title: Evaluation of sarcoglycans, vinculin-talin-integrin system and filamin2 in alpha- and gamma-sarcoglycanopathy: an immunohistochemical study.
abstract: The sarcoglycan subcomplex (SGC) is a well-known system of interaction between extracellular matrix and sarcolemma-associated cytoskeleton in skeletal and cardiac muscle. The SGC is included in the DGC made up of sarcoplasmic subcomplex and a dystroglycan subcomplex. Recent developments in molecular genetics have demonstrated that the mutation of each single sarcoglycan gene, causes a series of recessive autosomal muscular dystrophies, dystrophin-positive, called sarcoglycanopathies or limb girdle muscular dystrophies. Our recent studies have demonstrated that costameres are a proteic machinery made up of DGC and vinculin-talin-integrin system, also revealing the colocalization of sarcoglycans and integrins in adult human skeletal muscle. These results may support the hypothesis of the existence of a bidirectional signalling between sarcoglycans and integrins in cultured L6 myocytes. The hypothesis of bidirectional signalling between sarcoglycans and integrins could be supported by the identification of a skeletal and cardiac muscle filamin2 as a gamma-sarcoglycan, delta-sarcoglycan and, hypothetically, beta1 integrin interacting protein. Our results, acquired with an immunofluorescence study on adult human skeletal muscle affected by LGMD type 2D and 2C, showed that in LGMD2D: a) alpha-sarcoglycan staining is severely reduced; b) the beta-gamma-delta-sarcoglycan subunit and all tested integrins staining are clearly detectable; c) filamin2 is normal and shows a costameric distribution. In LGMD2C: a) alpha-sarcoglycan staining is preserved; b) the beta-gamma-delta-sarcoglycan subunit staining is severely reduced; c) the alpha7B-integrin is slightly reduced and beta1D-integrin is severely reduced; d) filamin2 is severely reduced. Other tested proteins of the two systems show a normal staining pattern in both sarcoglycanopathies. Our study seems to confirm, for the first time on adult human skeletal muscle of subjects affected by LGMDs, the hypo-theses of: a) the existence, in mouse myotubes in culture, of two distinct subunits in sarcoglycans subcomplex; b) the presence of a bidirectional signalling between sarcoglycans and integrins, previously demonstrated on rat cultured L6 myocytes; c) the interaction of FLN2 with both sarcoglycans and integrins. These results may stimulate the search of yet unidentified common interactors of both fiber-extracellular matrix interaction systems.
authors.affiliation: Department of Biomorphology and Biotechnologies, Policlinico Universitario 'G. Martino', University of Messina, I-98125 Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Anastasi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cutroneo
authors.forename: Fabio
authors.initials: F
authors.lastname: Trimarchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Santoro
authors.forename: Daniele
authors.initials: D
authors.lastname: Bruschetta
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Antonina
authors.initials: A
authors.lastname: Pisani
authors.forename: Angelo
authors.initials: A
authors.lastname: Favaloro
mesh_terms: D001706:Biopsy; D003285:Contractile Proteins / Q000378:metabolism*; D064448:Filamins; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits / Q000378:metabolism; D049031:Sarcoglycans / Q000378:metabolism*; D016608:Talin / Q000378:metabolism*; D016596:Vinculin / Q000378:metabolism*
chemical_list: D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D016023:Integrins; D008840:Microfilament Proteins; D021122:Protein Subunits; D049031:Sarcoglycans; D016608:Talin; D016596:Vinculin