Bag3+ P209L Transgene Provides a Cardiac‐Specific Murine Model of Protein Misfolding and Aggregation

Abstract

Bag3 is a heat shock protein expressed in skeletal muscle and cardiomyocytes that regulates proteasomal and lysosomal protein elimination pathways. Bag3, in association with Hsp70 and HspB8, assists in chaperone‐assisted selective autophagy. Several mutations in Bag3, including the P209L mutation, results in myofibrillar myopathy, a childhood‐onset disease with protein aggregation. The P209L mutation has been suggested to result in a toxic gain of function and Bag3 insufficiency. To test the role of P209L in the heart, we created a transgenic mouse with cardiac specific (α‐MHC) Bag3P209L. Longitudinal conscious echocardiography was performed over 12 months on mice, with histological analysis of apoptosis, protein aggregation, and fibroblast analysis performed upon harvest. In 8 months, Bag3 P209L Tg mice had significantly depressed fractional shortening compared to sibling wildtype control mice (FS% 38.9±1.0% vs. 48.1±0.95%, p=0.0005). However, no differences in apoptosis nor fibroblast number was identified at 12 months. No differences in amyloid protein aggregation were identified at 12 months (26.8±0.9 AU vs. 30.0±6.6 AU, p=0.76). However, analysis of cardiac tissue for pre‐amyloid oligomers will allow the more clinically relevant detection of proteotoxic intermediates that can lead to cytotoxicity, as is found in neurodegenerative diseases and other causes of heart failure. Since Bag3 is required for autophagosome formation during CASA, future studies will focus on pathological changes in cardiac autophagic flux and its related MAPK signaling. This novel Bag3 transgenic mouse model provides a useful model to characterize cardiac‐specific dysfunction we will use to identify therapeutic targets that protect against the development of cardiomyopathy.