Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.
Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.
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DOI：
10.1038/s41467-021-23272-z
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发表时间：
2021-05-19
影响因子：
16.6
通讯作者：
Kirk JA
中科院分区：
文献类型：
--
作者：
Martin TG;Myers VD;Dubey P;Dubey S;Perez E;Moravec CS;Willis MS;Feldman AM;Kirk JA
肌丝力产生能力（Fmax）降低与心力衰竭（HF）之间的关联是明确的，但其潜在的分子机制知之甚少。在这里，我们表明受损的Fmax来自BAG 3介导的肌节周转减少。肌丝BAG 3表达在人HF中降低并且与Fmax正相关。我们使用BAG 3单倍不足小鼠证实了这种关系，这些小鼠显示Fmax降低和肌丝泛素化增加，表明蛋白质周转受损。我们显示心脏BAG 3通过分子伴侣辅助的选择性自噬（CASA）进行操作，从骨骼肌中保存，并确认肌节CASA复合物定位是BAG 3/蛋白毒性应激依赖性的。使用质谱，我们表征了人类心脏中的肌丝CASA相互作用组，并确定了BAG 3介导的营业额的8个客户。为了确定增加HF中的BAG 3表达是否可以恢复肌节蛋白质稳态/Fmax，用rAAV 9-BAG 3处理HF小鼠。基因治疗在四周后完全挽救了Fmax和CASA蛋白质周转。我们的研究结果表明BAG 3介导的肌节周转是肌丝功能维持的基础。BAG 3在心脏中的表达减少与收缩功能障碍和心力衰竭相关。在这里，作者表明，这是由于BAG 3依赖性肌节蛋白周转减少，这损害了机械功能，并且肌节力产生能力通过BAG 3基因治疗恢复。
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. Decreased expression of BAG3 in the heart is associated with contractile dysfunction and heart failure. Here the authors show that this is due to decreased BAG3-dependent sarcomere protein turnover, which impairs mechanical function, and that sarcomere force-generating capacity is restored with BAG3 gene therapy.
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影响因子：
20.1
作者：
Luo M;Anderson ME
通讯作者：
Anderson ME
影响因子：
20.1
作者：
de Waard, Monique C.;van der Velden, Jolanda;Duncker, Dirk J.
通讯作者：
Duncker, Dirk J.
DOI：
10.1016/j.jacbts.2016.08.008
发表时间：
2016-12
期刊：
JACC. Basic to translational science
影响因子：
--
作者：
Knezevic T;Myers VD;Su F;Wang J;Song J;Zhang XQ;Gao E;Gao G;Muniswamy M;Gupta MK;Gordon J;Weiner KN;Rabinowitz J;Ramsey FV;Tilley DG;Khalili K;Cheung JY;Feldman AM
通讯作者：
Feldman AM
影响因子：
5
作者：
Feldman AM;Gordon J;Wang J;Song J;Zhang XQ;Myers VD;Tilley DG;Gao E;Hoffman NE;Tomar D;Madesh M;Rabinowitz J;Koch WJ;Su F;Khalili K;Cheung JY
通讯作者：
Cheung JY
影响因子：
20.1
作者：
Gao E;Lei YH;Shang X;Huang ZM;Zuo L;Boucher M;Fan Q;Chuprun JK;Ma XL;Koch WJ
通讯作者：
Koch WJ