Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies

Summary

Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (α-DG). Mutations in FKRP are associated with muscular dystrophies (MD) ranging from limb-girdle LGMDR9 to Walker-Warburg Syndrome (WWS), a severe type of congenital MD. Although hypoglycosylation of α-DG is the main hallmark of this group of diseases, a full understanding of the underlying pathophysiology is still missing. Here, we investigated molecular mechanisms impaired by FKRP mutations in pluripotent stem (PS) cell–derived myotubes. FKRP-deficient myotubes show transcriptome alterations in genes involved in extracellular matrix receptor interactions, calcium signaling, PI3K-Akt pathway, and lysosomal function. Accordingly, using a panel of patient-specific LGMDR9 and WWS induced PS cell–derived myotubes, we found a significant reduction in the autophagy-lysosome pathway for both disease phenotypes. In addition, we show that WWS myotubes display decreased ERK1/2 activity and increased apoptosis, which were restored in gene edited myotubes. Our results suggest the autophagy-lysosome pathway and apoptosis may contribute to the FKRP-associated MD pathogenesis.

Graphical abstract

Highlights

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  The lysosome pathway is deregulated in FKRP-deficient myotubes

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  Autophagy is decreased in patient-specific LGMDR9 and WWS iPS cell–derived myotubes

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  FKRP WWS and LGMDR9 iPS cell–derived myotubes have increased apoptosis

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  FKRP correction in WWS myotubes rescues changes in autophagy and apoptosis

Abstract

In this article, Perlingeiro and colleagues show that FKRP-deficient myotubes display transcriptome alterations in genes involved in extracellular matrix receptor interactions and lysosomal function. Using a panel of patient-specific LGMDR9 and WWS iPS cell–derived myotubes, they show a significant reduction in the autophagy-lysosome pathway and an increase in apoptosis, suggesting that these processes may contribute to the FKRP-associated MD pathogenesis.