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 impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirmed this relationship using BAG3+/- mice, which had reduced Fmax 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 protein turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with AAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings identify BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

INSTRUMENT(S): LTQ XL

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jonathan Kirk  

PROVIDER: MSV000086422 | MassIVE | Fri Nov 06 14:11:00 GMT 2020

SECONDARY ACCESSION(S): PXD022414

REPOSITORIES: MassIVE