Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B

• Published in: Molecular therapy Vol. 25; no. 10; pp. 2360 - 2371
• Main Authors: Gushchina, Liubov V., Bhattacharya, Sayak, McElhanon, Kevin E., Choi, Jin Hyuk, Manring, Heather, Beck, Eric X, Alloush, Jenna, Weisleder, Noah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.10.2017; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Animals; Calcium; Carrier Proteins - therapeutic use; cell repair; cell wounding; Disease Models, Animal; Dysferlin - deficiency; Dysferlin - genetics; endocytosis; Endocytosis - drug effects; exocytosis; Exocytosis - drug effects; Humans; Immunoglobulin G; Lasers; Male; Membrane proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscular Dystrophies, Limb-Girdle - drug therapy; Muscular Dystrophies, Limb-Girdle - metabolism; Muscular dystrophy; Musculoskeletal system; Mutation; myoshi myopathy; Original; Pathology; Plasma; protein therapy; Proteins; Recombinant Proteins - therapeutic use; Rodents; sarcolemma; Sarcolemma - drug effects; Sarcolemma - metabolism; Skeletal muscle; Software; Studies; TRIM72; tripartite motif; Wounding; Ohio; TRIM72; calcium; cell wounding; cell repair; myoshi myopathy; endocytosis; exocytosis; protein therapy; sarcolemma; tripartite motif
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2017.06.025

Limb girdle muscular dystrophy type 2B (LGMD2B) and other dysferlinopathies are degenerative muscle diseases that result from mutations in the dysferlin gene and have limited treatment options. The dysferlin protein has been linked to multiple cellular functions including a Ca2+-dependent membrane repair process that reseals disruptions in the sarcolemmal membrane. Recombinant human MG53 protein (rhMG53) can increase the membrane repair process in multiple cell types both in vitro and in vivo. Here, we tested whether rhMG53 protein can improve membrane repair in a dysferlin-deficient mouse model of LGMD2B (B6.129-Dysftm1Kcam/J). We found that rhMG53 can increase the integrity of the sarcolemmal membrane of isolated muscle fibers and whole muscles in a Ca2+-independent fashion when assayed by a multi-photon laser wounding assay. Intraperitoneal injection of rhMG53 into mice before acute eccentric treadmill exercise can decrease the release of intracellular enzymes from skeletal muscle and decrease the entry of immunoglobulin G and Evans blue dye into muscle fibers in vivo. These results indicate that short-term rhMG53 treatment can ameliorate one of the underlying defects in dysferlin-deficient muscle by increasing sarcolemmal membrane integrity. We also provide evidence that rhMG53 protein increases membrane integrity independently of the canonical dysferlin-mediated, Ca2+-dependent pathway known to be important for sarcolemmal membrane repair. Gushchina et al. test whether increasing the integrity of muscle cell membranes by applying recombinant MG53 to target the membrane repair process can improve the pathology in a mouse model of muscular dystrophy. They show that this protein improved membrane integrity and decreased biomarker levels following muscle injury.