A Drosophila Model of High Sugar Diet-Induced Cardiomyopathy

Diets high in carbohydrates have long been linked to progressive heart dysfunction, yet the mechanisms by which chronic high sugar leads to heart failure remain poorly understood. Here we combine diet, genetics, and physiology to establish an adult Drosophila melanogaster model of chronic high sugar-induced heart disease. We demonstrate deterioration of heart function accompanied by fibrosis-like collagen accumulation, insulin signaling defects, and fat accumulation. The result was a shorter life span that was more severe in the presence of reduced insulin and P38 signaling. We provide evidence of a role for hexosamine flux, a metabolic pathway accessed by glucose. Increased hexosamine flux led to heart function defects and structural damage; conversely, cardiac-specific reduction of pathway activity prevented sugar-induced heart dysfunction. Our data establish Drosophila as a useful system for exploring specific aspects of diet-induced heart dysfunction and emphasize enzymes within the hexosamine biosynthetic pathway as candidate therapeutic targets.长期以来，高碳水化合物饮食与进行性心脏功能障碍密切相关，但慢性高糖摄入导致心力衰竭的具体分子机制仍未得到充分阐释。本研究结合饮食干预、遗传学与生理学研究手段，成功构建了慢性高糖诱导心脏病的成年黑腹果蝇（Drosophila melanogaster）模型。研究发现，该模型果蝇的心脏功能出现衰退，同时伴随类纤维化胶原沉积、胰岛素信号通路缺陷与脂肪堆积，且当胰岛素与P38信号通路活性受抑时，果蝇的寿命缩短表型会进一步恶化。本研究证实了己糖胺通量（hexosamine flux）——一种由葡萄糖激活的代谢通路——在该过程中的关键作用：增强的己糖胺通量会引发心脏功能缺陷与结构损伤；反之，若在心脏组织中特异性抑制该通路的活性，则可阻断高糖诱导的心脏功能障碍。本研究结果证实，黑腹果蝇可作为探究饮食诱导心脏功能障碍特定机制的理想实验系统，同时也明确了己糖胺生物合成通路（hexosamine biosynthetic pathway）中的相关酶类可作为潜在的治疗靶点。