Abstract
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.
Highlights
The maintenance of proteome integrity is of great importance for cell viability
Chaperones are associated with co-chaperones and form a dynamic network that can adapt to the environment, as for example, when refolding is not possible the association of BAG1 or BAG3 co-chaperones to HspA1/A8 can redirect misfolded/aggregated proteins to degradation mechanisms; the proteasome for the former and the autophagy for the latter [6]
W1 and W2 cell lines were obtained from biopsies of healthy donors whereas D1 to D4 cell lines were derived from muscle biopsies of Duchenne muscular dystrophy (DMD) patients
Summary
The maintenance of proteome integrity is of great importance for cell viability. proteins must fold into specific three-dimensional structures to acquire their functional native states, which is in precarious equilibrium. We detected modulations of molecular chaperone levels, notably HSPB5 and HSPB8, a decreased activity of the 26S proteasome and a BAG1 to BAG3 molecular switch These modulations of PQC processes were associated with an up-regulation of NFκB transcription factor activity, increased levels of autophagy actors (ATG3, LC3-II, HDAC6) and stimulation of the autophagic flux, but partial deficiency of autophagy maturation steps along with down-regulation of proteasome activity.
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