Presenter: Ian Nano

Faculty Sponsor: Eric Owen Williams

School: Fitchburg State University

Research Area: Biology

Session: Poster Session 2, 11:30 AM - 12:15 PM, Auditorium, A66

ABSTRACT

Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle weakness and degeneration. Dysferlinopathy is a rare kind of muscular dystrophy caused by mutations in DYSF and is typically diagnosed in the mid 20s, with many patients requiring a wheelchair within 5–10 years. There are currently no effective drug treatments, and recent gene therapy attempts have been unsuccessful. Dysferlin is a protein that is required for the rapid repair of damaged muscle cell membranes. Mutations such as T252M lead to misfolding and reduced dysferlin at the membrane, which impairs the ability to repair and contributes to muscle loss. To identify possible candidates for rescuing mutant dysferlin, we performed a T252M drug-response study using flow cytometry to quantify dysferlin signal following treatment with 4-phenylbutyrate (4-PBA). In T252M myoblasts, 5 mM 4-PBA was seen to have increased dysferlin signal relative to the untreated controls, and this effect was reproducible across two experiments. We then created a human HEK transfection model expressing T252M dysferlin and found that 5 mM 4-PBA increased dysferlin levels compared to tested compounds such as TUDCA, C17, and the controls. Then, in a differentiation assay, WT and mutant-dysferlin myoblasts were induced to form multinucleated myotubes with or without the presence of 4-PBA. They were then imaged by fluorescence microscopy, and initial results suggested T252M cells formed more myotubes than WT under our conditions, while 4-PBA did not strongly alter differentiation in either line. Overall, this work supports future drug screening and helps relate dysferlin levels to muscle performance.