Dataset Information

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

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Publications

Blue toe syndrome.

Hart B B

Journal of vascular nursing : official publication of the Society for Peripheral Vascular Nursing 19910901 3

Taking a precise history from a patient who presents with a "bruised" toe in the absence of trauma requires sharp assessment skills and an investigative nature. Looking beyond the obvious in an otherwise healthy appearing individual calls for knowledge of many different disease processes including blue toe syndrome. Rapid identification, proper diagnosis, and correct medical and nursing management are essential for a positive outcome. ...[more]

PMID: 1747352

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