Dystroglycanopathy-type muscular dystrophy
Foltz, Steven James
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Muscular dystrophies are a group of genetic disorders characterized by muscle necrosis, atrophy, and progressive weakness. Several of these diseases are caused by defects in the dystrophin-glycoprotein complex, an integral membrane complex linking the extracellular matrix to the subcellular actin cytoskeleton in skeletal muscle. The central factors in this linkage are extracellular α-dystroglycan, which interacts with laminin and other matrix receptors via the presence of a unique O-mannose glycan structure, transmembrane β-dystroglycan, and intracellular dystrophin, which binds β-dystroglycan near its C-terminus and actin at its N-terminus. Mutations in genes processing α-dystroglycan disrupt its attachment to laminin and cause a subset of muscular dystrophy termed secondary dystroglycanopathy. Patient phenotypes span a broad spectrum that includes, on one end, congenital muscular dystrophy along with severe brain and eye abnormalities, and, on the other, mild, adult-onset muscle disease. Although dystroglycanopathies are fatal, they are currently without effective treatment or cure. A challenge to the development of therapeutic agents for muscular dystrophies is the identification of druggable targets. Because the primary biochemical defect in dystroglycanopathies (as well as other dystrophin-glycoprotein related muscular dystrophies) lies within a structural complex, one approach has been to upregulate compensatory or homologous protein complexes or to modulate certain physiological properties of muscles so that they are less vulnerable to contraction induced damage. While this strategy has yielded a number of promising results, it has primarily utilized genetic approaches that are technically infeasible for use in human patients. Thus, identification of small-molecule interventions that ameliorate dystrophic features is of great interest. We employ a novel Fktn-deficient mouse model of dystroglycanopathy to probe pathological features of disease, including abnormal muscle regeneration and fibrosis which are key determinants of disease progression. Furthermore, we identify abnormal activation of the mammalian target of rapamycin (mTOR) signaling pathway and show that it can be targeted to improve histological and functional parameters of dystroglycanopathy muscle. Our results set the stage for preclinical evaluation of mTORC1 inhibition as a novel therapeutic approach for muscular dystrophy.