Background: 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. Galectin-1 (Gal-1) is a galactoside-binding protein capable of stabilizing the sarcolemma by increasing levels of ECM proteins. Gal-1 has been proven to improve muscle repair capacity in Duchenne muscular dystrophy (DMD) models resulting in healthier muscle fibers.
Objective: We hypothesize that galectin-1 will increase membrane repair capacity, myogenic potential, and decrease inflammation in LGMD2B models. To test this hypothesis, we used recombinant human galectin-1 (rHsGal-1) to treat dysferlin-deficient models.
Results: We found that rHsGal-1 treatment for a 48-72h period promotes myogenic maturation with enhanced size, myotube alignment, and membrane repair capacity in both dysferlin-deficient myotubes and myofibers. In vitro, explant myofiber and multiple in vivo rHsGal-1 treatment studies show an increased membrane repair capacity in LGMD2B models. Improvements in membrane repair after only a 10min rHsGal-1 in vitro treatment suggests mechanical stabilization of membrane due to interaction with glycosylated membrane bound, ECM or yet to be identified ligands through the CRD domain of Gal-1. rHsGal-l significantly reduces inflammation through the canonical NF-κB pathway. A one-week treatment with Gal-1 in dysferlin-null mice resulted in decreased inflammatory macrophages (M1) and an increase in anti-inflammatory macrophages (M2). After a one-month treatment with Gal-1, M1 macrophages remained reduced, although the M2 population also returned to saline-treated levels. The levels of p50 and p65 in muscles were also reduced during the one- month treatment.
Conclusions: Together our novel results reveal Gal-1 remediates disease pathologies in LGMD2B through changes in integral myogenic protein expression, mechanical membrane stabilization, immune modulation, and reducing canonical NF-κB inflammation.