Cardiomyocyte Contractile Impairment in Heart Failure Results from Reduced BAG3-mediated Sarcomeric Protein Turnover

Abstract

The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show the Fmax decrease arises from impaired BAG3-mediated sarcomere turnover. Myofilament BAG3 decreased in human HF and predicted the extent of Fmax decrease. This relationship was confirmed using BAG3+/- mice, which had reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via the chaperone-assisted selective autophagy complex (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA localization is BAG3/proteotoxic stress-dependent. To determine if increasing BAG3 expression in HF would restore sarcomere proteostasis/Fmax, HF mice were treated with AAV9/BAG3. Gene therapy fully restored Fmax after four weeks and decreased ubiquitination. Using mass spectrometry, we identified several sarcomere proteins with increased ubiquitination in HF and four that decreased with AAV9/BAG3. Our findings indicate BAG3-mediated sarcomere turnover is required for myofilament functional maintenance.