Grant 30

Research Institution: University of Otago, Dunedin, New Zealand

Principle Investigator:

​Alison Heather

Type: ​International

Project title: ​HDL based therapy is a potential treatment for FSHD

Status: Completed


The pathogenesis of facioscapulohumeral dystrophy (FSHD) includes chronic elevation of DUX4 expression that drives oxidative stress, inflammation, mitochondrial dysfunction and ultimately skeletal muscle cell dysfunction and/or apoptosis. Therapies targeted to reducing the damage caused by oxidative stress including the oxidative modification of key calcium signaling proteins, CampKII and RyR will help to retard or even reverse skeletal muscle damage. High density lipoproteins (HDL’s) can protect cells via their anti-oxidant, anti-inflammatory and anti-apoptotic function. Moreover, HDL’s improved glucose uptake in skeletal muscle cells, restoring glucose signaling through key AMPK pathways. While HDL’s show these protective effects, drug therapy attempts to increase systemic HDL concentrations have not always achieved favourable outcomes (1). Moreover, HDL particle therapy is not feasible as a therapeutic option, despite their cellular and organ protective effects, because the generation of HDL particles is time consuming , expensive, and very difficult to generate in the quantities required for clinical based human therapies. However, HDL particles are made up of phospholipid cores surrounded by apolipoproteins, the most common one being apolipoprotein A-I (apoAI). Excitingly, recent data by Prof. HEather has shown that apoA-I injections into C57BI/6 mice reduce systemic as well as tissue (liver, skeletal muscle) inflammation and oxidative stress induced by overnutrition. Additionally, published studies by others show apoA-I mimetic peptides protect against ovarian cancer (2) and coronary heart disease (4); disease also underpinned by oxidative stress and inflammation. In this project, Prof. HEather will test apoA-I mimetic peptides for their ability to protect against the pathogenic mechanisms induced by elevated Dux4 levels in skeletal muscle cells, using sophisticated in vitro and in vivo approches.