RATIONALE: Unrepaired cardiomyocyte membrane injury causes irreplaceable cell loss, leading to myocardial fibrosis and eventually heart failure. However, the cellular and molecular mechanisms of cardiac membrane repair are largely unknown. MG53, a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. But the role of MG53 in the heart has not been determined. OBJECTIVE: We sought to investigate whether MG53 mediates membrane repair in cardiomyocytes and, if so, the cellular and molecular mechanism underlying MG53-mediated membrane repair in cardiomyocytes. Moreover, we determined possible cardioprotective effect of MG53-mediated membrane repair. METHODS AND RESULTS: We demonstrated that MG53 is crucial to the emergency membrane repair response in cardiomyocytes and protects the heart from stress-induced loss of cardiomyocytes. Disruption of the sarcolemmal membrane by mechanical, electric, chemical, or metabolic insults caused rapid and robust translocation of MG53 toward the injury sites. Ablation of MG53 prevented sarcolemmal resealing after infrared laser-induced membrane damage in intact heart, and exacerbated mitochondrial dysfunction and loss of cardiomyocytes during ischemia/reperfusion injury. Unexpectedly, the MG53-mediated cardiac membrane repair was mediated by a cholesterol-dependent mechanism: depletion of membrane cholesterol abolished, and its recovery restored injury-induced membrane translocation of MG53. The redox status of MG53 did not affect initiation of MG53 translocation, whereas MG53 oxidation conferred stability to the membrane repair patch. CONCLUSIONS: Thus, cholesterol-dependent MG53-mediated membrane repair is a vital, heretofore unappreciated cardioprotective mechanism against a multitude of insults and may bear important therapeutic implications.
RATIONALE: Unrepaired cardiomyocyte membrane injury causes irreplaceable cell loss, leading to myocardial fibrosis and eventually heart failure. However, the cellular and molecular mechanisms of cardiac membrane repair are largely unknown. MG53, a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. But the role of MG53 in the heart has not been determined. OBJECTIVE: We sought to investigate whether MG53 mediates membrane repair in cardiomyocytes and, if so, the cellular and molecular mechanism underlying MG53-mediated membrane repair in cardiomyocytes. Moreover, we determined possible cardioprotective effect of MG53-mediated membrane repair. METHODS AND RESULTS: We demonstrated that MG53 is crucial to the emergency membrane repair response in cardiomyocytes and protects the heart from stress-induced loss of cardiomyocytes. Disruption of the sarcolemmal membrane by mechanical, electric, chemical, or metabolic insults caused rapid and robust translocation of MG53 toward the injury sites. Ablation of MG53 prevented sarcolemmal resealing after infrared laser-induced membrane damage in intact heart, and exacerbated mitochondrial dysfunction and loss of cardiomyocytes during ischemia/reperfusion injury. Unexpectedly, the MG53-mediated cardiac membrane repair was mediated by a cholesterol-dependent mechanism: depletion of membrane cholesterol abolished, and its recovery restored injury-induced membrane translocation of MG53. The redox status of MG53 did not affect initiation of MG53 translocation, whereas MG53 oxidation conferred stability to the membrane repair patch. CONCLUSIONS: Thus, cholesterol-dependent MG53-mediated membrane repair is a vital, heretofore unappreciated cardioprotective mechanism against a multitude of insults and may bear important therapeutic implications.
Authors: Sabrina Bech Mathiesen; Marianne Lunde; Jan Magnus Aronsen; Andreas Romaine; Anita Kaupang; Marita Martinsen; Gustavo Antonio de Souza; Tuula A Nyman; Ivar Sjaastad; Geir Christensen; Cathrine Rein Carlson Journal: J Biol Chem Date: 2019-04-09 Impact factor: 5.157
Authors: Youn Wook Chung; Claudia Lagranha; Yong Chen; Junhui Sun; Guang Tong; Steven C Hockman; Faiyaz Ahmad; Shervin G Esfahani; Dahae H Bae; Nazari Polidovitch; Jian Wu; Dong Keun Rhee; Beom Seob Lee; Marjan Gucek; Mathew P Daniels; Christine A Brantner; Peter H Backx; Elizabeth Murphy; Vincent C Manganiello Journal: Proc Natl Acad Sci U S A Date: 2015-04-15 Impact factor: 11.205
Authors: Xinyu Zhou; Peihui Lin; Daiju Yamazaki; Ki Ho Park; Shinji Komazaki; S R Wayne Chen; Hiroshi Takeshima; Jianjie Ma Journal: Circ Res Date: 2014-02-14 Impact factor: 17.367