5 These conditions are caused by mutations in the gene encoding dysferlin, a transmembrane protein consisting of seven C2 domains, three Fer domains, and two DysF domains. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.ĭysferlinopathies are a group of progressive, recessively inherited muscular dystrophies that include Miyoshi myopathy, 1, 2 limb-girdle muscular dystrophy (LGMD) type 2B, 3, 4 and distal anterior compartment myopathy.
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Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca 2+, and the rate of accumulation was regulated by dysferlin. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies.
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