期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 112, 期 -, 页码 123-130出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2017.08.007
关键词
Cardiomyocytes; MG53 (or TRIM72); T-tubules; Calcium; Sodium-calcium exchanger; Excitation-contraction coupling
资金
- NIH [R01 HL090905, HL130346, AR070752, AR061385]
- United States Department of Veterans Affairs Biomedical Laboratory Research [I01BX002334, 2I01BX000776]
- China National Natural Science Foundation [NSFC 31371159, 57201701, 81570293]
The cardiac transverse (T)-tubule membrane system is the safeguard for cardiac function and undergoes dramatic remodeling in response to cardiac stress. However, the mechanism by which cardiomyocytes repair damaged T-tubule network remains unclear. In the present study, we tested the hypothesis that MG53, a muscle specific membrane repair protein, antagonizes T-tubule damage to protect against maladaptive remodeling and thereby loss of excitation-contraction coupling and cardiac function. Using MG53-knockout (MG53-KO) mice, we first established that deficiency of MG53 had no impact on maturation of the T-tubule network in developing hearts. Additionally, MG53 ablation did not influence T-tubule integrity in unstressed adult hearts as late as 10 months of age. Following left ventricular pressure overload-induced cardiac stress, MG53 protein levels were increased by approximately three-fold in wild-type mice, indicating that pathological stress induces a significant upregulation of MG53. MG53-deficient mice had worsened T-tubule disruption and pronounced dysregulation of Ca2+ handling properties, including decreased Ca2+ transient amplitude and prolonged time to peak and decay. Moreover, MG53 deficiency exacerbated cardiac hypertrophy and dysfunction and decreased survival following cardiac stress. Our data suggest MG53 is not required for T-tubule development and maintenance in normal physiology. However, MG53 is essential to preserve T-tubule integrity and thereby Ca2+ handling properties and cardiac function under pathological cardiac stress.
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