Abstract
Two of the main pathologies characterizing dysferlinopathies are disrupted muscle membrane repair and chronic inflammation, which lead to symptoms of muscle weakness and wasting. Here, we used recombinant human Galectin-1 (rHsGal-1) as a therapeutic for LGMD2B mouse and human models. Various redox and multimerization states of Gal-1 show that rHsGal-1 is the most effective form in both increasing muscle repair and decreasing inflammation, due to its monomer-dimer equilibrium. Dose-response testing shows an effective 25-fold safety profile between 0.54 and 13.5 mg/kg rHsGal-1 in Bla/J mice. Mice treated weekly with rHsGal-1 showed downregulation of canonical NF-κB inflammation markers, decreased muscle fat deposition, upregulated anti-inflammatory cytokines, increased membrane repair, and increased functional movement compared to non-treated mice. Gal-1 treatment also resulted in a positive self-upregulation loop of increased endogenous Gal-1 expression independent of NF-κB activation. A similar reduction in disease pathologies in patient-derived human cells demonstrates the therapeutic potential of Gal-1 in LGMD2B patients.
Highlights
We demonstrate that the reduced dimeric form of Gal-1 is responsible for inducing improvements to muscle membrane repair, while the monomeric form is responsible for changes in inflammation
Reduced Dimeric Galectin-1 Is Responsible for Optimal Membrane Repair
We designed several synthetic forms of Gal-1 to determine the effect of dimerization and redox states on membrane repair in models of dysferlinopathy (Figure S1)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Dysferlin is a 230-kDa protein that is highly expressed in skeletal muscle and involved in membrane repair [1]. Membrane repair is essential for maintaining cell integrity and is crucial for stressed skeletal muscle fibers [2,3,4]. Mutated dysferlin leads to compromised membrane integrity and repair, resulting in the phenotypes associated with Miyoshi
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