Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP
Skeletal muscle wasting results from numerous pathological conditions affecting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role of E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss-of-function models combined with in vivo cell biology and proteomic approaches, we reveal a role of atrogin-1 in regulating the levels of the endoplasmic reticulum chaperone BiP. Loss of atrogin-1 resulted in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fiber integrity. We further implicated a disruption in atrogin-1-mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We revealed that BiP was not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorated pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicate atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy and highlight atrogin-1's essential role in maintaining muscle homeostasis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
JCI insight - 9(2024), 8 vom: 26. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ruparelia, Avnika A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.04.2024 Date Revised 24.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.167578 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM37019912X |
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| 245 | 1 | 0 | |a Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Skeletal muscle wasting results from numerous pathological conditions affecting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role of E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss-of-function models combined with in vivo cell biology and proteomic approaches, we reveal a role of atrogin-1 in regulating the levels of the endoplasmic reticulum chaperone BiP. Loss of atrogin-1 resulted in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fiber integrity. We further implicated a disruption in atrogin-1-mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We revealed that BiP was not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorated pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicate atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy and highlight atrogin-1's essential role in maintaining muscle homeostasis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Genetic diseases | |
| 650 | 4 | |a Muscle | |
| 650 | 4 | |a Muscle biology | |
| 650 | 4 | |a Ubiquitin-proteosome system | |
| 650 | 7 | |a SKP Cullin F-Box Protein Ligases |2 NLM | |
| 650 | 7 | |a EC 2.3.2.27 |2 NLM | |
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| 700 | 1 | |a Montandon, Margo |e verfasserin |4 aut | |
| 700 | 1 | |a Merriner, Jo |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Siew Fen Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Sonntag, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Hardee, Justin P |e verfasserin |4 aut | |
| 700 | 1 | |a Lynch, Gordon S |e verfasserin |4 aut | |
| 700 | 1 | |a Miles, Lee B |e verfasserin |4 aut | |
| 700 | 1 | |a Siegel, Ashley |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Thomas E |e verfasserin |4 aut | |
| 700 | 1 | |a Schittenhelm, Ralf B |e verfasserin |4 aut | |
| 700 | 1 | |a Currie, Peter D |e verfasserin |4 aut | |
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