PUBLICATION

Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP

Authors
Ruparelia, A.A., Montandon, M., Merriner, J., Huang, C., Wong, S.F.L., Sonntag, C., Hardee, J.P., Lynch, G.S., Miles, L.B., Siegel, A., Hall, T.E., Schittenhelm, R.B., Currie, P.D.
ID
ZDB-PUB-240327-1
Date
2024
Source
JCI insight   9(8): (Journal)
Registered Authors
Currie, Peter D., Hall, Thomas, Merriner, Jo, Miles, Lee, Montandon, Margo, Ruparelia, Avnika, Siegel, Ashley, Sonntag, Carmen
Keywords
Genetic diseases, Muscle, Muscle biology, Ubiquitin-proteosome system
MeSH Terms
  • Heat-Shock Proteins/genetics
  • Heat-Shock Proteins/metabolism
  • Muscle Proteins*/genetics
  • Muscle Proteins*/metabolism
  • Animals
  • Mitochondrial Dynamics
  • Disease Models, Animal*
  • Endoplasmic Reticulum Chaperone BiP*/metabolism
  • Muscular Dystrophy, Duchenne*/genetics
  • Muscular Dystrophy, Duchenne*/metabolism
  • Muscular Dystrophy, Duchenne*/pathology
  • SKP Cullin F-Box Protein Ligases*/genetics
  • SKP Cullin F-Box Protein Ligases*/metabolism
  • Endoplasmic Reticulum/metabolism
  • Muscle, Skeletal*/metabolism
  • Muscle, Skeletal*/pathology
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Humans
  • Zebrafish*
  • Homeostasis*
(all 21)
PubMed
38530354 Full text @ JCI Insight
Abstract
Skeletal muscle wasting results from numerous pathological conditions impacting 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 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 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne muscular dystrophy. We reveal that BiP is not only upregulated in Duchenne muscular dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne muscular dystrophy. Collectively, our data implicates atrogin-1 and BiP in the pathogenesis of Duchenne muscular dystrophy, and highlights atrogin-1's essential role in maintaining muscle homeostasis.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gl37TgTransgenic Insertion
    pc2
      		Point Mutation
      pc21TgTransgenic Insertion
        pc22TgTransgenic Insertion
          pc57
            		Insertion
            pc58
              		Unknown
              pc59TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                fbxo32CRISPR1-fbxo32CRISPR
                hspa5CRISPR3-hspa5CRISPR
                hspa5CRISPR4-hspa5CRISPR
                1 - 3 of 3
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                Fish
                No data available
                Antibodies
                No data available
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                EGFPEFGEGFP
                KALTA4EFGKALTA4
                mCherryEFGmCherry
                RFPEFGRFP
                1 - 4 of 4
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                Mapping
                No data available
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                Citation
                Ruparelia, A.A., Montandon, M., Merriner, J., Huang, C., Wong, S.F.L., Sonntag, C., Hardee, J.P., Lynch, G.S., Miles, L.B., Siegel, A., Hall, T.E., Schittenhelm, R.B., Currie, P.D. (2024) Atrogin-1 promotes muscle homeostasis by regulating levels of endoplasmic reticulum chaperone BiP. JCI insight. 9(8):.