Abstract
We determined the short- and long-term effects of a ketogenic diet (KD) or ketone salt (KS) supplementation on multi-organ oxidative stress and mitochondrial markers. For short-term feedings, 4 month-old male rats were provided isocaloric amounts of KD (n = 10), standard chow (SC) (n = 10) or SC + KS (~1.2 g/day, n = 10). For long-term feedings, 4 month-old male rats were provided KD (n = 8), SC (n = 7) or SC + KS (n = 7) for 8 months and rotarod tested every 2 months. Blood, brain (whole cortex), liver and gastrocnemius muscle were harvested from all rats for biochemical analyses. Additionally, mitochondria from the brain, muscle and liver tissue of long-term-fed rats were analyzed for mitochondrial quantity (maximal citrate synthase activity), quality (state 3 and 4 respiration) and reactive oxygen species (ROS) assays. Liver antioxidant capacity trended higher in short-term KD- and SC + KS-fed versus SC-fed rats, and short-term KD-fed rats exhibited significantly greater serum ketones compared to SC + KS-fed rats indicating that the diet (not KS supplementation) induced ketonemia. In long term-fed rats: (a) serum ketones were significantly greater in KD- versus SC- and SC + KS-fed rats; (b) liver antioxidant capacity and glutathione peroxidase protein was significantly greater in KD- versus SC-fed rats, respectively, while liver protein carbonyls were lowest in KD-fed rats; and (c) gastrocnemius mitochondrial ROS production was significantly greater in KD-fed rats versus other groups, and this paralleled lower mitochondrial glutathione levels. Additionally, the gastrocnemius pyruvate-malate mitochondrial respiratory control ratio was significantly impaired in long-term KD-fed rats, and gastrocnemius mitochondrial quantity was lowest in these animals. Rotarod performance was greatest in KD-fed rats versus all other groups at 2, 4 and 8 months, although there was a significant age-related decline in performance existed in KD-fed rats which was not evident in the other two groups. In conclusion, short- and long-term KD improves select markers of liver oxidative stress compared to SC feeding, although long-term KD feeding may negatively affect skeletal muscle mitochondrial physiology.
Highlights
Ketogenic diets (KD) are high fat, moderate protein and low carbohydrate diets that have been associated with a myriad of health benefits including weight loss/management, neurological improvements and longevity [1,2]
Fold-change for each values (n = 7–8 per group), group means are indicated within each bar and analysis of variance (ANOVA) p-values are protein are expressed relative to the standard chow (SC) group, all bars are presented as mean ± standard error values oxidative stress-related and markersrats; in 8 ketogenic diet (KD), month-fed rats.diet-fed
Liver oxidative stress-related markers in 8presented month-fed rats.± Legend: Liver catalase catalase (Cat), glutathione peroxidase (Gpx), and mitochondrial superoxide dismutase (Sod2) protein values (n = 7–8 per group), group means are indicated within each bar, ANOVA p-values are
Summary
Ketogenic diets (KD) are high fat, moderate protein and low carbohydrate diets that have been associated with a myriad of health benefits including weight loss/management, neurological improvements (e.g., treatment of epilepsy and certain brain cancers) and longevity [1,2]. Nrf has been shown to upregulate the mRNA expression glutamate-cysteine ligase (GCL) subunits which is the rate limiting enzyme in glutathione biosynthesis [16,17] In support of this model, Milder and colleagues [18] reported that KD feeding stimulates H2 O2 and 4-HNE production in the hippocampus of rodents within a. Based upon the aforementioned supporting literature, it stands to reason that KD feeding or dietary ketone salt supplementation may mitigate ROS production or attenuate oxidative stress over long-term periods which, in turn, may improve mitochondrial quality. Rats, this would translate to a reduction in tissue oxidative stress markers and enhanced mitochondrial quantity and quality
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