The giant sarcomere protein titin is a major determinant of cardiomyocyte stiffness and contributor to cardiac strain sensing. Titin-based forces are highly regulated in health and disease, which aids in the regulation of myocardial function, including cardiac filling and output. Due to the enormous size, complexity, and malleability of the titin molecule, titin properties are also vulnerable to dysregulation, as observed in various cardiac disorders. This review provides an overview of how cardiac titin properties can be changed at a molecular level, including the role isoform diversity and post-translational modifications (acetylation, oxidation, and phosphorylation) play in regulating myocardial stiffness and contractility. We then consider how this regulation becomes unbalanced in heart disease, with an emphasis on changes in titin stiffness and protein quality control. In this context, new insights into the key pathomechanisms of human cardiomyopathy due to a truncation in the titin gene (TTN) are discussed. Along the way, we touch on the potential for titin to be therapeutically targeted to treat acquired or inherited cardiac conditions, such as HFpEF or TTN-truncation cardiomyopathy.

中文翻译：

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肌联蛋白 (TTN)：从分子到修饰、力学和医学意义

巨型肌节蛋白肌联蛋白是心肌细胞硬度的主要决定因素，也是心脏应变感知的贡献者。基于 Titin 的力量在健康和疾病中受到高度调节，这有助于调节心肌功能，包括心脏充盈和输出。由于肌联蛋白分子的巨大尺寸、复杂性和可塑性，肌联蛋白的特性也容易受到失调的影响，正如在各种心脏疾病中观察到的那样。本综述概述了心脏肌动蛋白特性如何在分子水平上发生变化，包括异构体多样性和翻译后修饰（乙酰化、氧化和磷酸化）在调节心肌硬度和收缩力方面的作用。然后我们考虑这种调节如何在心脏病中变得不平衡，重点是 titin 刚度和蛋白质质量控​​制的变化。在这种情况下，讨论了由于 titin 基因 (TTN) 截断引起的人类心肌病的关键病理机制的新见解。在此过程中，我们探讨了 titin 治疗获得性或遗传性心脏病的潜力，例如 HFpEF 或 TTN 截短型心肌病。