Poster abstracts
Poster number 53 submitted by Gianni Giarrano
Modulating the PI3K/Akt1 Kinase Pathway Increases Skeletal Muscle Plasma Membrane Repair in Muscular Dystrophy Models.
Gianni Giarrano (Ohio State Biochemistry Program ), Kassidy Banford (Department of Physiology and Cell Biology, The Ohio State University ), Hannah Bulgart (Department of Physiology and Cell Biology, The Ohio State University ), Noah Weisleder (Department of Physiology and Cell Biology, The Ohio State University )
Abstract:
The dysferlin protein is an essential component of the skeletal muscle plasma membrane repair response, with dysferlin-deficient muscle having a high susceptibility to mechanical membrane damage leading to muscle cell death. Mutations in the dysferlin gene result in the onset of dysferlinopathies, a debilitating subclass of muscular dystrophies. The large size of dysferlin (230 kDa) creates significant challenges in developing gene and protein-based therapies for these disorders. To circumvent this, we leveraged the ability of the phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt1) signaling axis to regulate exocytosis and endocytosis-dependent membrane repair events. Our preliminary data indicated that endocytosis was reduced in dysferlinopathy patient-derived myoblast cell lines, and upregulation of PI3K/Akt1 increased endocytic and exocytotic activity. Here, we find that the PI3K/Akt1 signaling pathway remains intact in dysferlin-deficient muscle and treatment with Akt1 agonist SC79 results in improved membrane repair in both dysferlinopathy patient cells and dysferlin-deficient mouse skeletal muscle. Treating dysferlin-deficient mice with SC79 also decreases pathology, resulting in increased body weight and a trend toward lower creatine kinase levels. Together, these results suggest that modulation of the PI3K/Akt1 kinase pathway represents a promising therapeutic approach for dysferlinopathies.
Keywords: Plasma Membrane Repair, Muscular Dystrophy, PI3KAkt1