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

Thomas G. Martin, Valerie D. Myers, Praveen Dubey, Shubham Dubey, Edith Perez, Christine S. Moravec, Monte S. Willis, Arthur M. Feldman and Jonathan A. Kirk ()
Additional contact information
Thomas G. Martin: Loyola University Stritch School of Medicine
Valerie D. Myers: Temple University Lewis Katz School of Medicine
Praveen Dubey: Temple University Lewis Katz School of Medicine
Shubham Dubey: Temple University Lewis Katz School of Medicine
Edith Perez: Loyola University Stritch School of Medicine
Christine S. Moravec: Cleveland Clinic Lerner College of Medicine
Monte S. Willis: Indiana University School of Medicine
Arthur M. Feldman: Temple University Lewis Katz School of Medicine
Jonathan A. Kirk: Loyola University Stritch School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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 confirm this relationship using BAG3 haploinsufficient mice, which display 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 turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-23272-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23272-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-23272-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().