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Therapeutic Targeting of Akt/mTOR Signaling in Fktn‐deficient Muscle
Author(s) -
Foltz Steven,
Patel Ankit,
Peissig Kristen,
Beedle Aaron
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1038.12
Subject(s) - mtorc1 , pi3k/akt/mtor pathway , pten , tensin , protein kinase b , biology , cancer research , microbiology and biotechnology , mtorc2 , signal transduction , ampk , kinase , protein kinase a
Secondary dystroglycanopathies are a subset of muscular dystrophy caused by improper glycosylation of α‐dystroglycan (αDG). Hypoglycosylation of αDG prevents it from binding to laminin and other extracellular matrix receptors, disrupting structural and signaling axes. Mutations in as many as 15 genes have been identified as causative for secondary dystroglycanopathy, including FKTN , which encodes fukutin. We found that mammalian target of rapamycin complex 1 (mTORC1) is activated in muscle of aged Fktn ‐deficient mice and that Akt kinase/mTOR signaling is also altered in younger 12 week old knockouts. Chronic inhibition of mTORC1 by rapamycin (RAPA) treatment reduced fibrosis and activity‐induced damage, and increased muscle fiber size in Fktn ‐KO mice compared to controls suggesting a delayed disease progression in treated mice. Furthermore, multiple Akt‐related signaling factors showed RAPA‐sensitivity in KO mice, including AMP‐activated kinase α (AMPKα), mTOR, and phosphatase and tensin homolog (PTEN). These findings validate mTOR signaling as a potential therapeutic target, but additional studies are needed to understand and enhance benefits of mTOR inhibition in dystroglycanopathy. This work was funded by the University of Georgia College of Pharmacy.