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

Compromised force-generating capacity is a hallmark of heart failure both at the organ1 and single-cell level2-6. This is primarily due to changes at the sarcomere7, the functional unit in cardiomyocytes responsible for contraction. However, the mechanisms of sarcomeric force depression in heart failure are incompletely understood. We show in human heart failure that myofilament BAG3 levels predict the severity of sarcomere dysfunction and in a mouse heart failure model, increasing BAG3 expression rescues contractile function. Further, myofilament ubiquitin increases in heart failure, indicating impaired protein turnover, but is reduced with increased BAG3 expression. Mass spectrometry revealed Hsp70, HspB8 associate with myofilament BAG3, forming a conserved selective autophagy complex, which localizes to the Z-disc. Assembly of this complex at the sarcomere is BAG3-dependent and triggered by proteotoxic stress, however, its clearance stalls in heart failure. Together, these findings identify BAG3-dependent autophagy as essential for functional maintenance of the cardiac sarcomere.