon, Kenneth C.H. ; Greig, Carolyn A. ; Jacobi, Carsten. / Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia. In: Journal of Cachexia, Sarcopenia and Muscle. 2017 ; Vol. 9, No. 1. pp. 93-105.
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abstract = "BackgroundSarcopenia is defined as the age‐related loss of skeletal muscle mass and function. While all humans lose muscle with age, 2–5{\%} of elderly adults develop functional consequences (disabilities). The aim of this study was to investigate muscle myogenesis in healthy elderly adults, with or without sarcopenia, compared with middle‐aged controls using both in vivo and in vitro approaches to explore potential biomarker or causative molecular pathways associated with sarcopenic versus non‐sarcopenic skeletal muscle phenotypes during ageing.MethodsBiomarkers of multiple molecular pathways associated with muscle regeneration were analysed using quantitative polymerase chain reaction in quadriceps muscle samples obtained from healthy elderly sarcopenic (HSE, n = 7) or non‐sarcopenic (HENS, n = 21) and healthy middle‐aged control (HMC, n = 22) groups. An in vitro system of myogenesis (using myoblasts from human donors aged 17–83 years) was used to mimic the environmental challenges of muscle regeneration over time.ResultsThe muscle biopsies showed evidence of satellite cell activation in HENS (Pax3, P < 0.01, Pax7, P < 0.0001) compared with HMC. Early myogenesis markers Myogenic Differentiation 1 (MyoD1) and Myogenic factor 5 (Myf5) (P < 0.0001) and the late myogenesis marker myogenin (MyoG) (P < 0.01) were increased in HENS. In addition, there was a 30‐fold upregulation of TNF‐α in HENS compared with HMC (P < 0.0001). The in vitro system demonstrated age‐related upregulation of pro‐inflammatory cytokines (2‐fold upregulation of interleukin (IL)‐6, IL‐8 mRNA, increased secretion of tumor necrosis factor‐α (TNF‐α) and IL‐6, all P < 0.05) associated with impaired kinetics of myotube differentiation.The HSE biopsy samples showed satellite cell activation (Pax7, P < 0.05) compared with HMC. However, no significant upregulation of the early myogenesis (MyoD and Myf5) markers was evident; only the late myogenesis marker myogenin was upregulated (P < 0.05).Higher activation of the oxidative stress pathway was found in HENS compared with the HSE group. In contrast, there was 10‐fold higher upregulation of HSPA1A a stress‐induced chaperone acting upon misfolded proteins in HSE compared with the HENS group.ConclusionsBoth pathological and adaptive processes are active in skeletal muscle during healthy ageing. Muscle regeneration pathways are activated during healthy ageing, but there is evidence of dysregulation in sarcopenia. In addition, increased cellular stress, with an impaired oxidative‐stress and mis‐folded protein response (HSPA1A), may be associated with the development of sarcopenia. The in vitro system of young and old myoblasts replicated some of the differences between young and old muscle.",
keywords = "Ageing, Satellite cells, Sarcopenia, Muscle regeneration, Cellular stress",
author = "Joanna Brzeszczyńska and Angelika Meyer and Robin McGregor and Alain Schilb and Simone Degen and Valentina Tadini and Neil Johns and Ramon Langen and Annemie Schols and Glass, {David J.} and Ronenn Roubenoff and Ross, {James A.} and Fearon, {Kenneth C.H.} and Greig, {Carolyn A.} and Carsten Jacobi",
year = "2017",
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pages = "93--105",
journal = "Journal of Cachexia, Sarcopenia and Muscle",
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Brzeszczyńska, J, Meyer, A, McGregor, R, Schilb, A, Degen, S, Tadini, V, Johns, N, Langen, R, Schols, A, Glass, DJ, Roubenoff, R, Ross, JA, Fearon, KCH, Greig, CA & Jacobi, C 2017, 'Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia' Journal of Cachexia, Sarcopenia and Muscle, vol. 9, no. 1, pp. 93-105. https://doi.org/10.1002/jcsm.12252

Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia. / Brzeszczyńska, Joanna; Meyer, Angelika; McGregor, Robin; Schilb, Alain; Degen, Simone; Tadini, Valentina; Johns, Neil; Langen, Ramon; Schols, Annemie; Glass, David J.; Roubenoff, Ronenn; Ross, James A.; Fearon, Kenneth C.H.; Greig, Carolyn A.; Jacobi, Carsten.

In: Journal of Cachexia, Sarcopenia and Muscle, Vol. 9, No. 1, 06.12.2017, p. 93-105.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia

AU - Brzeszczyńska, Joanna

AU - Meyer, Angelika

AU - McGregor, Robin

AU - Schilb, Alain

AU - Degen, Simone

AU - Tadini, Valentina

AU - Johns, Neil

AU - Langen, Ramon

AU - Schols, Annemie

AU - Glass, David J.

AU - Roubenoff, Ronenn

AU - Ross, James A.

AU - Fearon, Kenneth C.H.

AU - Greig, Carolyn A.

AU - Jacobi, Carsten

PY - 2017/12/6

Y1 - 2017/12/6

N2 - BackgroundSarcopenia is defined as the age‐related loss of skeletal muscle mass and function. While all humans lose muscle with age, 2–5% of elderly adults develop functional consequences (disabilities). The aim of this study was to investigate muscle myogenesis in healthy elderly adults, with or without sarcopenia, compared with middle‐aged controls using both in vivo and in vitro approaches to explore potential biomarker or causative molecular pathways associated with sarcopenic versus non‐sarcopenic skeletal muscle phenotypes during ageing.MethodsBiomarkers of multiple molecular pathways associated with muscle regeneration were analysed using quantitative polymerase chain reaction in quadriceps muscle samples obtained from healthy elderly sarcopenic (HSE, n = 7) or non‐sarcopenic (HENS, n = 21) and healthy middle‐aged control (HMC, n = 22) groups. An in vitro system of myogenesis (using myoblasts from human donors aged 17–83 years) was used to mimic the environmental challenges of muscle regeneration over time.ResultsThe muscle biopsies showed evidence of satellite cell activation in HENS (Pax3, P < 0.01, Pax7, P < 0.0001) compared with HMC. Early myogenesis markers Myogenic Differentiation 1 (MyoD1) and Myogenic factor 5 (Myf5) (P < 0.0001) and the late myogenesis marker myogenin (MyoG) (P < 0.01) were increased in HENS. In addition, there was a 30‐fold upregulation of TNF‐α in HENS compared with HMC (P < 0.0001). The in vitro system demonstrated age‐related upregulation of pro‐inflammatory cytokines (2‐fold upregulation of interleukin (IL)‐6, IL‐8 mRNA, increased secretion of tumor necrosis factor‐α (TNF‐α) and IL‐6, all P < 0.05) associated with impaired kinetics of myotube differentiation.The HSE biopsy samples showed satellite cell activation (Pax7, P < 0.05) compared with HMC. However, no significant upregulation of the early myogenesis (MyoD and Myf5) markers was evident; only the late myogenesis marker myogenin was upregulated (P < 0.05).Higher activation of the oxidative stress pathway was found in HENS compared with the HSE group. In contrast, there was 10‐fold higher upregulation of HSPA1A a stress‐induced chaperone acting upon misfolded proteins in HSE compared with the HENS group.ConclusionsBoth pathological and adaptive processes are active in skeletal muscle during healthy ageing. Muscle regeneration pathways are activated during healthy ageing, but there is evidence of dysregulation in sarcopenia. In addition, increased cellular stress, with an impaired oxidative‐stress and mis‐folded protein response (HSPA1A), may be associated with the development of sarcopenia. The in vitro system of young and old myoblasts replicated some of the differences between young and old muscle.

AB - BackgroundSarcopenia is defined as the age‐related loss of skeletal muscle mass and function. While all humans lose muscle with age, 2–5% of elderly adults develop functional consequences (disabilities). The aim of this study was to investigate muscle myogenesis in healthy elderly adults, with or without sarcopenia, compared with middle‐aged controls using both in vivo and in vitro approaches to explore potential biomarker or causative molecular pathways associated with sarcopenic versus non‐sarcopenic skeletal muscle phenotypes during ageing.MethodsBiomarkers of multiple molecular pathways associated with muscle regeneration were analysed using quantitative polymerase chain reaction in quadriceps muscle samples obtained from healthy elderly sarcopenic (HSE, n = 7) or non‐sarcopenic (HENS, n = 21) and healthy middle‐aged control (HMC, n = 22) groups. An in vitro system of myogenesis (using myoblasts from human donors aged 17–83 years) was used to mimic the environmental challenges of muscle regeneration over time.ResultsThe muscle biopsies showed evidence of satellite cell activation in HENS (Pax3, P < 0.01, Pax7, P < 0.0001) compared with HMC. Early myogenesis markers Myogenic Differentiation 1 (MyoD1) and Myogenic factor 5 (Myf5) (P < 0.0001) and the late myogenesis marker myogenin (MyoG) (P < 0.01) were increased in HENS. In addition, there was a 30‐fold upregulation of TNF‐α in HENS compared with HMC (P < 0.0001). The in vitro system demonstrated age‐related upregulation of pro‐inflammatory cytokines (2‐fold upregulation of interleukin (IL)‐6, IL‐8 mRNA, increased secretion of tumor necrosis factor‐α (TNF‐α) and IL‐6, all P < 0.05) associated with impaired kinetics of myotube differentiation.The HSE biopsy samples showed satellite cell activation (Pax7, P < 0.05) compared with HMC. However, no significant upregulation of the early myogenesis (MyoD and Myf5) markers was evident; only the late myogenesis marker myogenin was upregulated (P < 0.05).Higher activation of the oxidative stress pathway was found in HENS compared with the HSE group. In contrast, there was 10‐fold higher upregulation of HSPA1A a stress‐induced chaperone acting upon misfolded proteins in HSE compared with the HENS group.ConclusionsBoth pathological and adaptive processes are active in skeletal muscle during healthy ageing. Muscle regeneration pathways are activated during healthy ageing, but there is evidence of dysregulation in sarcopenia. In addition, increased cellular stress, with an impaired oxidative‐stress and mis‐folded protein response (HSPA1A), may be associated with the development of sarcopenia. The in vitro system of young and old myoblasts replicated some of the differences between young and old muscle.

KW - Ageing

KW - Satellite cells

KW - Sarcopenia

KW - Muscle regeneration

KW - Cellular stress

U2 - 10.1002/jcsm.12252

DO - 10.1002/jcsm.12252

M3 - Article

VL - 9

SP - 93

EP - 105

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

SN - 2190-5991

IS - 1

ER -