Abstract
Sex differences affect several diseases and are organ-and parameter-specific. In humans and animals, sex differences also influence the metabolism and homeostasis of amino acids and fatty acids, which are linked to the onset of diseases. Thus, the use of targeted metabolite profiles in tissues represents a powerful approach to examine the intermediary metabolism and evidence for any sex differences. To clarify the sex-specific activities of liver, heart and kidney tissues, we used targeted metabolomics, linear discriminant analysis (LDA), principal component analysis (PCA), cluster analysis and linear correlation models to evaluate sex and organ-specific differences in amino acids, free carnitine and acylcarnitine levels in male and female Sprague-Dawley rats. Several intra-sex differences affect tissues, indicating that metabolite profiles in rat hearts, livers and kidneys are organ-dependent. Amino acids and carnitine levels in rat hearts, livers and kidneys are affected by sex: male and female hearts show the greatest sexual dimorphism, both qualitatively and quantitatively. Finally, multivariate analysis confirmed the influence of sex on the metabolomics profiling. Our data demonstrate that the metabolomics approach together with a multivariate approach can capture the dynamics of physiological and pathological states, which are essential for explaining the basis of the sex differences observed in physiological and pathological conditions.
Highlights
Numerous sex differences in the epidemiology, prevention, natural history, therapy and outcomes of diseases have recently been recognized[1,2]
Carnitine and ACs are essential for the metabolism of fatty acids because they are vital for the transport of fatty acids across the mitochondrial membrane for beta oxidation, which produces acetyl-Coenzyme A and chain-shortened acyl products to preserve cellular coenzyme A (CoA) homeostasis[12,13]
Using a target metabolomic approach, we confirm that some amino acids and AC levels are organ-dependent in the rat heart, liver and kidney
Summary
Numerous sex differences in the epidemiology, prevention, natural history, therapy and outcomes of diseases have recently been recognized[1,2]. Cardiovascular diseases, diabetes mellitus, renal and liver diseases are strongly influenced by sex[1,2,3]. The exact influence of sex on carnitine and its acyl esters (acylcarnitines, ACs) is not known, some sex differences have been described, as in the case of free carnitine (C0) in plasma, liver, heart and skeletal muscle of pre-weaning rats[10]. Carnitine and ACs are essential for the metabolism of fatty acids because they are vital for the transport of fatty acids across the mitochondrial membrane for beta oxidation, which produces acetyl-Coenzyme A and chain-shortened acyl products to preserve cellular coenzyme A (CoA) homeostasis[12,13]. ACs are very relevant in tissues characterized by high rates of beta oxidation, such as cardiac muscle, in which approximately 70–80% of the energy requirements are derived from fatty acid oxidation[14]. Other intermediates can produce ACs7,16, whereas other tissues, such as skeletal muscle and heart acquire C0 from the blood[15,17]
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