The role of inflammation on disease progression in alpha-sarcoglycan-related limb girdle muscular dystrophy (LGMDR3): new insights from human histological analysis and in vivo studies on Sgca-null mice.

Limb Girdle Muscular Dystrophy R3 (LGMDR3), previously known as LGMD2D, is a rare autosomal recessive primary myopathy, clinically characterized by progressive involvement of the pelvic and shoulder girdles, and genetically by mutations in the αsarcoglycan gene (SGCA) coding for α-sarcoglycan (SG). The clinical course of LGMDR3 presents a great variability, ranging from severe form with onset in the first decade of life and rapid progression, to milder form with later onset. Currently, physical therapy and prevention of secondary cardiac, pulmonary or orthopedic complications are the only possible care interventions and no disease-specific therapies are yet available. As other muscular dystrophies, LGMDR3 muscle histology is characterized by myofibernecrosis and regeneration, reactive fibrosis, and inflammatory infiltrates. However, to date, no data exploring the role of immune response on disease progression have been published. The primary objective of this PhD thesis was therefore to deepen the contribution of inflammatory processes to the severity of α-sarcoglycanopathy. AIM1. -to correlate the inflammatory infiltrates extension with the age at onset, the clinical severity, and the muscle involvement at MRI, in a cohort of patients followed at Istituto Giannina Gaslini, Genova In a cohort of 8 LGMDR3 patients, we characterized the clinical course, the MRI muscle pattern, and the histological parameters, focusing on inflammatory features. AIM2.-to immunophenotype the composition of muscular immune infiltrates in different sarcoglycanopathies and verify whether differences would be detectable between distinct subtypes of sarcoglycan-related LGMDs In a multicenter study involving Italian tertiary centers for neuromuscular disorders, we analysed muscle expression of inflammatory markers in two forms of sacoglycanopathies LGMDR3 and LGMDR5, the latter due to deficiency of γ-sarcoglycan. AIM3.-to study the in vivo effect of anti-purinergic molecules on disease progression in the Sgca null mouse In two pre-clinical studies, we explored the role of the P2X7 receptor, a ionotrophic receptor involved in the inflammasome pathway which mediates the release of pro-inflammatory cytokines, in a mouse model lacking the α-sarcoglycan gene (Sgca-null)