Galectin-1 therapy recalibrates lipid remodeling in skeletal muscle and enhances muscle function in a model of LGMD2B/R2

Abstract

Limb-Girdle Muscular Dystrophy type 2B/R2 (LGMD2B/R2) is a progressive myopathy caused by mutations in the DYSF gene, leading to dysferlin deficiency, impaired membrane repair, chronic inflammation, and lipid accumulation. No approved treatments currently exist. Galectin-1, a redox-sensitive lectin with reparative and immunomodulatory properties, has shown therapeutic potential in short-term models of muscular dystrophies. We evaluated the long-term efficacy of recombinant human Galectin-1 (rHsGal-1) in Bla/J mice, a model of LGMD2B/R2. Mice received weekly rHsGal-1 treatment for six months. Functional, histological, and molecular analyses were performed, including mobility assessments, sarcolemmal repair assays, NF-κB activation assays, quantification of fibro-adipogenic progenitors (FAPs), apoptosis and proliferation analyses, lipid infiltration analysis, and targeted lipidomics. Long-term rHsGal-1 therapy preserved mobility, enhanced sarcolemmal repair, and improved muscle architecture, evidenced by increased fiber size and reduced central nucleation. Treatment suppressed NF-κB activation, reduced FAP abundance, increased apoptotic FAPs without detectable changes in proliferating Ki67 + FAPs, and decreased lipid infiltration. Lipidomic profiling revealed treatment-associated lipid remodeling characterized by reduced neutral lipid accumulation, altered sphingolipid and phospholipid signatures, and selective changes in inflammatory lipid classes. These lipid changes were associated with histological and functional improvements. Long-term rHsGal-1 therapy provides durable, multifaceted benefits in LGMD2B/R2, improving muscle structure, membrane repair, and lipid remodeling while reducing fibro-adipogenic remodeling and lipid accumulation. The identification of increased apoptotic FAPs together with reduced FAP abundance suggests a potential mechanism contributing to these therapeutic effects. These findings support the continued development of Gal-1 as a therapeutic strategy for LGMD2B/R2 and other dysferlinopathies.