Molecular pathways of protein degradation in muscular dystrophies targets for therapeutic intervention

Abstract

This study shows that LGMD is common in the Indian population. Dysferlinopathy is more predominant than Calpainopathy (LGMD 2A) in India. Absence of calpain 3 or dysferlin induces oxidative and nitrosative stress in dystrophic muscle. The ubiquitin proteasomal pathway, the major pathway that governs protein degradation in DMD and other cachectic conditions, is also newlineupregulated in LGMD 2A and dysferlinopathy. Ubiquitin E3 ligases MAFbx and MURF 1 underlie protein ubiquitinylation of LGMD 2A muscle. MAFbx but not MURF 1 plays a role in ubiquitinylation of dysferlinopahtic muscle. IKKand#946; mediated activation of NF-and#954;Bp65 appears critical in the pathology of LGMD 2A and dysferlinopathy (Figure 5.1). Loss of major myofibrillar proteins and failure of the antioxidant system may underlie selective loss of muscle in LGMD. Oxidative stress mediated activation of NF-and#954;Bp65 that causes protein ubiquitinylation and myoblast death indicates this as the probable order of pathological events in LGMD muscle. Oxidative stress mediated intracellular calcium disturbance and myoblast death is related to NF-and#954;Bp65 signalling and could be effectively prevented by curcumin, an anti-oxidant and NF-and#954;B inhibitor. Curcumin is effective in preventing basal and oxidative stress induced NO generation in myoblasts. Importantly curcumin induces myoblast division (Figure 5.1). All these properties of curcumin suggest it could be used as a therapeutic drug for muscular dystrophies especially LGMD 2A and dysferlinopathy. Further studies are needed to determine bio-delivery and therapeutic doses of curcumin. There are no comprehensive studies from the Indian subcontinent on muscular dystrophies, especially LGMD and very few centers diagnose LGMD 2A and dysferlinopathy. This thesis describes Western blots suitable for the diagnosis of LGMD in the Indian population, which were used to determine the frequency of LGMD 2A and dysferlinopathy in a series of dystrophic muscles of patients from several parts of India. newline