{"title":"Fatty acid species differentially regulate macrophage polarization and oxidative stress with secondary effects on macrophage-HSC crosstalk.","authors":"Koichi Nakanishi, Hiroji Shinkawa, Shigekazu Takemura, Kanako Nakagawa, Yukiko Minamiyama, Takeaki Ishizawa","doi":"10.14814/phy2.71082","DOIUrl":"10.14814/phy2.71082","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipid accumulation, inflammation, and fibrosis. Macrophage-hepatic stellate cell (HSC) communication plays a key role in fibrogenesis; however, how fatty acid species influence macrophage polarization remains unclear. Bone marrow-derived macrophages (BMDMs) were polarized toward M1 or M2 phenotypes in the presence of palmitic acid (PA), oleic acid (OA), or palmitoleic acid (PO). Polarization markers, reactive oxygen species (ROS), and peroxisome proliferator-activated receptor gamma (PPARγ) expression were analyzed by RT-qPCR, Western blotting, and chemiluminescence. Primary HSCs were exposed to fatty acids or conditioned media from treated macrophages. PA enhanced selected inflammatory macrophage responses and increased ROS production under M1-polarizing conditions. OA enhanced ROS production in M1 macrophages and suppressed several M2-associated markers, whereas PO reduced inflammatory responses and ROS under M1-polarizing conditions. Direct fatty acid exposure did not significantly alter HSC activation markers. Conditioned media from polarized macrophages, particularly M1 macrophages, reduced α-SMA and cytoglobin protein expression in HSCs, while fatty acid-specific effects were modest and marker-dependent. Fatty acid species differentially modulate macrophage polarization and redox activity, partly in association with PPARγ signaling. These macrophage changes may secondarily affect macrophage-HSC communication and stellate cell redox-related responses, providing insight into lipid regulation of immune-stromal interactions in the liver.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71082"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13562811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Takahiro Masuda, Masahide Yoshida, Young Chul Kim, Volker Vallon, Yoshiyuki Morishita, Daisuke Nagata, Tatsushi Onaka
{"title":"SGLT2 gene expression in thirst-promoting NOS1 neurons and vasopressin-synthesizing neurons in male rats.","authors":"Takahiro Masuda, Masahide Yoshida, Young Chul Kim, Volker Vallon, Yoshiyuki Morishita, Daisuke Nagata, Tatsushi Onaka","doi":"10.14814/phy2.71100","DOIUrl":"10.14814/phy2.71100","url":null,"abstract":"<p><p>While sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects, they cause only mild changes in body fluid balance, partly through compensatory increases in water intake and vasopressin (AVP) secretion. However, whether SGLT2 inhibitors directly influence central pathways governing these fluid-regulatory responses remains unclear. We here investigated Sglt2 expression in thirst-regulating centers, the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO) and hypothalamic AVP-synthesizing regions, including the supraoptic nucleus (SON) and paraventricular nucleus (PVN). Droplet digital PCR analysis revealed Sglt2 expression in all regions, at levels comparable to angiotensin receptor 1a, a key regulator of drinking behavior. In situ hybridization confirmed Sglt2 mRNA signals in OVLT, SFO, SON, and PVN. Double in situ hybridization revealed that Sglt2 is co-expressed in approximately 48%-60% of thirst-promoting NOS1 neurons in the OVLT and SFO. Furthermore, Sglt2 was detected in over 80% of AVP-synthesizing neurons and approximately 60% of oxytocin neurons within the SON and PVN. Our findings suggest that SGLT2 inhibitors have the potential to directly modulate central thirst and neuroendocrine responses, offering a novel anatomical framework for understanding their systemic effects on fluid balance and cardio-renal protection.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71100"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucynda Pham, Lauren Pavelich, Natascha Sommer, Lawrence I Grossman, Maik Hüttemann, Tasnim Arroum
{"title":"Arterial tracing-based technique for rapid purification of pulmonary arterial smooth muscle cells from rat lungs.","authors":"Lucynda Pham, Lauren Pavelich, Natascha Sommer, Lawrence I Grossman, Maik Hüttemann, Tasnim Arroum","doi":"10.14814/phy2.71098","DOIUrl":"10.14814/phy2.71098","url":null,"abstract":"<p><p>Primary pulmonary arterial smooth muscle cells (PASMCs) of pre-capillary vessels are used to study the molecular mechanism of hypoxic pulmonary vasoconstriction (HPV). Cytochrome c oxidase subunit IV isoform 2 (COX4i2) is highly expressed in these PASMCs and an essential player in HPV, as its knockout abolishes the response. However, the exact molecular mechanism is not fully understood; therefore, fast and reliable methods to isolate PASMC from small pulmonary vessels that retain their phenotype during culture are essential. In the current study, we aimed to develop a fast and user-friendly method to isolate and culture homogeneous PASMCs from rat lungs. PASMCs were isolated utilizing agar mixed with a food-safe blue dye to delineate pulmonary arteries (PAs) within the lung, facilitating the tissue dissection process. Cox4i2 expression was determined by qPCR and mass spectrometry. Highly enriched populations of PASMCs expressing the classic smooth muscle cell markers α-SMA (alpha-smooth muscle actin) and SM-MHC (smooth muscle myosin heavy chain) were obtained for rat lungs. The cells were cultured up to passage 4, remained homogeneous, and maintained their identity. Additionally, the cells expressed Cox4i2 under normoxia and demonstrated an increase in Cox4i2 expression after exposure to chronic hypoxia, a known PASMC response. PASMCs were easily and rapidly obtained from rat lungs and provide a cell culture model to study mechanisms of HPV in which a key player, COX4i2, is retained during the cell culture process.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71098"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Passive thigh heating increases peak torque but does not attenuate declines in force production during repeated isokinetic knee extensor exercise in older adults.","authors":"Desmond Denny, Daniel C Low, Oliver R Gibson","doi":"10.14814/phy2.71105","DOIUrl":"10.14814/phy2.71105","url":null,"abstract":"<p><p>Aging is associated with declines in muscle function, leading to increased functional fatigability. Passive heating has demonstrated positive effects on muscle function during brief exercise in older adults, but the impact of heating on repeated contractions remains unknown. This study examined the effects of passive thigh heating on torque production during repeated and prolonged maximal dynamic isokinetic exercise. Fifteen healthy older adults (68 ± 8 years) completed a protocol involving 90 min of unilateral thigh heating (50°C) via a custom garment (HEAT), while the contralateral limb served as an unheated control (CONT). Participants performed 30 maximal isokinetic knee extensions at 180°/s before and after heating to assess peak torque during a single contraction, and average torque and total work done. Peak torque increased by 6 ± 7 N.m in HEAT (from 74 ± 33 N.m to 81 ± 33 N.m, +9%, p < 0.05), whereas CONT saw a no significant change (73 ± 31 N.m to 76 ± 28 N.m). Average torque declined significantly (p < 0.05), with decreases from the first third (68 ± 30 N.m) to the middle (57 ± 26 N.m) and final third of the fatigue task (51 ± 22 N.m). There was no difference in averaged torque thirds between HEAT and CONT highlighting that fatigue resistance was unaltered by the intervention. Total work done showed a non-significant 7% increase in HEAT (from 1619 ± 1100 J to 1751 ± 976 J, p = 0.273), a non-significant decrease of -4% was noted in CONT (from 1589 ± 790 J to 1528 ± 784 J p = 0.284). Passive heating enhanced peak torque production, but not fatigue resistance or work done during repetitive dynamic contractions in older adults indicating that the acute benefits of passive heating, may not extend to sustained or repetitive tasks.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 18","pages":"e71105"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aiwei Yan, Rui Mai, Ting Cao, Changen Duan, Sheng Liu, Xianwei Wang
{"title":"CD47 is a regulator in doxorubicin-induced cardiac aging in male mice.","authors":"Aiwei Yan, Rui Mai, Ting Cao, Changen Duan, Sheng Liu, Xianwei Wang","doi":"10.14814/phy2.71111","DOIUrl":"10.14814/phy2.71111","url":null,"abstract":"<p><p>Cardiac aging is a natural process that occurs with age, leading to structural and functional abnormalities of the heart. In addition to chronological age, anticancer therapies can accelerate this process. Doxorubicin, an anthracycline class antitumor drug, is known to have significant cardiac toxicity including cardiac aging, but the underlying mechanisms remain incompletely understood. In this study, we identified that CD47 was significantly increased in aged hearts through bioinformatic analyses. We next established a doxorubicin-induced cardiac aging model in mice. Doxorubicin increased p53, p16, and p21 expression in mouse hearts, accompanied by marked CD47 upregulation. Similar effects were observed in AC16 cardiomyocytes, in which doxorubicin induced CD47 expression and a senescence-like phenotype, including increased p16 and p21 levels and SA-β-gal positivity. Blocking CD47 with a specific antibody attenuated doxorubicin-induced cardiac aging and cardiomyocyte senescence in vivo and in vitro, and improved doxorubicin-induced cardiac dysfunction. These results identify CD47 as a functional mediator of doxorubicin-induced cardiac aging and support CD47 blockade as a potential strategy to mitigate anthracycline-associated cardiac dysfunction.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 18","pages":"e71111"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zander J Williams, Giovanni Cenerini, Fabian Schwendinger, Raphael Knaier, Jonathan Wagner, James H Hull, Arno Schmidt-Trucksäss
{"title":"The ventilatory response pattern to exercise across the age-span in healthy adults.","authors":"Zander J Williams, Giovanni Cenerini, Fabian Schwendinger, Raphael Knaier, Jonathan Wagner, James H Hull, Arno Schmidt-Trucksäss","doi":"10.14814/phy2.71065","DOIUrl":"10.14814/phy2.71065","url":null,"abstract":"<p><p>Healthy aging is associated with a progressive decline in respiratory function and altered ventilatory mechanics, typically characterized on static physiological measurements. We aimed to evaluate the ventilatory response to exhaustive exercise across the age-span and hypothesized that aging would be associated with inefficient alterations that may be relevant in the etiology of breathlessness. We analyzed ventilatory data obtained from cardiopulmonary exercise tests performed in 526 healthy adults (aged 20-91 years; 52% female) from the COmPLETE cohort. Sample Entropy (SampEn) was used to quantify the irregularity of minute ventilation (V̇<sub>E</sub>), breathing frequency (Bf), and tidal volume (V<sub>T</sub>) time series. Age versus entropy relationships were assessed using penalized cubic splines, adjusting for sex, BMI, peak oxygen uptake, and FEV<sub>1</sub>. As a result, older age was associated with a progressive decline in peak oxygen uptake, V̇<sub>E</sub>, Bf, and V<sub>T</sub> (all p < 0.001). Ventilatory efficiency also decreased across the age span, evidenced by an increased V<sub>E</sub>/VCO<sub>2</sub> nadir, and older adults demonstrated a tachypneic breathing pattern, with a higher Bf to V̇<sub>E</sub> ratio (p < 0.001). Contrary to our hypothesis, ventilatory SampEn remained stable through early adulthood but increased after the sixth decade (SampEn Bf p = 0.023; SampEn V<sub>T</sub>: p = 0.004; SampEn V̇<sub>E</sub>: p = 0.001). In conclusion, older age is accompanied by a shift in the ventilatory response to exercise, characterized by a mechanically constrained, frequency-dominant breathing pattern and diminished ventilatory efficiency. This is associated with increases in ventilatory irregularity that become most apparent after the sixth decade. Further work is needed to determine how these alterations relate to exertional breathlessness.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71065"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emely A Hoffman, Aiden M Phoebe, Marissa N Trujillo, Wei Chen Zhang, Erin Q Jennings, Dominique O Farrera, David J Orlicky, Lauren N Rutt, Rebecca L McCullough, Andrea A Huacachino, Mariola M Marcinkiewicz, Nathaniel W Snyder, Kassandra R Bruner, Kimberly Bassoco Payan, Diego Juan Federico Martinez, Jennifer H Stern, James J Galligan
{"title":"Glyoxalase 1 loss reduces fatty liver but impairs glucose handling in male mice.","authors":"Emely A Hoffman, Aiden M Phoebe, Marissa N Trujillo, Wei Chen Zhang, Erin Q Jennings, Dominique O Farrera, David J Orlicky, Lauren N Rutt, Rebecca L McCullough, Andrea A Huacachino, Mariola M Marcinkiewicz, Nathaniel W Snyder, Kassandra R Bruner, Kimberly Bassoco Payan, Diego Juan Federico Martinez, Jennifer H Stern, James J Galligan","doi":"10.14814/phy2.71106","DOIUrl":"10.14814/phy2.71106","url":null,"abstract":"<p><p>We demonstrate the generation and characterization of the methylglyoxal detoxifying enzyme, glyoxalase 1, knockout mice (Glo1<sup>-/-</sup>). With a 16-week high-fat high sucrose (HFHS) diet, Glo1<sup>-/-</sup> mice had a significant reduction of hepatic lipid accumulation when compared to WT counterparts. Paradoxically, these effects are limited to the liver, as no significant impact on white adipose tissue was observed. We also show that Glo1<sup>-/-</sup> mice have a significant worsening of glycemic control, showing a significant increase in fasting blood glucose and oral glucose tolerance. Although previous findings have suggested a role for GLO1 in kidney health, our results show no overt kidney phenotype resulting from Glo1 loss. Collectively, these results demonstrate a role for GLO1 in hepatic lipid metabolism while having a minimal impact on adipose or kidney function.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71106"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frederick Sibbenga, David Chisompola, Mumbo Chipuma, Martin Chakulya, Propheria Lwiindi, Masiliso A Liamba, Benson M Hamooya, Joreen P Povia, Situmbeko Liweleya, Sepiso K Masenga
{"title":"Sex differences in insulin resistance and associated metabolic and inflammatory markers among adults with and without HIV in Zambia.","authors":"Frederick Sibbenga, David Chisompola, Mumbo Chipuma, Martin Chakulya, Propheria Lwiindi, Masiliso A Liamba, Benson M Hamooya, Joreen P Povia, Situmbeko Liweleya, Sepiso K Masenga","doi":"10.14814/phy2.71093","DOIUrl":"10.14814/phy2.71093","url":null,"abstract":"<p><p>Insulin resistance (IR) contributes substantially to cardiovascular disease and type 2 diabetes mellitus, with increasing concern among people living with HIV (PLWH). However, sex-specific factors of IR in sub-Saharan Africa remain poorly understood. This study evaluated sex-specific associations between IR and clinical, metabolic, and inflammatory markers among adults with and without HIV in Zambia. A cross-sectional study was conducted among 233 adults in Zambia. Insulin resistance was assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Sex-stratified multivariable linear regression models were used to identify factors associated with IR. Females had higher body mass index (26.9 vs. 23.5 kg/m<sup>2</sup>, p < 0.001), waist circumference (88.3 vs. 83.2 cm, p = 0.008), fasting insulin, and HOMA-IR compared with males. In the adjusted overall model, female sex was associated with higher HOMA-IR (β = 0.95, 95% CI: 0.06-1.84; p = 0.037), while HIV-positive status was associated with lower HOMA-IR (β = -1.54, 95% CI: -3.06 to -0.02; p = 0.046). Among males, hypertension was associated with higher HOMA-IR (β = 0.61; p = 0.019), whereas among females, HIV-positive status was inversely associated with HOMA-IR (β = -2.31; p = 0.049). Insulin resistance highlighted sex-specific patterns, with greater metabolic risk among females and distinct clinical factors among males. Future studies incorporating lifestyle and hormonal factors are needed to clarify these relationships.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71093"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Interstitial glucose during sanctioned competition and during high-intensity training in highly trained collegiate male endurance athletes: A real-world continuous glucose monitoring study.","authors":"Taira Kajisa, Toshiyuki Sakai","doi":"10.14814/phy2.71099","DOIUrl":"10.14814/phy2.71099","url":null,"abstract":"<p><p>Real-world evidence on glucose behavior during competition in highly trained athletes is scarce. We characterized interstitial glucose dynamics in collegiate endurance athletes during sanctioned competitions using continuous glucose monitoring (CGM), with within-subject comparisons to high-intensity training performed at the same prescribed race pace. Twenty male runners and race walkers (Tier 3: Highly Trained/National) wore CGM during 36 races, contributing 20 paired race-versus-training comparisons. Glucose rose from baseline to 8.3 ± 1.5 mM 1 h pre-race, peaked at 11.2 ± 2.2 mM during competition (mean difference + 3.12 mM, 95% CI +2.72 to +3.53; Cohen's dz. = 1.45), and declined to 6.7 ± 1.7 mM post-race (F(2,220) = 225.79, p < 0.001, partial η<sup>2</sup> = 0.67). Within-subject maximum glucose was higher during competition than during training (12.91 ± 1.93 vs. 11.02 ± 1.18 mM; mean difference + 1.89 mM, 95% CI 1.06-2.72; Cohen's dz. = 1.07), with a geometric mean ratio of 1.166 (95% CI 1.088-1.249), approximately 17% higher peaks in competition. These findings describe a reproducible pattern of higher peak glucose in competition than in training matched on the recorded external characteristics. Internal exercise load was not measured, so the difference cannot be attributed to the competitive context rather than to differing internal exercise intensity.</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71099"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13555798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nora García-Alonso, Mikel Izquierdo, Hugo Arasanz, Robinson Ramírez-Vélez
{"title":"Immunological effects of supervised exercise in long COVID in adults: A secondary analysis of a randomized crossover trial.","authors":"Nora García-Alonso, Mikel Izquierdo, Hugo Arasanz, Robinson Ramírez-Vélez","doi":"10.14814/phy2.71031","DOIUrl":"10.14814/phy2.71031","url":null,"abstract":"<p><p>Long COVID (post-acute sequelae of SARS-CoV-2 infection) affects approximately 5%-30% of survivors and is characterized by persistent fatigue, dyspnea, exercise intolerance, and cognitive impairment. We evaluated the immunological effects of supervised exercise in adults with long COVID. In this pre-specified exploratory substudy of the EXER-COVID randomized 2 × 2 crossover trial, participants completed a 6-week supervised exercise program (twice weekly) or usual care before crossing over after a 3-5 day washout. Plasma cytokines (IL-1β, IL-6, IL-10, TNF-α, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, and IP-10/CXCL10) were measured by multiplex immunoassay. Immunophenotyping included 20 CD4<sup>+</sup> and CD8<sup>+</sup> T-cell subsets and five innate immune populations. Treatment effects were estimated using within-period change scores, with multiple testing controlled by the Benjamini-Hochberg procedure (false discovery rate < 5%). Five variables reached nominal significance before correction (two CD8<sup>+</sup> T-cell subsets and IL-1β, IL-10, and MIP-1α), but none remained significant after adjustment. No changes were observed in innate immune populations, and no evidence of carryover was detected. Supervised exercise was not associated with significant immunological changes after correction for multiple comparisons, supporting the short-term immunological safety of moderate-intensity exercise in PESE-negative adults with long COVID (ClinicalTrials.gov: NCT04797871).</p>","PeriodicalId":20083,"journal":{"name":"Physiological Reports","volume":"14 17","pages":"e71031"},"PeriodicalIF":2.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}