Exercise affects almost all tissues of the human body. Scientists have found that physical exercise can reduce the risk of cancer and improve the prognosis of cancer patients. People who keep exercising tend to have a lower incidence of cancer, which is proportional to the frequency and intensity of exercise. The metabolic demands of strenuous physical activity usually lead to major changes in nutrient utilization, mainly through central carbon metabolism. The metabolic changes caused by these exercises will affect the ratio of energy substrates used and may change the distribution of metabolic products in the muscle.
The activity of immune cells is closely related to their metabolism. Many aspects of immune cell energetics may be sensitive to metabolic changes caused by exercise. It is well known that exercise affects the function of immune cells, and the altered immune response is considered to be the potential mechanism of exercise for cancer risk and progression. Recently, researchers at the Karolinska Institute in Sweden used mice to study how exercise helps the immune system to resist the progression of tumors, and found an explanation why exercise helps to slow down cancer growth in mice: physical activity Changes the metabolism of cytotoxic T cells of the immune system, thereby increasing their ability to attack cancer cells. This study was published in the journal e Life.
When mice exercise, the growth of tumors decreases, and this decrease depends on the level of CD8 + T cells of specific types of immune cells circulating in the blood. Researchers found that the molecules released by muscles into the blood during exercise make CD8 + T cells more active. When the immune cells of frequently exercised mice are transferred to non-exercising mice, the resistance of non-exercising mice to tumor cells Power is higher. These results indicate that CD8 + T cells are altered through exercise to increase their effectiveness against tumors. The ability of T cells to recognize and eliminate cancer cells is essential to prevent tumor growth and is also one of the foundations of current immunotherapy methods. Exercise can improve the effects of these treatments by enhancing the activation of the immune system, thereby making anti-tumor cells more effective.
In order to study how the systemic utilization of metabolites changes with exercise, the researchers conducted metabolomics studies on muscle and plasma that respond to exercise. A detailed endurance test was performed on wild-type mice under the background of FVB. Skeletal muscle and plasma were obtained immediately after exercise, frozen and analyzed by mass spectrometry (GC-MS).
Exercise affects a wide range of metabolic pathways, especially exercise reduces the frequency of glycolytic metabolites in skeletal muscle, such as fructose 6 phosphate, glucose 6 phosphate and 3-phosphoglycerate, and the frequency of certain TCA metabolites such as muscle after exercise The citric acid, fumaric acid and malic acid in the citric acid are significantly increased, which is consistent with the rate limitation of mitochondrial metabolism in high-intensity exercise. Interestingly, the TCA metabolites citric acid, malic acid and alpha ketoglutarate in plasma after exercise are all higher, indicating that these metabolites are released from the muscles into the plasma.
To extend the information to the lymphatic organs, the researchers performed another detailed set of endurance tests on mice, and then immediately harvested skeletal muscle, plasma, spleen, muscle draining (axillary) and non-draining (groin) lymph nodes. In addition, plasma was collected before exercise, after exercise, and 1 hour after exercise for people who were often sedentary, and then analyzed these tissues by ultra-high performance liquid chromatography/mass spectrometry and changed the intramuscular and circulating levels of TCA metabolites. In these experiments, acute exercise also caused changes in the metabolic curve of the lymphatic organs, thus supporting the view that acute exercise would change the metabolic environment of the lymphatic organs. It is worth noting that the amount of metabolites in the muscles of draining lymph nodes is significantly increased compared to non-draining lymph nodes, which suggests that the changes seen in draining lymph nodes may be due to the production of muscle metabolites. Interestingly, plasma, draining lymph nodes and non-draining lymph nodes all showed higher levels of corticosterone after exercise, and changes in amino acid and fatty acid levels were also found in multiple organs.
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In order to study how the systemic utilization of metabolites changes with exercise, the researchers conducted metabolomics studies on muscle and plasma that respond to exercise. A detailed endurance test was performed on wild-type mice under the background of FVB. Skeletal muscle and plasma were obtained immediately after exercise, frozen and analyzed by mass spectrometry (GC-MS).
Exercise affects a wide range of metabolic pathways, especially exercise reduces the frequency of glycolytic metabolites in skeletal muscle, such as fructose 6 phosphate, glucose 6 phosphate and 3-phosphoglycerate, and the frequency of certain TCA metabolites such as muscle after exercise The citric acid, fumaric acid and malic acid in the citric acid are significantly increased, which is consistent with the rate limitation of mitochondrial metabolism in high-intensity exercise. Interestingly, the TCA metabolites citric acid, malic acid and alpha ketoglutarate in plasma after exercise are all higher, indicating that these metabolites are released from the muscles into the plasma.
To extend the information to the lymphatic organs, the researchers performed another detailed set of endurance tests on mice, and then immediately harvested skeletal muscle, plasma, spleen, muscle draining (axillary) and non-draining (groin) lymph nodes. In addition, plasma was collected before exercise, after exercise, and 1 hour after exercise for people who were often sedentary, and then analyzed these tissues by ultra-high performance liquid chromatography/mass spectrometry and changed the intramuscular and circulating levels of TCA metabolites. In these experiments, acute exercise also caused changes in the metabolic curve of the lymphatic organs, thus supporting the view that acute exercise would change the metabolic environment of the lymphatic organs. It is worth noting that the amount of metabolites in the muscles of draining lymph nodes is significantly increased compared to non-draining lymph nodes, which suggests that the changes seen in draining lymph nodes may be due to the production of muscle metabolites. Interestingly, plasma, draining lymph nodes and non-draining lymph nodes all showed higher levels of corticosterone after exercise, and changes in amino acid and fatty acid levels were also found in multiple organs.
However, the most obvious metabolic change caused by exercise is an instantaneous increase in circulating lactate. The level of lactic acid in the circulation rises very rapidly during exercise, and can increase up to 100 times in skeletal muscle and 10 times in plasma, but the rapid post-mortem accumulation of systemic lactic acid makes it impossible for researchers to distinguish between mice. The level of lactic acid in the organ sample. However, when the lactic acid in the blood of the tail vein of a living animal is directly measured in human plasma after exercise and on a treadmill, both lactic acid and TCA circulating metabolites increase. In human samples, these samples returned to near resting levels 1 hour after exercise, indicating that the changes in central carbon availability may be retained between mice and humans.
Given that metabolism and T cell differentiation are closely related, the researchers next tried to determine whether the central carbon metabolites produced during exercise might be the determining factor. Although the production of lactic acid is a direct result of the increase in glycolytic flux during exercise, in healthy tissues, the increase in H + is quickly buffered in the surrounding tissues and plasma. Therefore, the lactic acid produced during exercise does not significantly change the circulating plasma pH. Therefore, before adding all the metabolites to the cell culture medium, the researchers adjusted its pH to 7.35.
TCA metabolites can be transported across the plasma membrane together with sodium carboxylate cotransporter. Although no metabolites provide proliferative advantages after 3 days of activation, high-dose T cells are particularly tolerant of malic acid, succinic acid and aKG . Increasing the concentration of pyruvate and citric acid will reduce the expansion of CD8 + T cells.
Malic acid, succinic acid, fumaric acid, aKG, and lactic acid all cause the loss of CD62L at a concentration of about 1 m M. The loss of CD62L surface expression is caused by TCR activation and contributes to the migration ability of cells in secondary lymphoid organs. Based on the data from metabolite screening, TCA metabolites seem to enhance the activation response of CD62L.
In order to solve the problem of whether exercise can change the central carbon metabolism of activated CD8 + T cells in the body, the researchers applied transgenic OT-1 CD8 + CD45.1 + T cells to recipient animals, and then used bone marrow that presents ovalbumin. Derived macrophages (BMDM) are vaccinated to activate OT-1 T cells. Two or three days after inoculation, [U-13 C 6] glucose was introduced into resting and exercising mice, and the central carbon metabolism of OT-1 CD8 + T cells isolated from the spleen was analyzed. After preheating on a treadmill at low speed for 10 minutes, [U-13 C 6] glucose is introduced into the body to ensure that the skeletal muscles can take up glucose to the maximum during injection. The data shows that exercised CD8 + T cells have differential carbon metabolism at the levels of m + three labeled pyruvate and m + two labeled aKG, indicating changes in enzyme activity or extracellular marker molecules, proving that exercise can change CD8 + T cell metabolism in the body.
To determine the functional impact of exercise on the CD8 + T cell population, the researchers transferred CD8 + T obtained from exercise OT-1 animals to C57B16 inbred mouse recipients that had been inoculated with OVA-expressing melanoma. After T cells were transferred to non-exercising mice, tumor growth was monitored for 40 days. The blood profile on the 10th day after transfer confirmed the expansion of the OT-1 population in the recipient mice, and also showed a significant increase in the expression of iCOS in the cells transferred from the exercise donor, and the sedentary animals that received T cells showed Higher survival rate and reduced tumor growth rate. This indicates that when T cells are derived from sports animals, their efficacy against tumor CD8 + T cells has a lasting and positive effect.
In view of the above-mentioned exercise-induced metabolites can change the characteristics of immune cells, researchers want to infer whether it can affect the growth of tumors in the body by studying the increase in CD8 + T cell differentiation markers and cytotoxicity induced by lactic acid. Therefore, the researchers infused L-sodium lactate into tumor-bearing animals every day at a dose such that the plasma lactic acid level was similar to that during strenuous exercise (about 10-20 mM). As shown in the figure, intraperitoneal injection of 2 g/kg L-sodium lactate will increase the serum lactic acid concentration by 18 mM 20 minutes after injection. After taking this dose, the level drops to 4 mM within 60 minutes. The expected time from this peak amplitude to the baseline value is about 180 minutes after injection. This dose is selected as the increase and continuous increase in plasma lactic acid levels after strenuous short-term exercise Approximate value.
After being inoculated with the I3TC tumor cell line in female FVB mice given 2 g/kg L-sodium lactate daily, the overall tumor growth rate decreased. On C57BL/6 animals, the colon adenocarcinoma MC38 cell line obtained similar results, accompanied by an increase in the survival rate of tumor-bearing animals. The lower dose of lactate (0.5–1 g/kg) did not significantly change the growth of tumors, while the daily higher dose of L-lactate 3 g/kg led to a significant reduction in tumor growth, about 2 g/kg The effect of the dose is the same. Although the number of tumor infiltrating CD8 + T cells was found to increase, daily lactic acid did not change the percentage of GzmB + cells on CD8 + infiltrating cells or the intensity of GzmB, PD1 or CTLA.
Exercise is a multi-modal stimulus that will reduce the recurrence rate and mortality of cancer, and the effect of exercise on tumorigenic progression has been proven in a variety of animal models. Strenuous exercise, the body level of CD8 + T cells and NK cells will rise transiently. These immune cell populations exhibit an effector phenotype and increased peripheral tissue homing ability, both of which are important for antitumor activity.
In the current study, researchers have shown how exercise can significantly regulate metabolic parameters other than local skeletal muscle. After strenuous exercise, lactic acid and TCA metabolites accumulate in active skeletal muscle, plasma and secondary lymphoid organs. As transporting immune cells circulate, they are often exposed to high levels of accumulated metabolites in disease sites and metabolically active tissues. However, the main shaping of immune function occurs at the activation point, mainly in the lymphatic organs. When evaluating the role of the altered metabolic environment in the process of modifying the function of CD8 + T cells, the researchers found that key metabolites including lactic acid have unexpected functions in activating CD8 + T cells. Various TCA metabolites stimulate Loss of CD62L. In an experimental environment where animals were given high doses of L-sodium lactate every day, the researchers found that the CD8 + T cells in the tumor increased while the overall tumor growth decreased. In addition, high levels of CD4+ cells and reduced NK cell infiltration indicate that lactic acid can affect multiple cells of the immune system. These findings indicate that lactic acid infusion can mimic certain effects of exercise, but exercise not only has an increased lactic acid level, but also has other comprehensive components.
In summary, researchers have shown that the anti-tumor effect of exercise depends on CD8 + T cells, and strenuous exercise can change the internal metabolism of cytotoxic T cells and anti-tumor effector functions. This indicates that in the physiological environment, whether the metabolites derived from exercise are delivered systemically or discharged into adjacent lymph nodes, they can play a role in promoting the response of new-born T cells. This indicates that the adaptive immune system is a key component of exercise-induced suppression of tumorigenesis.
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