P.79 - Mouse model of BAG3 myofibrillar myopathy

Abstract

Bcl-2-associated athanogene 3 (BAG3) is a protein that serves as a co-chaperone to heat-shock proteins, inhibits apoptosis and facilitates the degradation of misfolded proteins. Mutations to BAG3, specifically the dominantly expressed BAG3P209L, can result in a severe childhood myofibrillar myopathy. Bag3 myofibrillar myopathy causes progressive muscle weakness with cardiomyopathy and respiratory failure developing in the second decade of life, eventually leading to death. Two mouse lines were developed to study this disease: a knock-out line, and a knock-in line with a mutation homologous to the P209L mutation seen in humans. Mice with homozygous knock-out of the BAG3 gene exhibit stunted growth and die 7–10 days after birth. Three-month-old knock-in mice do not show any obvious muscle weakness in preliminary phenotyping tests using rotarod and inverted grid, nor did knock-in/knock-out crosses. Preliminary results from immunoflourescent staining appears to show z-line streaming and aggregation of BAG3 in two-month-old knock-in mice, and fiber size appears to be small in H&E stains. Future testing will include using exercise to attempt to induce a phenotype and further histological examination in older mice.