Abstract
The mechanistic target of rapamycin (mTOR) is a nutrient-sensitive cellular signaling kinase that has been implicated in the excess production of reactive oxygen species (ROS). NADPH oxidase-derived ROS have been implicated in erectile dysfunction pathogenesis. The objective of this study was to determine if mTOR is an activator of NADPH oxidase in the penis and to determine the functional relevance of this pathway in a translationally relevant model of diet-induced erectile dysfunction. Male mice were fed a control diet or a high-fat, high-sucrose Western style diet (WD) for 12 weeks and treated with vehicle or rapamycin for the final 4 weeks of the dietary intervention. Following the intervention, erectile function was assessed by cavernous nerve-stimulated intracavernous pressure measurement, in vivo ROS production was measured in the penis using a microdialysis approach, and relative protein contents from the corpus cavernosum were determined by Western blot. Erectile function was impaired in vehicle treated WD-mice and was preserved in rapamycin treated WD-mice. Penile NADPH oxidase-mediated ROS were elevated in WD-mice and suppressed by rapamycin treatment. Western blot analysis suggests mTOR activation with WD by increased active site phosphorylation of mTOR and p70S6K, and increased expression of NADPH oxidase subunits, all of which were suppressed by rapamycin. These data suggest that mTOR is an upstream mediator of NADPH oxidase in the corpus cavernosum in response to a chronic Western diet, which has an adverse effect on erectile function.
Highlights
There has been a steady decline in the amount of time that Americans spend preparing their own food over the past six decades, a trend that spans all socioeconomic classes [1].This trend has led to a steady incline in the consumption of processed, packaged, and pre-prepared foods, which are often replete with added sugar and fat from cheap vegetable oils [2]
Lean mass was similar among all groups, while fat mass and body fat percentage were doubled in mice fed the Western style diet (WD)
Post hoc analysis revealed WD fed mice treated with rapamycin had higher total and LDL-cholesterol levels than all other groups
Summary
There has been a steady decline in the amount of time that Americans spend preparing their own food over the past six decades, a trend that spans all socioeconomic classes [1] This trend has led to a steady incline in the consumption of processed, packaged, and pre-prepared foods, which are often replete with added sugar and fat from cheap vegetable oils [2]. Epidemiological studies indicate that Western style diets increase risk for erectile dysfunction (ED) [8,9] This is of concern as recent dietary trends and projections suggest an increased consumption of ultraprocessed foods, sugar-sweetened foods and beverages, and vegetable oils in many regions of the world not traditionally associated with
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