title: Pathophysiology of limb girdle muscular dystrophy type 2A: hypothesis and new insights into the IkappaBalpha/NF-kappaB survival pathway in skeletal muscle.
abstract: Limb girdle muscular dystrophies (LGMDs) are a group of clinically heterogeneous genetic diseases characterized by progressive weakness and atrophy of scapular and pelvic muscles, with either a dominant or recessive autosomic mode of inheritance. The first symptoms of the disorder appear during the first 20 years of life and progresses gradually, and a walking disability develops 10-20 years later. The gene responsible for LGMD2A has been identified and encodes calpain 3, a protease expressed mainly in skeletal muscle. Apoptotic myonuclei were recently detected in muscular biopsy specimens of LGMD2A patients, and apoptosis was found to be correlated with altered subcellular distribution of inhibitory protein kappaBalpha (IkappaBalpha) and nuclear factor kappaB (NF-kappaB), resulting in sarcoplasmic sequestration of NF-kappaB. Calpain 3 dependent IkappaBalpha degradation was reconstituted in vitro, supporting a possible in vivo sequence of events leading from calpain 3 deficiency to IkappaBkappa accumulation, prevention of nuclear translocation of NF-kappaB, and ultimately apoptosis. Therefore calpain 3, present in healthy muscle as sarcoplasmic and nuclear forms, may control IkappaBalpha turnover and indirectly regulate NF-kappaB dependent expression of survival genes. Recent data reported from a new model of LGMD2A in mice and from other muscular disorders strengthen understanding of the molecular links between calpain 3 and the Ikappaalpha/NF-kappaB pathway. Finally, in light of the lack of apoptosis observed in inflammatory myopathies, a unifying model for the control of cell survival in muscle is proposed and discussed
authors.affiliation: Laboratoire de Dynamique Moléculaire des Interactions Membranaires, CNRS-UMR 5539, Université Montpellier, France. stbaghdi@univ-montp2.fr
authors.forename: S
authors.initials: S
authors.lastname: Baghdiguian
authors.forename: I
authors.initials: I
authors.lastname: Richard
authors.forename: M
authors.initials: M
authors.lastname: Martin
authors.forename: P
authors.initials: P
authors.lastname: Coopman
authors.forename: J S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: P
authors.initials: P
authors.lastname: Mangeat
authors.forename: G
authors.initials: G
authors.lastname: Lefranc
mesh_terms: D000818:Animals; D017209:Apoptosis; D002154:Calpain / Q000172:deficiency / Q000378:metabolism; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008954:Models, Biological; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009220:Myositis / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007527:Isoenzymes; D009124:Muscle Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; C105884:CAPN3 protein, human; D002154:Calpain