Abstract

Limb-girdle muscular dystrophy type 2B (LGMD2B) is caused by mutations in the dysferlin gene, resulting in non-functional dysferlin, a key protein found in muscle membrane. Treatment options available for patients are chiefly palliative in nature and focus on maintaining ambulation. Our hypothesis is that galectin-1 (Gal-1), a soluble carbohydrate binding protein, increases membrane repair capacity and myogenic potential of dysferlin-deficient muscle cells and muscle fibers. To test this hypothesis, we used recombinant human galectin-1 (rHsGal-1) to treat dysferlin-deficient models. We show that rHsGal-1 treatments of 48 h-72 h promotes myogenic maturation as indicated through improvements in size, myotube alignment, myoblast migration, and membrane repair capacity in dysferlin-deficient myotubes and myofibers. Furthermore, increased membrane repair capacity of dysferlin-deficient myotubes, independent of increased myogenic maturation is apparent and co-localizes on the membrane of myotubes after a brief 10min treatment with labeled rHsGal-1. We show the carbohydrate recognition domain of Gal-1 is necessary for observed membrane repair. Improvements in membrane repair after only a 10 min rHsGal-1treatment suggest mechanical stabilization of the membrane due to interaction with glycosylated membrane bound, ECM or yet to be identified ligands through the CDR domain of Gal-1. rHsGal-1 shows calcium-independent membrane repair in dysferlin-deficient and wild-type myotubes and myofibers. Together our novel results reveal Gal-1 mediates disease pathologies through both changes in integral myogenic protein expression and mechanical membrane stabilization.

Highlights

  • Limb-girdle muscular dystrophy 2B (LGMD2B) belongs to a family of muscular dystrophies called dysferlinopathies

  • We explore the effects of rHsGal-1 treatment in A/J dysferlin-deficient (A/J-/-) cells and exvivo muscle assessment using Dysf-/- (B6.129.Dysftm1Kcam/J), Bla/J (B6.A-Dysfprmd/GeneJ), and BL/6 (C57BL/6) mice

  • Our results showed no significant differences in membrane repair between non-treated A/J-/- and WT myotubes treated with EGTA

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Summary

Introduction

Limb-girdle muscular dystrophy 2B (LGMD2B) belongs to a family of muscular dystrophies called dysferlinopathies. Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models proteomic data that support the findings of this study are openly available in MassIVE Repository Statistic at ftp://massive.ucsd.edu/ MSV000085835/

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