The activation of cardiac dSir2-related pathways mediates physical exercise resistance to heart aging in old Drosophila

Abstract

Cardiac aging is majorly characterized by increased diastolic dysfunction, lipid accumulation, oxidative stress, and contractility debility. The Sir2/Sirt1 gene overexpression delays cell aging and reduces obesity and oxidative stress. Exercise improves heart function and delays heart aging. However, it remains unclear whether exercise delaying heart aging is related to cardiac Sir2/Sirt1-related pathways. In this study, cardiac dSir2 overexpression or knockdown was regulated using the UAS/hand-Gal4 system in Drosophila. Flies underwent exercise interventions from 4 weeks to 5 weeks old. Results showed that either cardiac dSir2 overexpression or exercise remarkably increased the cardiac period, systolic interval, diastolic interval, fractional shortening, SOD activity, dSIR2 protein, Foxo, dSir2, Nmnat, and bmm expression levels in the aging flies; they also notably reduced the cardiac triacylglycerol level, malonaldehyde level, and the diastolic dysfunction index. Either cardiac dSir2 knockdown or aging had almost opposite effects on the heart as those of cardiac dSir2 overexpression. Therefore, we claim that cardiac dSir2 overexpression or knockdown delayed or promoted heart aging by reducing or increasing age-related oxidative stress, lipid accumulation, diastolic dysfunction, and contractility debility. The activation of cardiac dSir2/Foxo/SOD and dSir2/Foxo/bmm pathways may be two important molecular mechanisms through which exercise works against heart aging in Drosophila.

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

“…Both rats and mice can improve heart disease induced by high glucose or high fat through regular exercise [ 38 , 39 ]. Drosophila has shown similar results to mammals in terms of heart damage caused by high fat or high sugar [ 40 , 41 ]. In addition, exercise also has many benefits for flies.…”

Exercise-induced signaling pathways to counteracting cardiac apoptotic processes

“…Akt phosphorylates the transcription factors of the FOXO family, leading to their exit from the nucleus and their destruction in the cytosol via the ubiquitin-proteasome pathway ( Xia et al, 2016 ). In drosophila , after exercise (2 weeks), SIRT1 appears to inhibit the ability of FOXO3 to induce cell death, leading to an increase in a variety of antioxidant genes, including MnSOD ( Wen et al, 2019 ). Long-term and moderate exercise (75% of VO 2max for 6 weeks) before infarction injury has also been shown to increase FOXO3 and its two downstream targets, MnSOD, and catalase, compared to sedentary rats with infarction ( Donniacuo et al, 2019 ).…”

“…Increase (Burgess et al, 2001;Burgess et al, 2002;Brancaccio et al, 2006;Wilkinson et al, 2008;Manso et al, 2009;Flueck et al, 2011;Muthuchamy et al, 2012;Li et al, 2013;Watson and Baar, 2014;Graham et al, 2015a;Graham et al, 2015b;Franchi et al, 2018) Aerobic exercise 56-66% of VO2max for 4 weeks FSTL1-USP10-Notch1, Notch3, sFLT1 Increase (Xi et al, 2016;Lu et al, 2021) Aerobic exercise 75% of maximal metabolic for 12 weeks Notch1/Akt/eNOS Increase Liang et al (2021) Aerobic exercise 75% of VO2max for 6 weeks SIRT1, MnSOD, PGC-1α, HIF-1α, VEGF, catalase Increase (Rinaldi et al, 2013;Wen et al, 2019) Swimming training 48-72% of VO2max for 5 weeks…”

Endurance exercise protects agingDrosophilafrom high-salt diet(HSD)-induced climbing capacity decline and lifespan decrease by enhancing antioxidant capacity

“…Recent studies report that endurance exercise protects flies from obesity and lifespan reduction induced by a high-fat diet when exercise and a high-fat diet are present at the same time (Wen et al, 2018). Endurance exercise can delay heart aging by enhancing antioxidant ability and NAD/SIR2 related pathway (Wen et al, 2019). Moreover, different CG9940 gene expression and PGC-1α expression can affect the adaption of climbing ability and lifespan to exercise in flies (Tinkerhess et al, 2012;Wen et al, 2016).…”

“…For instance, the dFOXO overexpression decreased mortality and increased lifespan of flies via reducing oxidative stress, and the dFOXO is required both for transcriptional changes that mark the fly's dietary history and for nutritional programming of lifespan by excess dietary sugar (Blice-Baum et al, 2015;Dobson et al, 2017;Lee et al, 2017;Liu et al, 2012). In addition, endurance exercise can delay heart aging by activating dFOXO/SOD pathway (Wen et al, 2019). In here, we identified that the dFOXO gene overexpression played an important role in fighting the effects of a HSD on reduced exercise capacity and life expectancy.…”