title: FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway.
abstract: Limb-girdle muscular dystrophy type 2A (LGMD2A) is characterised by muscle wasting and progressive degeneration of proximal muscles because of mutations in the CAPN3 gene. However, the underlying pathophysiological mechanisms of muscle degeneration are still not well understood. The objective of this study was to assess the relevance of genes with differential expression in the muscle of LGMD2A patients. For this purpose, we analysed their in vitro expression in primary cultures of human myoblasts and myotubes. Abnormal fusion was observed in the myotubes of these patients, which may be explained by the lack of physiological replacement of integrin β1D. Owing to this observation, we focused on deregulated genes coding proteins that directly interact with integrin, ITGB1BP2 and CD9, as well as FRZB gene, because of its in vitro upregulation in myotubes. Silencing studies established that these genes are closely regulated, CD9 and FRZB being positive regulators of the expression of ITGB1BP2, and in turn, this gene being a negative regulator of the expression of FRZB. Interestingly, we observed that FRZB regulates integrin β1D expression, its silencing increasing integrin β1D expression to levels similar to those in controls. Finally, the administration of LiCl, an enhancer of the Wnt-signalling pathway showed similar experimentally beneficial effects, suggesting FRZB silencing or LiCl administration as potential therapeutic targets, though further studies are required.
authors.affiliation: Centre of Human and Aerospace Physiological Sciences,King's College London,London,UK.
authors.forename: Oihane
authors.initials: O
authors.lastname: Jaka
authors.affiliation: Neurosciences Area,Biodonostia Health Research Institute,San Sebastián,Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Casas-Fraile
authors.affiliation: Neurosciences Area,Biodonostia Health Research Institute,San Sebastián,Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Azpitarte
authors.affiliation: Neurosciences Area,Biodonostia Health Research Institute,San Sebastián,Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aiastui
authors.affiliation: Neurosciences Area,Biodonostia Health Research Institute,San Sebastián,Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.affiliation: Neurosciences Area,Biodonostia Health Research Institute,San Sebastián,Spain.
authors.forename: Amets
authors.initials: A
authors.lastname: Sáenz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D020033:Protein Isoforms; D015398:Signal Transduction / Q000187:drug effects; D060449:Wnt Signaling Pathway; D055815:Young Adult; D000099274:Frizzled-Related Proteins
chemical_list: D015415:Biomarkers; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D018021:Lithium Chloride; D009124:Muscle Proteins; D020033:Protein Isoforms; D000099274:Frizzled-Related Proteins; C492400:ITGB1BP2 protein, human