The significant role of Na⁺/Ca²⁺ exchanger 1 on local Ca²⁺ control beneath T-tubule membrane

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Na⁺/Ca²⁺ exchanger (NCX1) is essential Ca²⁺ regulator of myocyte Ca²⁺ homeostasis and specially localized at transverse tubules (T-tubules) membrane. T-tubules are invaginations of the sarcolemma and critical for myocyte contraction, especially as the main site of excitation-contraction coupling. Therefore, T-tubule disorganization is linked to decreased contractility in heart failure, but the molecular mechanism is not clear. We analyzed the alteration of T-tubule structure and Ca2+ handling during the progression of heart failure after transverse aortic constriction (TAC)-surgery, using cardiac-specific and inducible NCX1 transgenic mice. In progression of cardiac dysfunction, sarcoplasmic reticulum Ca²⁺ ATPase and NCX1 activity were down-regulated before T-tubule disorganization. The inducing NCX1 overexpression after TAC-surgery prevented T-tubule disorganization and contractile dysfunction under prolonged pressure-overload, with improvement of myocyte Ca²⁺ handling. These results suggest that local Ca²⁺ control beneath the T-tubule membrane is crucial for the maintenance of myocyte structure and function, in which NCX1 has a pivotal role.