Activin A induces skeletal muscle catabolism via p38β mitogen-activated protein kinase
© 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders..
BACKGROUND: Activation of type IIB activin receptor (ActRIIB) in skeletal muscle leads to muscle atrophy because of increased muscle protein degradation. However, the intracellular signalling mechanism that mediates ActRIIB-activated muscle catabolism is poorly defined.
METHODS: We investigated the role of p38β mitogen-activated protein kinases (MAPK) in mediating ActRIIB ligand activin A-activated muscle catabolic pathways in C2C12 myotubes and in mice with perturbation of this kinase pharmacologically and genetically.
RESULTS: Treatment of C2C12 myotubes with activin A or myostatin rapidly activated p38 MAPK and its effector C/EBPβ within 1 h. Paradoxically, Akt was activated at the same time through a p38 MAPK-independent mechanism. These events were followed by up-regulation of ubiquitin ligases atrogin1 (MAFbx) and UBR2 (E3α-II), as well as increase in LC3-II, a marker of autophagosome formation, leading to myofibrillar protein loss and myotube atrophy. The catabolic effects of activin A were abolished by p38α/β MAPK inhibitor SB202190. Using small interfering RNA-mediated gene knockdown, we found that the catabolic activity of activin A was dependent on p38β MAPK specifically. Importantly, systemic administration of activin A to mice similarly activated the catabolic pathways in vivo, and this effect was blocked by SB202190. Further, activin A failed to activate the catabolic pathways in mice with muscle-specific knockout of p38β MAPK. Interestingly, activin A up-regulated MuRF1 in a p38 MAPK-independent manner, and MuRF1 did not appear responsible for activin A-induced myosin heavy chain loss and muscle atrophy.
CONCLUSIONS: ActRIIB-mediated activation of muscle catabolism is dependent on p38β MAPK-activated signalling.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Journal of cachexia, sarcopenia and muscle - 8(2017), 2 vom: 10. Apr., Seite 202-212 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ding, Hui [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.02.2018 Date Revised 09.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/jcsm.12145 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM266647030 |
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| 245 | 1 | 0 | |a Activin A induces skeletal muscle catabolism via p38β mitogen-activated protein kinase |
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| 500 | |a Date Revised 09.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders. | ||
| 520 | |a BACKGROUND: Activation of type IIB activin receptor (ActRIIB) in skeletal muscle leads to muscle atrophy because of increased muscle protein degradation. However, the intracellular signalling mechanism that mediates ActRIIB-activated muscle catabolism is poorly defined | ||
| 520 | |a METHODS: We investigated the role of p38β mitogen-activated protein kinases (MAPK) in mediating ActRIIB ligand activin A-activated muscle catabolic pathways in C2C12 myotubes and in mice with perturbation of this kinase pharmacologically and genetically | ||
| 520 | |a RESULTS: Treatment of C2C12 myotubes with activin A or myostatin rapidly activated p38 MAPK and its effector C/EBPβ within 1 h. Paradoxically, Akt was activated at the same time through a p38 MAPK-independent mechanism. These events were followed by up-regulation of ubiquitin ligases atrogin1 (MAFbx) and UBR2 (E3α-II), as well as increase in LC3-II, a marker of autophagosome formation, leading to myofibrillar protein loss and myotube atrophy. The catabolic effects of activin A were abolished by p38α/β MAPK inhibitor SB202190. Using small interfering RNA-mediated gene knockdown, we found that the catabolic activity of activin A was dependent on p38β MAPK specifically. Importantly, systemic administration of activin A to mice similarly activated the catabolic pathways in vivo, and this effect was blocked by SB202190. Further, activin A failed to activate the catabolic pathways in mice with muscle-specific knockout of p38β MAPK. Interestingly, activin A up-regulated MuRF1 in a p38 MAPK-independent manner, and MuRF1 did not appear responsible for activin A-induced myosin heavy chain loss and muscle atrophy | ||
| 520 | |a CONCLUSIONS: ActRIIB-mediated activation of muscle catabolism is dependent on p38β MAPK-activated signalling | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ActRIIB | |
| 650 | 4 | |a Activin A | |
| 650 | 4 | |a Cachexia | |
| 650 | 4 | |a Muscle wasting | |
| 650 | 4 | |a Myostatin | |
| 650 | 4 | |a p38β MAPK | |
| 650 | 7 | |a CCAAT-Enhancer-Binding Protein-beta |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a activin A |2 NLM | |
| 650 | 7 | |a Activins |2 NLM | |
| 650 | 7 | |a 104625-48-1 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase 11 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Activin Receptors, Type II |2 NLM | |
| 650 | 7 | |a EC 2.7.11.30 |2 NLM | |
| 650 | 7 | |a activin receptor type II-B |2 NLM | |
| 650 | 7 | |a EC 2.7.11.30 |2 NLM | |
| 700 | 1 | |a Zhang, Guohua |e verfasserin |4 aut | |
| 700 | 1 | |a Sin, Ka Wai Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhelong |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Ren-Kuo |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yi-Ping |e verfasserin |4 aut | |
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