Endurance exercise resistance to lipotoxic cardiomyopathy is associated with cardiac NAD+/dSIR2/PGC-1αpathway activation in oldDrosophila

Abstract

Lipotoxic cardiomyopathy is caused by excessive lipid accumulation in myocardial cells and it is a form of cardiac dysfunction. Cardiac PGC-1α overexpression prevents lipotoxic cardiomyopathy induced by a high-fat diet (HFD). The level of NAD+ and Sir2 expression upregulate the transcriptional activity of PGC-1α. Exercise improves cardiac NAD+ level and PGC-1α activity. However, the relationship between exercise, NAD+/dSIR2/PGC-1α pathway and lipotoxic cardiomyopathy remains unknown. In this study, flies were fed a HFD and exercised. The heart dSir2 gene was specifically expressed or knocked down by UAS/hand-Gal4 system. The results showed that either a HFD or dSir2 knockdown remarkably increased cardiac TG level and dFAS expression, reduced heart fractional shortening and diastolic diameter, increased arrhythmia index, and decreased heart NAD+ level, dSIR2 protein, dSir2 and PGC-1α expression levels. Contrarily, either exercise or dSir2 overexpression remarkably reduced heart TG level, dFAS expression and arrhythmia index, and notably increased heart fractional shortening, diastolic diameter, NAD+ level, dSIR2 level, and heart dSir2 and PGC-1α expression. Therefore, we declared that exercise training could improve lipotoxic cardiomyopathy induced by a HFD or cardiac dSir2 knockdown in old Drosophila. The NAD+/dSIR2/PGC-1α pathway activation was an important molecular mechanism of exercise resistance against lipotoxic cardiomyopathy.

Effects of Drosophila melanogaster regular exercise and apolipoprotein B knockdown on abnormal heart rhythm induced by a high-fat diet

“…An HFD can cause cardiac lipid toxicity and induce cardiac dysfunction, mainly including arrhythmia, fibrillation, and weakened contractility [ 5 , 11 , 12 , 31 ]. However, it is unclear whether abnormal heart rhythm induced by an HFD is affected by apoLpp .…”

“…Atrial fibrillation (AF) in humans is a clinically severe arrhythmia, similar to the fibrillation of the Drosophila myocardium. A HFD in Drosophila can increase the heart rate and arrhythmia index and cause fibrillation [ 5 ]. Fibrillation of the Drosophila heart may result from lipotoxic damage related to the insulin-TOR signal, which is moderate reduction in insulin-TOR signaling prevents HFD-induced obesity and cardiac dysfunction [ 4 ].…”

“…Obesity increases the incidence of atrial fibrillation, but this can be reduced by exercise [ 10 ]. In Drosophila , moderate exercise can reduce HFD-induced lipid toxicity damage to the heart, reduce the occurrence of fibrillation, and improve heart rhythm and contractile function [ 5 , 11 , 12 ]. However, the effects of regular exercise combined with cardiomyocyte apoLpp knockdown on abnormal heart rhythm under HFD are unclear.…”

Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases

“…A recent study performed in 48 young middle-aged recreationally trained runners supplemented with NMN for 6 weeks revealed that exercise training combined with NMN further elevated the ventilatory threshold in amateur runners, most likely due to enhanced O 2 utilization of skeletal muscle rather than cardiac muscle [ 273 ]. Although cardiac function was not analyzed in this study, recent data in aged Drosophila demonstrated that exercise training can improve lipotoxic cardiomyopathy induced by a high-fat diet [ 274 , 275 ]. Because activation of the cardiac NMNAT/NAD+/SIR2/FOXO and NMNAT/NAD+/SIR2/PGC-1α pathways was identified to mediate the beneficial effects of endurance training in this animal model, NMN administration can be hypothesized to further potentiate exercise resistance to high-fat diet-induced cardiomyopathy.…”

Physical exercise prevents age-related heart dysfunction induced by high-salt intake and heart salt-specific overexpression in Drosophila

“…Besides, a long-term endurance exercise can prevent heart premature aging induced by a high fat diet in fruit flies [25]. The mechanism of exercise delay heart aging is also related to the TOR, the FOXO, and the PGC-1α activity [6,10,26,27]. However, it remains unknown whether a long-term endurance exercise can efficiently prevent heart presenility induced by a long-term highsalt stress.…”