Talk abstracts
Talk on Tuesday 03:00-03:15pm submitted by Thomas Bodnar
Downstream factors that facilitate vesicle trafficking responses during sarcolemmal membrane repair
Dr. Sayak Bhaattcharya (Post Doc ), Kevin Mcelhanon (BSGP), Brian Paleo (BSGP)
Abstract:
Duchenne Muscular Dystrophy (MD) is a fatal genetic disorder caused by the loss of the X-linked gene dystrophin that affects one in every 5,000 males. In MD patients harboring a mutation in dystrophin, the sarcolemmal membrane is fragile and the normal load of mechanical stress can lead to rupture of the sarcolemma and death of the myocyte. The accumulation of myocyte death will exceed the regenerative capacity of the muscle causing MD patients to display structural damage, reduced skeletal muscle strength and eventual death in the third decade of life. Treatments that improve the membrane repair process in MD have been greatly overlooked and underutilized as therapeutic approaches. This project investigates a novel membrane repair signaling cascade in skeletal muscle which could lead to new treatment options for MD. Recent findings from our lab have identified that the phosphoinositide-3 kinase (PI3K)/Akt1 pathway is a major activator of the repair response. Here we established key downstream repair regulators that are more specific to skeletal muscle. Two of which are Akt Substrate 160 kDa (AS160) and glucose storage vesicle (GSV) associated rab proteins. Based on our preliminary data we hypothesize that PI3K/Akt1 signaling improves membrane repair in skeletal muscle by regulating translocation of intercellular GSVs to disruptions in the sarcolemma by phosphorylating AS160, which then facilitates glucose storage vesicle trafficking through associated rabs. Thus, modulating the function of these proteins will have therapeutic benefits for MD. Through the use of microRNA and mutant plasmids, AS160 plays a substantial role in membrane repair in both cultured muscle cells, and mouse skeletal muscle. We also identify a translocation of Glut4 (GSV) to injury sites in myoblasts, as well as the ubiquitination of IRS-1 from MG53 immediately after injury. This project explores a novel signaling cascade that regulates the repair machinery of the sarcolemma, and could lead to new treatment options for MD.
Keywords: Duchenne Muscular Dystrophy, Sarcolemma, Repair