Acute Exercise Increases NK Cell Mitochondrial Respiration and Cytotoxicity against Triple-Negative Breast Cancer Cells under Hypoxic Conditions.

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic malignancy with high recurrence rates. Hypoxia is a hallmark of the TNBC tumor microenvironment, which promotes tumor growth while impairing natural killer (NK) cell cytotoxic functions. Although acute exercise improves NK cell function under normoxic conditions, the effect of exercise on NK cell cytotoxic functions under hypoxic conditions mimicking O 2 tensions observed in solid tumors is unknown. METHODS: The cytotoxic functions of resting and postexercise NK cells isolated from thirteen young inactive healthy women were assessed against breast cancer cells expressing different levels of hormone receptors (MCF-7 and MDA-MB-231) under normoxic and hypoxic conditions. Mitochondrial respiration and H 2 O 2 efflux rates of the TNBC-activated NK cells were assessed via high-resolution respirometry. RESULTS: Under hypoxia, postexercise NK cells exhibited greater killing of TNBC than resting NK cells. Further, postexercise NK cells were more likely to kill TNBC under hypoxia than normoxic conditions. In addition, mitochondrial respiration associated with oxidative (OXPHOS) capacity of TNBC-activated NK cells was greater in postexercise cells than resting cells under normoxia, but not under hypoxia. Finally, acute exercise was associated with reduced mitochondrial H 2 O 2 efflux by NK cells in both conditions. CONCLUSIONS: Together, we present crucial interrelationships between hypoxia and exercise-induced changes in NK cell functions against TNBC cells. By modulating their mitochondrial bioenergetic functions, we postulate that acute exercise improves NK cell function under hypoxic conditions. Specifically, NK cell O 2 and H 2 O 2 flow (pmol·s -1 ·million NK cells -1 ) changes in response to 30-min cycling suggest that exercise primes NK cell tumor killing by reducing mitochondrial oxidative stress and, thus, rescuing their function when exposed to harsh hypoxic environments as observed in the microenvironment of breast solid tumors.

Impact of maximal exercise on immune cell mobilization and bioenergetics.

Acute aerobic exercise increases the number and proportions of circulating peripheral blood mononuclear cells (PMBC) and can alter PBMC mitochondrial bioenergetics. In this study, we aimed to examine the impact of a maximal exercise bout on immune cell metabolism in collegiate swimmers. Eleven (7 M/4F) collegiate swimmers completed a maximal exercise test to measure anaerobic power and capacity. Pre- and postexercise PBMCs were isolated to measure the immune cell phenotypes and mitochondrial bioenergetics using flow cytometry and high-resolution respirometry. The maximal exercise bout increased circulating levels of PBMCs, particularly in central memory (KLRG1+/CD57-) and senescent (KLRG1+/CD57+) CD8+ T cells, whether measured as a % of PMBCs or as absolute concentrations (all p < 0.05). At the cellularlevel, the routine oxygen flow (IO2 [pmol·s-1 ·106 PBMCs-1 ]) increased following maximal exercise (p = 0.042); however, there were no effects of exercise on the IO2 measured under the LEAK, oxidative phosphorylation (OXPHOS), or electron transfer (ET) capacities. There were exercise-induced increases in the tissue-level oxygen flow (IO2-tissue [pmol·s-1 ·mL blood-1 ]) for all respiratory states (all p < 0.01), except for the LEAK state, after accounting for the mobilization of PBMCs. Future subtype-specific studies are needed to characterize further maximal exercise's true impact on immune cell bioenergetics.

Monitoring body composition change for intervention studies with advancing 3D optical imaging technology in comparison to dual-energy X-ray absorptiometry.

BACKGROUND: Recent 3-dimensional optical (3DO) imaging advancements have provided more accessible, affordable, and self-operating opportunities for assessing body composition. 3DO is accurate and precise in clinical measures made by DXA. However, the sensitivity for monitoring body composition change over time with 3DO body shape imaging is unknown. OBJECTIVES: This study aimed to evaluate the ability of 3DO in monitoring body composition changes across multiple intervention studies. METHODS: A retrospective analysis was performed using intervention studies on healthy adults that were complimentary to the cross-sectional study, Shape Up! Adults. Each participant received a DXA (Hologic Discovery/A system) and 3DO (Fit3D ProScanner) scan at the baseline and follow-up. 3DO meshes were digitally registered and reposed using Meshcapade to standardize the vertices and pose. Using an established statistical shape model, each 3DO mesh was transformed into principal components, which were used to predict whole-body and regional body composition values using published equations. Body composition changes (follow-up minus the baseline) were compared with those of DXA using a linear regression analysis. RESULTS: The analysis included 133 participants (45 females) in 6 studies. The mean (SD) length of follow-up was 13 (5) wk (range: 3-23 wk). Agreement between 3DO and DXA (R2) for changes in total FM, total FFM, and appendicular lean mass were 0.86, 0.73, and 0.70, with root mean squared errors (RMSEs) of 1.98 kg, 1.58 kg, and 0.37 kg, in females and 0.75, 0.75, and 0.52 with RMSEs of 2.31 kg, 1.77 kg, and 0.52 kg, in males, respectively. Further adjustment with demographic descriptors improved the 3DO change agreement to changes observed with DXA. CONCLUSIONS: Compared with DXA, 3DO was highly sensitive in detecting body shape changes over time. The 3DO method was sensitive enough to detect even small changes in body composition during intervention studies. The safety and accessibility of 3DO allows users to self-monitor on a frequent basis throughout interventions. This trial was registered at clinicaltrials.gov as NCT03637855 (Shape Up! Adults; https://clinicaltrials.gov/ct2/show/NCT03637855); NCT03394664 (Macronutrients and Body Fat Accumulation: A Mechanistic Feeding Study; https://clinicaltrials.gov/ct2/show/NCT03394664); NCT03771417 (Resistance Exercise and Low-Intensity Physical Activity Breaks in Sedentary Time to Improve Muscle and Cardiometabolic Health; https://clinicaltrials.gov/ct2/show/NCT03771417); NCT03393195 (Time Restricted Eating on Weight Loss; https://clinicaltrials.gov/ct2/show/NCT03393195), and NCT04120363 (Trial of Testosterone Undecanoate for Optimizing Performance During Military Operations; https://clinicaltrials.gov/ct2/show/NCT04120363).

Impact of acute exercise on peripheral blood mononuclear cells nutrient sensing and mitochondrial oxidative capacity in healthy young adults.

Regular exercise is associated with changes in peripheral blood mononuclear cell (PBMC) proportions that have enhanced effector functions in young and old adults; however, the effects of acute exercise on PBMC nutrient sensors and metabolic function in active young adults is unknown. To fill this gap, activation status and nutrient-sensing mechanisms of PBMCs isolated from 21 healthy active adults (20-35 yr; 36.5 ± 6.3 V̇O2peak ) were characterized before and after 30 min of moderate-to-vigorous cycling (65%-75% V̇O2peak ). In addition, changes in PBMC mitochondrial respiratory function in response to exercise were assessed using high-resolution respirometry. There was an increase in the number of activated CD69+/CD4 (79% increase) and CD69+/CD8 (166% increase) T-cells in response to the acute bout of exercise, while the nutrient-sensing mechanisms remained unchanged. PBMC mitochondrial respiration did not increase on a cell-per-cell basis, however, mitochondrial oxidative capacity (OXPHOS) increased at the tissue level (18.6 pmol/(s*ml blood) versus 29.3 pmol/(s*ml blood); p < 0.05) in response to acute exercise. Thus, this study shows that acute exercise preferentially mobilizes activated T-cells while concomitantly increasing PBMC mitochondrial oxidative capacity at the tissue level, rather than acutely changing mitochondrial oxidative capacity at the cellular level in young adults.

Cytomegalovirus Infection Impairs the Mobilization of Tissue-Resident Innate Lymphoid Cells into the Peripheral Blood Compartment in Response to Acute Exercise.

Circulating immune cell numbers and phenotypes are impacted by high-intensity acute bouts of exercise and infection history with the latent herpesviruses cytomegalovirus (CMV). In particular, CMV infection history impairs the exercise-induced mobilization of cytotoxic innate lymphoid cells 1 (ILC1) cells, also known as NK cells, in the blood. However, it remains unknown whether exercise and CMV infection modulate the mobilization of traditionally tissue-resident non-cytotoxic ILCs into the peripheral blood compartment. To address this question, 22 healthy individuals with or without CMV (20-35 years-45% CMVpos) completed 30 min of cycling at 70% VO2 max, and detailed phenotypic analysis of circulating ILCs was performed at rest and immediately post-exercise. We show for the first time that a bout of high-intensity exercise is associated with an influx of ILCs that are traditionally regarded as tissue-resident. In addition, this is the first study to highlight that latent CMV infection blunts the exercise-response of total ILCs and progenitor ILCs (ILCPs). These promising data suggest that acute exercise facilitates the circulation of certain ILC subsets, further advocating for the improvements in health seen with exercise by enhancing cellular mobilization and immunosurveillance, while also highlighting the indirect deleterious effects of CMV infection in healthy adults.

The Association between Poor Diet Quality, Physical Fatigability and Physical Function in the Oldest-Old from the Geisinger Rural Aging Study.

More perceived physical fatigability and poor diet quality are associated with impairments in physical function in older adults. However, the degree to which more perceived fatigability explains the association between poor diet quality and low physical function is unknown. We examined this relationship in 122 (66F, 56M) of the oldest-old participants from the Geisinger Rural Aging Study (GRAS). We used 24-h dietary recalls to assess the Healthy Eating Index (HEI), the Pittsburgh Fatigability Scale (PFS, 0-50) to assess perceived physical fatigability, and the PROMIS Physical Function 20a* to assess physical function. We grouped participants into three age categories: 80-84 (n = 51), 85-89 (n = 51), and 90+ (n = 20) years. Multiple linear regression revealed that a lower HEI was associated with higher PFS Physical score after adjusting for age group, sex, body mass index, and the number of medical conditions (p = 0.001). Several macro- and micro-nutrient intakes were also lower in those reporting more (≥15) compared to less (<15) perceived physical fatigability. Mediation analysis revealed that PFS Physical scores explained ~65% (p = 0.001) of the association between HEI total score and PROMIS19 Physical Function score. Poor diet quality may contribute to more perceived physical fatigability, which could exacerbate impairments in the oldest-old's physical function.

An Ethanolic Extract of Artemisia dracunculus L. Enhances the Metabolic Benefits of Exercise in Diet-induced Obese Mice.

PURPOSE: The purpose of this study was to determine the effect of an ethanolic extract of Artemisia dracunculus L. (5011) combined with exercise on in vivo glucose and fat metabolism in diet-induced obese male mice. METHODS: After 8 wk of high-fat diet (HFD) feeding, 52 mice were randomly allocated to a voluntary wheel running group (HFD Ex), a 5011 + HFD sedentary group (5011 Sed), a 5011 + HFD Ex (5011 Ex), or an HFD sedentary group (HFD Sed) for 4 wk. Real-time energy expenditure and substrate utilization were measured by indirect calorimetry. A stable isotope glucose tolerance test was performed before and after the 4-wk wheel running period to determine changes in endogenous glucose production and glucose disposal. We also performed an analysis of genes and proteins associated with the early response to exercise and exercise adaptations in skeletal muscle and liver. RESULTS: When compared with HFD Ex mice, 5011 Ex mice had increased fat oxidation during speed- and distance-matched wheel running bouts. Both HFD Ex and 5011 Ex mice had reduced endogenous glucose during the glucose tolerance test, whereas only the 5011 Sed and the 5011 Ex mice had improved glucose disposal after the 4-wk experimental period when compared with HFD Sed and HFD Ex mice. 5011 Ex mice had increased Pgc1-α and Tfam expression in skeletal muscle when compared with HFD Ex mice, whereas Pdk4 expression was reduced in the liver of HFD Ex and 5011 Ex mice. CONCLUSIONS: Our study demonstrates that 5011, an ethanolic extract of A. dracunculus L., with a history of medicinal use, enhances the metabolic benefits of exercise to improve in vivo fat and glucose metabolism.

Chronic Nucleoside Reverse Transcriptase Inhibitors Disrupt Mitochondrial Homeostasis and Promote Premature Endothelial Senescence.

Combination antiretroviral therapy (cART) has improved the life expectancy of HIV patients, thus increasing the number of people living with HIV (PLWH). However, cardiovascular diseases (CVD) are now one of the most prevalent causes of death among PLWH. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of cART, and the emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) coformulation is commonly used. In prior studies, acute NRTI treatment-induced endothelial dysfunction, increased reactive oxygen species production, and mitophagic activity, suggesting that mitochondrial dysfunction may be critical to NRTI-induced endothelial dysfunction. Mitochondrial dysfunction plays a causal role in endothelial senescence, whereas premature endothelial senescence can promote the development of CVD. We hypothesize that for chronic NRTI treatment, a disruption in mitochondrial homeostasis leads to premature endothelial senescence and predisposes PLWH to CVD. We used human aortic endothelial cells (HAEC) and HIV-1 transgenic (Tg26) mice to test the interrelationship between mitochondrial and vascular dysfunction after chronic NRTI treatment in vitro and in vivo. Mitochondrial DNA copy number was decreased in late-passage HAEC treated with NRTIs, and senescence-associated ß-galactosidase accumulation was elevated. In late-passage HAEC, NRTIs decreased the activity of Parkin-mediated mitophagy. In Tg26 mice treated with FTC, plasma nitrite levels were decreased. Endothelium-dependent vasodilation in NRTI-treated Tg26 mice was also reduced. Our work suggests that long-term use of NRTI may disrupt mitochondrial homeostasis, induce premature endothelial senescence, and impair vascular function.