Pathophysiology of limb girdle muscular dystrophy type 2A: hypothesis and new insights into the I kappa B alpha/NF-kappa B survival pathway in skeletal muscle

Limb girdle muscular dystrophies (LGMDs) are a group of clinically heteroge neous 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 d evelops 10-20 years later. The gene responsible for LGMD2A has been identif ied 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 subc ellular distribution of inhibitory protein kappaB alpha (I kappaB alpha) an d nuclear factor kappaB (NF-kappaB), resulting in sarcoplasmic sequestratio n of NF-kappaB. Calpain 3 dependent I kappaB alpha degradation was reconsti tuted in vitro, supporting a possible in vivo sequence of events leading fr om calpain 3 deficiency to I kappaB alpha accumulation, prevention of nucle ar translocation of NF-kappaB, and ultimately apoptosis. Therefore calpain 3, present in healthy muscle as sarcoplasmic and nuclear forms, may control I kappaB alpha turnover and indirectly regulate NF-kappaB dependent expres sion of survival genes. Recent data reported from a new model of LGMD2A in mice and from other muscular disorders strengthen understanding of the mole cular links between calpain 3 and the I kappaB alpha NF-kappaB pathway. Fin ally, 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.