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

Deng‐tai Wen; Lan Zheng; Jinxiu Li; Dan Cheng; Yang Liu; Kai Lǚ; Wen-Qi Hou

doi:10.1242/bio.044719

October 15, 2019Biology OpenOpen Access

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

View Full Paper

Ask AI

Bookmark

Share

Why the study?

The relationship between exercise, the NAD+/dSIR2/PGC-1α pathway, and lipotoxic cardiomyopathy remained unknown.

Structured PICO

P

Population

Old Drosophila (flies) fed a high-fat diet (HFD) or with cardiac dSir2 knockdown via UAS/hand-Gal4 system

I

Intervention

Endurance exercise training or cardiac dSir2 overexpression

C

Comparator

No exercise (HFD alone) or dSir2 knockdown alone

O

Outcome

Cardiac triglyceride (TG) level, dFAS expression, heart fractional shortening, diastolic diameter, arrhythmia index, and NAD+/dSIR2/PGC-1α pathway expressionsurrogate

Exercise training improves lipotoxic cardiomyopathy in old Drosophila via activation of the NAD+/dSIR2/PGC-1α pathway.

Implication

Hypothesis-generating for NAD+/SIR2/PGC-1α activation in lipotoxic cardiomyopathy; warrants mammalian validation before clinical consideration.

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.