Nutrition Sciences Division, Department of Human Sciences and Design, Robbins College of Health and Human Sciences, Baylor University, Waco, TX, USA.
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA.
Sci Rep. 2021 Dec 8;11(1):23627. doi: 10.1038/s41598-021-02688-z.
Cachexia is a muscle wasting syndrome occurring in many advanced cancer patients. Cachexia significantly increases cancer morbidity and mortality. Cardiac atrophy and contractility deficits have been observed in patients and in animal models with cancer cachexia, which may contribute to cachexia pathophysiology. However, underlying contributors to decreased in vivo cardiac contractility are not well understood. In this study, we sought to distinguish heart-intrinsic changes from systemic factors contributing to cachexia-associated cardiac dysfunction. We hypothesized that isolated heart and cardiac myocyte functional deficits underlie in vivo contractile dysfunction. To test this hypothesis, isolated heart and cardiac myocyte function was measured in the colon-26 adenocarcinoma murine model of cachexia. Ex vivo perfused hearts from cachectic animals exhibited marked contraction and relaxation deficits during basal and pacing conditions. Isolated myocytes displayed significantly decreased peak contraction and relaxation rates, which was accompanied by decreased peak calcium and decay rates. This study uncovers significant organ and cellular-level functional deficits in cachectic hearts outside of the catabolic in vivo environment, which is explained in part by impaired calcium cycling. These data provide insight into physiological mechanisms of cardiomyopathy in cachexia, which is critical for the ultimate development of effective treatments for patients.
恶病质是一种发生在许多晚期癌症患者中的肌肉消耗综合征。恶病质显著增加了癌症的发病率和死亡率。在患有恶病质的癌症患者和动物模型中，已经观察到心脏萎缩和收缩功能缺陷，这可能导致恶病质的病理生理学发生。然而，导致体内心脏收缩力下降的潜在因素尚不清楚。在这项研究中，我们试图区分导致恶病质相关心脏功能障碍的心脏内在变化和系统性因素。我们假设孤立心脏和心肌细胞功能缺陷是导致体内收缩功能障碍的基础。为了验证这一假设，我们在结肠-26 腺癌恶病质的小鼠模型中测量了孤立心脏和心肌细胞的功能。在基础和起搏条件下，来自恶病质动物的离体心脏表现出明显的收缩和舒张功能障碍。分离的心肌细胞的峰值收缩和舒张速度明显降低，同时伴有峰值钙和衰减速度降低。这项研究揭示了恶病质心脏在代谢环境之外的明显器官和细胞水平的功能缺陷，这部分是由钙循环受损引起的。这些数据为恶病质性心肌病的生理机制提供了深入的了解，这对于最终为患者开发有效的治疗方法至关重要。
