Myocardial pyruvate dehydrogenase kinase 4 drives sex-specific cardiac responses to endotoxemia
John Q. Yap, Azadeh Nikouee, Matthew Kim, Quan Cao, David J. Rademacher, Jessie E. Lau, Ananya Arora, Leila Y. Zou, Yuxiao Sun, Luke Szweda, Hesham Sadek, Sharon Elliot, Benjamin Roos, Marilyn K. Glassberg, Hong-Long Ji, Xiang Gao, Qunfeng Dong, Qun Sophia Zang
John Q. Yap, Azadeh Nikouee, Matthew Kim, Quan Cao, David J. Rademacher, Jessie E. Lau, Ananya Arora, Leila Y. Zou, Yuxiao Sun, Luke Szweda, Hesham Sadek, Sharon Elliot, Benjamin Roos, Marilyn K. Glassberg, Hong-Long Ji, Xiang Gao, Qunfeng Dong, Qun Sophia Zang
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Research Article Inflammation Metabolism

Myocardial pyruvate dehydrogenase kinase 4 drives sex-specific cardiac responses to endotoxemia

Abstract

Males often experience worse cardiac outcomes than females in sepsis. This study identified pyruvate dehydrogenase kinase 4 (PDK4) as a key mediator of this disparity. PDK4 regulates glucose utilization by inhibiting pyruvate dehydrogenase (PDH) in mitochondria. In a mouse endotoxemia model, a sublethal dose of lipopolysaccharide (LPS, 5 mg/kg) significantly upregulated myocardial PDK4 and induced cardiac dysfunction in males but not females. Cardiac-specific PDK4 overexpression promoted this cardiac dysfunction in both sexes, whereas PDK4 knockout provided protection. In WT males, LPS reduced PDH activity and fatty acid oxidation (FAO) while increasing lactate levels, suggesting a shift toward glycolysis. These effects were exacerbated by PDK4 overexpression but attenuated by knockout. In females, metabolic changes were minimal, aside from reduced FAO in LPS-challenged females overexpressing PDK4. Additionally, a higher LPS dose (8 mg/kg) triggered cardiac dysfunction in females, accompanied by modest upregulation of PDK4, but without changes in PDH or lactate. Dichloroacetate (DCA), restraining PDK-mediated PDH inhibition, improved cardiac function in males but not females during endotoxemia. PDK4 overexpression also exacerbated cardiac mitochondrial damage, reduced mitophagy, and increased oxidative stress and inflammation during endotoxemia — effects that were prevented by PDK4 knockout. These findings suggest that PDK4 drives sex-specific cardiac responses in sepsis.

Authors

John Q. Yap, Azadeh Nikouee, Matthew Kim, Quan Cao, David J. Rademacher, Jessie E. Lau, Ananya Arora, Leila Y. Zou, Yuxiao Sun, Luke Szweda, Hesham Sadek, Sharon Elliot, Benjamin Roos, Marilyn K. Glassberg, Hong-Long Ji, Xiang Gao, Qunfeng Dong, Qun Sophia Zang

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Figure 1

Association between PDK4 expression and cardiac performance in endotoxemia.

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Association between PDK4 expression and cardiac performance in endotoxem...
In A–C, mice were given LPS challenge (5 mg/kg) or sham treatment and experiments were conducted 18 hours after treatment. (A) PDK4 levels in cardiac mitochondria of WT mice were examined by Western blot. Signals were quantified by densitometry, and results were normalized to total protein (n = 5). (B) PDK4 mRNA expression in cardiac tissue of WT mice was examined by qPCR. Results were normalized to GAPDH (n = 6–9). (C) The cardiac function of WT, PDK4-Tg, and PDK4-KO mice was evaluated by echocardiography. Values of fractional shortening were compared (n = 5–7). (D) PDK4 mRNA expression in cardiac tissue of FCG mice was examined by qPCR. Results were normalized to GAPDH (n = 4–8). The FCG mice have 4 genotypes, including genetic males (XY) with male gonads, genetic males (XY) with female gonads, genetic females (XX) with male gonads, and genetic females (XX) with female gonads. Data are presented as mean ± SEM and were analyzed by 2-way ANOVA. *P < 0.05.