Molecular Mechanism(s) of Sex Differences in Lipid Metabolism in Human Skeletal Muscle

Abstract

<p> It is well understood that compared with men, women are better able to withstand starvation, have better ultra-endurance capacity, oxidize more fat during endurance exercise, and are more resistant to fat oxidation defects i.e. diet-induced insulin resistance. However, the mechanism(s) for the observed sex differences are unknown. It was my hypothesis that women have greater fat oxidation capacity in skeletal muscle than men.</p> <p> The objectives of my thesis were to determine the mechanism(s) by which women oxidize more lipids; including the role of estrogen as a possible regulator. The most significant findings were that: 1) mRNA for fatty acid oxidation genes are higher in women compared with men, which was confirmed by Stringent Affymetrix GeneChip array analysis, combined with RT-PCR (chapter 2); 2) long-chain acyl-CoA dehydrogenase in human skeletal muscle is not quantifiable despite the majority (90%) of fatty acids oxidized during exercise are long-chain fatty acids (chapter 3); 3) β-oxidation enzymes: tri-functional protein alpha, very long chain acyl-CoA dehydrogenase, and medium chain acyl-CoA dehydrogenase are significantly higher in women compared with men (chapter 4); 4) Acute (8 days) 17β-estradiol supplementation in men significantly increased protein content of β-oxidation enzymes in skeletal muscle, possibly through the regulation of PGC-1α and microRNA (chapter 5).</p> <p> In conclusion, my data provided novel insights into the enhanced ability of women to oxidize fat under periods of metabolic stress by showing that: 1) women are transcriptionally (mRNA) "primed" for known physiological differences in metabolism; 2) women have more protein content of the major enzymes involved in long and medium chain fatty acid oxidation; 3) E2 partially regulates lipid metabolism in skeletal muscle by pre-translational modifications of factors involved in β-oxidation. These findings contribute to the molecular understanding of sex differences in substrate utilization.</p>