Key result
Endurance exercise and cardiac Nmnat overexpression protected against high-fat diet-induced lipotoxic cardiomyopathy in Drosophila by activating cardiac Nmnat/NAD+/SIR2 pathways.
Why the study?
The molecular mechanisms by which endurance exercise resists and treats high-fat diet-induced lipotoxic cardiomyopathy are poorly understood.
Does endurance exercise or cardiac Nmnat overexpression prevent HFD-induced lipotoxic cardiomyopathy in Drosophila?
Does endurance exercise or cardiac Nmnat overexpression prevent HFD-induced lipotoxic cardiomyopathy in Drosophila?
Endurance exercise protects against high-fat diet-induced lipotoxic cardiomyopathy in Drosophila by activating the cardiac Nmnat/NAD+/SIR2 pathways.
Caution against human translation from Drosophila data; leaves open Nmnat/NAD+ pathway targeting in lipotoxic cardiomyopathy.
Endurance exercise is an important way to resist and treat high-fat diet (HFD)-induced lipotoxic cardiomyopathy, but the underlying molecular mechanisms are poorly understood. Here, we used Drosophila to identify whether cardiac Nmnat/NAD+/SIR2 pathway activation mediates endurance exercise-induced resistance to lipotoxic cardiomyopathy. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and the Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO and PGC-1α expression, superoxide dismutase (SOD) activity and NAD+ levels, and it prevented HFD-induced or cardiac Nmnat knockdown-induced cardiac lipid accumulation, malondialdehyde (MDA) content and fibrillation increase, and fractional shortening decrease. Cardiac Nmnat overexpression also activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiac Nmnat knockdown flies. Therefore, the current results confirm that cardiac Nmnat/NAD+/SIR2 pathways are important antagonists of HFD-induced lipotoxic cardiomyopathy. Cardiac Nmnat/NAD+/SIR2 pathway activation is an important underlying molecular mechanism by which endurance exercise and cardiac Nmnat overexpression give protection against lipotoxic cardiomyopathy in Drosophila.
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Wen et al. (2021) studied High-fat diet (HFD)-induced lipotoxic cardiomyopathy. Endurance exercise and cardiac Nmnat overexpression vs. High-fat diet alone / cardiac Nmnat knockdown was evaluated on Cardiac Nmnat/NAD+/SIR2 pathway activation, cardiac lipid accumulation, MDA content, fibrillation, and fractional shortening. Endurance exercise and cardiac Nmnat overexpression protected against high-fat diet-induced lipotoxic cardiomyopathy in Drosophila by activating cardiac Nmnat/NAD+/SIR2 pathways.
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