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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Thomas G. Martin & Valerie D. Myers & Praveen Dubey & Shubham Dubey & Edith Perez & Christine S. Moravec & Monte S. Willis & Arthur M. Feldman & Jonathan A. Kirk, 2021. "Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23272-z
    DOI: 10.1038/s41467-021-23272-z
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    Cited by:

    1. Jordan Currie & Vyshnavi Manda & Sean K. Robinson & Celine Lai & Vertica Agnihotri & Veronica Hidalgo & R. W. Ludwig & Kai Zhang & Jay Pavelka & Zhao V. Wang & June-Wha Rhee & Maggie P. Y. Lam & Edwar, 2024. "Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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