A.P.10: Investigating a novel knock-in mouse model with a mutation (E247K) in the skeletal muscle-specific filamin C gene

Abstract

Filamin proteins play an essential role in the binding of actin to the cytoskeleton of cells. Filamin C ( FLNC ) is the skeletal muscle specific isoform in this gene family. Mutations in the actin binding domain (ABD) of FLNC cause distal myopathy, whilst mutations in other FLNC domains cause myofibrillar myopathy. Until now there has not been an appropriate mouse model to observe the effects of these mutations in the ABD FLNC region and studies have been limited to in vitro analyses. We have characterised the first mouse model with an ABD FLNC mutation, specifically a knock-in mutation (p.E247K), to determine if it is a suitable mouse model for distal myopathy. KI (Flnc) E247K mice have lower bodyweight than wild-type mice, and they run less on average than wild-type mice as determined by voluntary running wheel activity. Analysis of skeletal muscle pathology by histological and immunostaining techniques at varying timepoints has revealed that the soleus in particular shows pathological features in older muscle, especially at the oldest time point examined of 1year of age. This is interesting, given that the soleus was one of the most affected muscles in distal myopathy patients with an ABD FLNC mutation. Accumulations of desmin are present in KI (Flnc) E247K mice at the later timepoints suggesting that age-related pathological changes are occurring in these mice. However levels of desmin protein expression by western blotting are not altered in the soleus of KI (Flnc) E247K mice. Further investigation of these mice, including analysis of force generation, will hopefully allow better understanding of the mechanism by which FLNC ABD mutations lead to muscle disease and may provide a valuable model for evaluating potential therapies.