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: Giuseppe Anastasi, Giuseppina Cutroneo, Fabio Trimarchi, Giuseppe Santoro, Daniele Bruschetta, Placido Bramanti, Antonina Pisani, Angelo Favaloro
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 14 Issue 6 Pg. 989-99 (Dec 2004) ISSN: 1107-3756 [Print] Greece
• PMID: 15547664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Contractile Proteins
• FLNC protein, human
• Filamins
• Integrins
• Microfilament Proteins
• Protein Subunits
• Sarcoglycans
• Talin
• Vinculin

Topics

• Biopsy
• Contractile Proteins (metabolism)
• Filamins
• Humans
• Immunohistochemistry
• Integrins (metabolism)
• Microfilament Proteins (metabolism)
• Microscopy, Confocal
• Muscle, Skeletal (metabolism, pathology)
• Muscular Dystrophies, Limb-Girdle (metabolism, pathology)
• Protein Subunits (metabolism)
• Sarcoglycans (metabolism)
• Talin (metabolism)
• Vinculin (metabolism)