Modulation of Protein Quality Control and Proteasome to Autophagy Switch in Immortalized Myoblasts from Duchenne Muscular Dystrophy Patients

Int J Mol Sci. 2018 Jan 7;19(1):178. doi: 10.3390/ijms19010178.


The maintenance of proteome integrity is of primary importance in post-mitotic tissues such as muscle cells; thus, protein quality control mechanisms must be carefully regulated to ensure their optimal efficiency, a failure of these processes being associated with various muscular disorders. Duchenne muscular dystrophy (DMD) is one of the most common and severe forms of muscular dystrophies and is caused by mutations in the dystrophin gene. Protein quality control modulations have been diversely observed in degenerating muscles of patients suffering from DMD or in animal models of the disease. In this study, we investigated whether modulations of protein quality control mechanisms already pre-exist in undifferentiated myoblasts originating from DMD patients. We report for the first time that the absence of dystrophin in human myoblasts is associated with protein aggregation stress characterized by an increase of protein aggregates. This stress is combined with BAG1 to BAG3 switch, NFκB activation and up-regulation of BAG3/HSPB8 complexes that ensure preferential routing of misfolded/aggregated proteins to autophagy rather than to deficient 26S proteasome. In this context, restoration of pre-existing alterations of protein quality control processes might represent an alternative strategy for DMD therapies.

Keywords: BAG3; DMD; HSPB8; NFκB; autophagy; chaperones; muscle; proteasome; protein aggregation; protein quality control.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Humans
  • Muscular Dystrophy, Duchenne / metabolism*
  • Myoblasts / metabolism*
  • Myoblasts / pathology
  • NF-kappa B / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Transcription Factors / metabolism
  • Unfolded Protein Response*


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BAG3 protein, human
  • BCL2-associated athanogene 1 protein
  • DNA-Binding Proteins
  • NF-kappa B
  • Transcription Factors
  • Proteasome Endopeptidase Complex