Molecular signatures of membrane protein complexes underlying muscular dystrophy

Mutations in genes encoding components of the sarcolemmal dystrophin-glycoprotein complex (DGC) are responsible for a large number of muscular dystrophies. As such, molecular dissection of the DGC is expected to both reveal pathological mechanisms, and provides a biological framework for validating new DGC components. Establishment of the molecular composition of plasma-membrane protein complexes has been hampered by a lack of suitable biochemical approaches. Here we present an analytical workflow based upon the principles of protein correlation profiling that has enabled us to model the molecular composition of plasma-membrane protein complexes in mouse skeletal muscle. We also report our analysis of protein complexes in mice harboring mutations in DGC components, which implicates cell-adhesion pathways directly targeted by NFκB in the pathophysiology of DGC-related muscular dystrophies. Our study suggests that inflammatory and compensatory mechanisms are activated in these diseases. Additionally, it provides a molecular framework that will facilitate refinement of our understanding of the DGC, identification of protein biomarkers of neuromuscular disease, and pharmacological interrogation of the DGC in adult skeletal muscle.