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.
Highlights
The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, the underlying molecular mechanisms are poorly understood
We asked whether inadequate sarcomeric protein turnover in heart failure could serve as an explanation for functional impairment and, if so, to identify the key players involved
We show sarcomere protein turnover is impaired in human dilated cardiomyopathy (DCM) samples with reduced myofilament force-generating capacity (Fmax), where elevated ubiquitinated proteins remained integrated into the sarcomere
Summary
The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, the underlying molecular mechanisms are poorly understood. 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. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance. The distinct mechanisms of sarcomere protein turnover in the adult heart are poorly characterized, and the functional relevance of sarcomere PQC has not been determined. Sarcomere structure is unimpaired at the neonatal stage with germline BAG3 knockout (KO), but rapidly disintegrates postnatum[23] These findings suggest separate or additional sarcomeric roles for BAG3 in the adult
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
