Laboratory of Cell Electrophysiology, Heart Science Centre, Harefield Hospital, London UB9 6JH, UK.
Hum Mol Genet. 2013 Jan 15;22(2):372-83. doi: 10.1093/hmg/dds434. Epub 2012 Oct 25.
The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
横管（t）系统在健康和患病的心肌中起着至关重要的作用，特别是在 Ca(2+)-诱导的 Ca(2+)释放（CICR）中，其结构破坏是心力衰竭的早期事件。机械性负荷过重和卸载都会改变 t 小管的结构，但对于在负荷变化时调节 t 小管的正常紧密调节的机制知之甚少。Telethonin（Tcap）是一种拉伸敏感的 Z 盘蛋白，可与 t 小管膜中的蛋白质结合。为了评估其在调节 t 小管结构和功能中的作用，我们使用 Tcap 敲除（KO）小鼠，并在机械负荷过重前后随时间研究心肌细胞 t 小管和细胞结构以及 CICR。在 3 个月大的 KO（3mKO）的心肌细胞中，存在孤立的 t 小管缺陷和 Ca(2+)瞬变不同步，而没有整个心脏和细胞功能障碍。Ca(2+)火花频率在 3mKO 中增加了一倍以上。在 8 个月大（8mKO）时，心肌细胞显示出 t 小管逐渐丧失和细胞表面重塑，伴有延长和不同步的 Ca(2+)瞬变。Ca(2+)火花频率在 8 个月时仅升高，而 L 型 Ca(2+)通道则降低。在主动脉缩窄缩窄获得机械负荷过重后，野生型和 KO 中的 Ca(2+)瞬变均延长。机械负荷过重仅在 KO 中增加了 Ca(2+)火花频率，其中 t 小管的损失也明显更多，t 小管规则性恶化更严重。同时，Tcap KO 显示出细胞表面超微结构的严重丧失。这些数据表明，Tcap 是 t 小管结构和功能的关键、负荷敏感调节剂。
