Antioxidative stress metabolic pathways in moderately active individuals.

Almuraikhy S, Anwardeen N, Doudin A, Sellami M, Domling A, Agouni A, Althanu AA, and Elrayess MA. (2023) Antioxidative stress metabolic pathways in moderately active individuals. Metabolites

Physical activity is a well-established component of maintaining physical and mental well-being. In addition to improving blood pressure, improving lipid profile, lowering body fat percentage, and reducing risk of cardiovascular disease, it can also cause adaptions to cellular metabolism and immune cells and decrease oxidative stress. Oxidative stress is the inequality in the generation of free radicals, which are highly reactive, and the ability to rid the body of them using antioxidants. Although free radicals are produced through normal metabolic processes, the body needs to be able to successfully scavenge them. An antioxidant response from physical activity can be measured through protein oxidation, lipid oxidation, and exogenous antioxidant utilization though total antioxidant capacity (TAC), or antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase. Metabolomics can demonstrate the current metabolic state of an individual, however the understanding of the metabolic pathway behind the antioxidative response from physical activity is not well understood. Because of this, Almuraikhy et al were interested in elucidating these metabolic pathways from moderate physical activity in healthy individuals using untargeted metabolomics.

For this study, 305 participants were included and completed questionnaires regarding their physical activity, laboratory results for 66 clinically relevant metabolic traits were collected, and over 1000 metabolites were analysed. Physically active was defined as people who practice moderate physical activity for at least 150 minutes per week and not more than 300 minutes per week. Of the participants, 42% were physically active and 58% were sedentary. When the metabolic traits were examined, the active group showed reduced average pulse rate and mean cell hemoglobin concentration and increased level of handgrip, maximum heart rate, creatine kinase, AST, and HDL cholesterol compared to the sedentary group. When separating by sex some of these differences were found to be only in one sex, including reduced insulin, C-peptide, and triglycerides and increased handgrip in active males compared to sedentary males, while active females had lower maximum heartbeat and % of basophils and increased % lymphocytes, HDL, and total protein compared to the sedentary females.

Non-targeted metabolomics was used to compare whether the active and sedentary groups had different metabolic signatures throughout these participants. An obvious distinction was seen between the two groups, and it was found that a few specific metabolites drove the differences, seen below in Figure 1. The authors found that xanthine metabolites were greater in the sedentary group, and that vitamin A, glutathione metabolites, lysoplasmalogens, and plasmalogens were enriched in the active group. The authors looked further into the glutathione metabolism shown to be increased in the active group and specially found that cysteine-glutathione disulfide, 2-aminobutryate, cys-gly oxidized, and 2-hydroxybutyrate were elevated.

Almuraikhy et al were interested in determining the metabolic pathways behind the antioxidative response of moderate activity. Typical metabolism, which increases during exercise, also produces free radicals, therefore the body must have a way to compensate for this production as well as neutralizing additional free radicals for this process to be antioxidative. The body has several possible pathways that can be used to scavenge free radicals such as SOD, catalase, glutathione peroxidase, or producing antioxidant molecules including vitamin C, vitamin E, or plasmalogens. Plasmalogens are a unique type of lipid that contain a vinyl-ether bond at the sn-1 position which is able to scavenge two radical oxygen species, giving these lipids antioxidative properties. This study demonstrated a difference in oxidative stress-related metabolite levels between a sedentary and physically active group. One example is with plasmalogen and lysoplasmalogen metabolism where both were found to be enriched in the active group. As plasmalogens have antioxidative properties, this increase could be one mechanism that physical activity is increasing the antioxidant level in cells. Glutathione metabolism was another pathway that was enriched in the active participants. Its synthesis is known to remove peroxides and xenobiotic molecules and glutathione has protective functions through interactions with other non-enzymatic antioxidants. One challenge with a study on physical activity is that every person’s body is going to respond very differently, and type and level of activity and nutrition will have very influential roles in the metabolic pathways. Although Almuraikhy et al demonstrated some trends in their data, it would be interesting to see how this differs regionally, by age, and health status. There has been plenty of work looking at the short-term effects of exercise on metabolism, but this work could provide clarity on its long-term effects.