Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

<jats:title>Abstract</jats:title><jats:p>The association between reduced myofilament force-generating capacity (F<jats:sub>max</jats:sub>) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired F<jats:sub>max</jats:sub> arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with F<jats:sub>max</jats:sub>. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced F<jats:sub>max</jats:sub> and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/F<jats:sub>max</jats:sub>, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued F<jats:sub>max</jats:sub> and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.</jats:p>