Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models

PLoS One. 2020 Sep 3;15(9):e0238441. doi: 10.1371/journal.pone.0238441. eCollection 2020.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Dysferlin / genetics*
  • Dysferlin / metabolism
  • Galectin 1 / metabolism
  • Galectin 1 / pharmacology*
  • Male
  • Membrane Proteins / metabolism
  • Membranes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Development / genetics
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophies, Limb-Girdle / metabolism
  • Muscular Dystrophies, Limb-Girdle / therapy*
  • Myofibrils / metabolism

Substances

  • Dysferlin
  • Galectin 1
  • Membrane Proteins
  • Muscle Proteins

Supplementary concepts

  • Limb-girdle muscular dystrophy, type 2B

Grants and funding

This study was supported by the following Brigham Young University awards: Roland K. Robbins Research Fellowship to MLVZ and Earl M. Woolley Research Innovation Award to PMVR. The authors also thank the Jain Foundation for their funding and support to PMVR.