The genetic basis of heart development is remarkably conserved from Drosophila to mammals, and insights from flies have greatly informed our understanding of vertebrate heart development. Recent ev...

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. Heart disease remains the most common source of mortality in the American population. The Western diet has been implicated as an important factor, though the mechanisms by which high levels of dietary sugar and fat contribute to heart failure remain controversial. Here, we use the fruit fly Drosophila to explore the role of diet on progressive heart failure. We show that elevated levels of dietary sugar are sufficient to direct progressive heart failure in flies including arrhythmia, reduced fractional shortening, and aspects of fibrosis. We demonstrate the importance of multiple cellular pathways, including the hexosamine biosynthetic pathway, as important for mediating these progressive defects, suggesting a potential avenue towards therapeutics.

Amyloid-like inclusions have been associated with Huntington's disease (HD), which is caused by expanded polyglutamine repeats in the Huntingtin protein. HD patients exhibit a high incidence of cardiovascular events, presumably as a result of accumulation of toxic amyloid-like inclusions. We have generated a Drosophila model of cardiac amyloidosis that exhibits accumulation of PolyQ aggregates and oxidative stress in myocardial cells, upon heart-specific expression of Huntingtin protein fragments (Htt-PolyQ) with disease-causing poly-glutamine repeats (PolyQ-46, PolyQ-72, and PolyQ-102). Cardiac expression of GFP-tagged Htt-PolyQs resulted in PolyQ length-dependent functional defects that included increased incidence of arrhythmias and extreme cardiac dilation, accompanied by a significant decrease in contractility. Structural and ultrastructural analysis of the myocardial cells revealed reduced myofibrillar content, myofibrillar disorganization, mitochondrial defects and the presence of PolyQ-GFP positive aggregates. Cardiac-specific expression of disease causing Poly-Q also shortens lifespan of flies dramatically. To further confirm the involvement of oxidative stress or protein unfolding and to understand the mechanism of PolyQ induced cardiomyopathy, we co-expressed expanded PolyQ-72 with the antioxidant superoxide dismutase (SOD) or the myosin chaperone UNC-45. Co-expression of SOD suppressed PolyQ-72 induced mitochondrial defects and partially suppressed aggregation as well as myofibrillar disorganization. However, co-expression of UNC-45 dramatically suppressed PolyQ-72 induced aggregation and partially suppressed myofibrillar disorganization. Moreover, co-expression of both UNC-45 and SOD more efficiently suppressed GFP-positive aggregates, myofibrillar disorganization and physiological cardiac defects induced by PolyQ-72 than did either treatment alone. Our results demonstrate that mutant-PolyQ induces aggregates, disrupts the sarcomeric organization of contractile proteins, leads to mitochondrial dysfunction and increases oxidative stress in cardiomyocytes leading to abnormal cardiac function. We conclude that modulation of both protein unfolding and oxidative stress pathways in the Drosophila heart model can ameliorate the detrimental PolyQ effects, thus providing unique insights into the genetic mechanisms underlying amyloid-induced cardiac failure in HD patients. Huntington's disease (HD) is associated with amyloid-like inclusions in the brain and heart, and accumulation of amyloid protein is associated with neurodegeneration and cardiomyopathy. Recent studies suggest that HD patients show increased susceptibility to cardiac failure. However, the mechanisms by which disease-causing poly-glutamine repeats (PolyQ) cause heart dysfunction in these patients are unclear. We have developed a novel Drosophila heart model that exhibits significant GFP-positive aggregates upon HD-causing PolyQ expression in myocardial cells resulting in PolyQ length-dependent physiological defects. Modulation of protein folding and oxidative stress pathways in this system reduced the number of aggregates and reversed the cardiac dysfunction in response to expression of disease-causing PolyQ. The ability to explore PolyQ-associated mechanisms of cardiomyopathy in a genetically tractable whole organism, Drosophila melanogaster, promises to provide novel insights into the relationship between amyloid accumulation and heart dysfunction. Our findings not only impact the understanding of PolyQ-induced cardiomyopathy but also other human cardiac diseases associated with oxidative stress, mitochondrial defects and protein homeostasis.

Technique required for visualizing the beating heart in larval and adult Drosophila are presented. Each life stage requires a...