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Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B
- Source :
- Molecular Therapy. 25:2360-2371
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- 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.
- Subjects :
- Male
0301 basic medicine
Endocytosis
Exocytosis
Tripartite Motif Proteins
Dysferlin
Mice
03 medical and health sciences
chemistry.chemical_compound
Sarcolemma
Drug Discovery
Genetics
medicine
Animals
Humans
Muscle, Skeletal
Molecular Biology
Evans Blue
Mice, Knockout
Pharmacology
biology
Skeletal muscle
medicine.disease
Recombinant Proteins
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Muscular Dystrophies, Limb-Girdle
Biochemistry
chemistry
biology.protein
Molecular Medicine
Original Article
Carrier Proteins
Intracellular
Limb-girdle muscular dystrophy
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....70f7a6b5f4b940165ddd381d56a1f460