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The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca²⁺-induced Ca²⁺ 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 Ca²⁺ transient dysynchrony without whole heart and cellular dysfunction. Ca²⁺ spark frequency more than …