Key result
Swimming exercise improved left ventricular ejection fraction following ischemia-reperfusion injury in mice (57.72% vs 51.29%), an effect that was attenuated by G6PD knockdown.
Why the study?
The molecular mechanism by which exercise benefits cardiac metabolism and function, particularly via NADPH and the pentose phosphate pathway, remains largely unknown.
Does activation of the pentose phosphate pathway-derived NADPH or treatment with lyciumspermidine-0527 promote physiological cardiomyocyte growth and alleviate ischemia-reperfusion injury in preclinical models?
Does activation of the pentose phosphate pathway-derived NADPH or treatment with lyciumspermidine-0527 promote physiological cardiomyocyte growth and alleviate ischemia-reperfusion injury in preclinical models?
Absolute Event Rate: 57.72% vs 51.29%
p-value: p=<0.05
Activation of the pentose phosphate pathway and resulting cytosolic NADPH elevation promotes physiological cardiac hypertrophy and protects against ischemia-reperfusion injury, revealing a potential novel therapeutic target.
Exercise promotes physiological cardiomyocyte growth and protects against ischaemia-reperfusion (IR) injury in the heart. The molecular mechanism by which exercise benefits cardiac metabolism and function remains largely unknown. Here, using a genetically encoded fluorescent sensor, we show that exercise increases cytosolic, but not mitochondrial, NADPH levels in cardiomyocytes. This effect is mediated by activation of the pentose phosphate pathway (PPP). Inhibition of PPP activity or depletion of cytosolic NADPH attenuates exercise-induced heart hypertrophy in mice. We observe that NADPH promotes cardiomyocyte growth by inhibiting HDAC3/C/EBPβ pathways. Moreover, exercise-activated PPP/NADPH pathway suppresses acute IR injury and preserves heart function 4 weeks after IR. Among 310 tested Tibetan compounds, the spermidine derivative lyciumspermidine-0527 directly activates the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase, elevates intracellular NADPH levels and alleviates IR injury. Altogether, these results show that PPP-derived NADPH is a critical metabolic checkpoint that regulates exercise-induced physiological cardiomyocyte growth and protects against IR-induced heart injury.
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Wu et al. (2026) studied Myocardial ischemia-reperfusion injury. Swimming exercise vs. Sedentary control was evaluated on Left ventricular ejection fraction (EF) after ischemia-reperfusion injury (p=<0.05). Swimming exercise improved left ventricular ejection fraction following ischemia-reperfusion injury in mice (57.72% vs 51.29%), an effect that was attenuated by G6PD knockdown.
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