Sex differences in metabolic pathways are regulated by Pfkfb3 and Pdk4 expression in rodent muscle

Abstract

Skeletal muscles display sexually dimorphic features. Biochemically, glycolysis and fatty acid β-oxidation occur preferentially in the muscles of males and females, respectively. However, the mechanisms of the selective utilization of these fuels remains elusive. Here, we obtain transcriptomes from quadriceps type IIB fibers of untreated, gonadectomized, and sex steroid-treated mice of both sexes. Analyses of the transcriptomes unveil two genes, Pfkfb3 (phosphofructokinase-2) and Pdk4 (pyruvate dehydrogenase kinase 4), that may function as switches between the two sexually dimorphic metabolic pathways. Interestingly, Pfkfb3 and Pdk4 show male-enriched and estradiol-enhanced expression, respectively. Moreover, the contribution of these genes to sexually dimorphic metabolism is demonstrated by knockdown studies with cultured type IIB muscle fibers. Considering that skeletal muscles as a whole are the largest energy-consuming organs, our results provide insights into energy metabolism in the two sexes, during the estrus cycle in women, and under pathological conditions involving skeletal muscles.

Roles of Estrogen, Estrogen Receptors, and Estrogen-Related Receptors in Skeletal Muscle: Regulation of Mitochondrial Function

“…Nitric oxide synthase, a known downstream target of estrogen, is a candidate that mediates the enhanced exercise performance in females. A recent transcriptomic study demonstrated that pyruvate dehydrogenase kinase isoform 4 (Pdk4), a key mitochondrial enzyme to inhibit pyruvate dehydrogenase in glycolysis, is upregulated by estrogen treatment in ovariectomized mice [30]. The report further revealed that the fatty acid-dependent oxidative metabolism is enhanced by estrogen treatment.…”