MassIVE MSV000086422

Complete Public PXD022414

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

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Description

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. [doi:10.25345/C58B6Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Heart failure, sarcomere, ubiquitination, protein turnover

Contact

Principal Investigators:
(in alphabetical order) 		Jonathan Kirk, Loyola University Chicago, USA
Submitting User: tmartin7

Publications

Martin TG, Myers VD, Dubey P, Dubey S, Perez E, Moravec CS, Willis MS, Feldman AM, Kirk JA.
Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.
Nat Commun. 2021 May 19;12(1):2942. Epub 2021 May 19.

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