Abstract
The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. However, many aspects of its structural organization remain largely unknown, particularly in cells with a highly differentiated SR/ER network. Here, we report a cardiac enriched, SR/ER membrane protein, REEP5 that is centrally involved in regulating SR/ER organization and cellular stress responses in cardiac myocytes. In vitro REEP5 depletion in mouse cardiac myocytes results in SR/ER membrane destabilization and luminal vacuolization along with decreased myocyte contractility and disrupted Ca2+ cycling. Further, in vivo CRISPR/Cas9-mediated REEP5 loss-of-function zebrafish mutants show sensitized cardiac dysfunction upon short-term verapamil treatment. Additionally, in vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction. These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development.
Highlights
The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases
We investigated the role of REEP5 in the cardiac myocyte
This study details a fundamental role of REEP5 in the cardiac myocyte, demonstrates that this protein is essential for SR/ER organization and proper function, identify its protein interactions, and shows that its deletion can result in cardiac functional and developmental defects
Summary
The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. In vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development. Many aspects of its structural organization and function remain largely unknown, in highly differentiated muscle cells. Members of the reticulon and Yop1p/DP1/REEP protein families contain a reticulon-homology domain (RHD) which is essential for inducing and stabilizing high membrane curvature in cross-sections of ER tubules[7,8,9]. Their ER structures have adapted to handle a large concentration of Ca2+, important for regulated release of Ca2+ into the cytoplasm for muscle contraction This specialized smooth ER, termed the SR, evolved to function in striated muscle[22]. While a great deal is known about SR structure and function in terms of cardiac muscle contraction, considerably less is understood about how the SR is formed and maintained
Sign-in/Register to view highlights & summary 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.
