Frontiers in Physiology最新文献

{"title":"Male mouse skeletal muscle lacking HuR shows enhanced glucose disposal at a young age.","authors":"Robert C Noland, Sujoy Ghosh, Carlos J Crisanto, Antonio Aleman, McKenna K Chaney, Maitri K Chauhan, Layla G Loftis, Ally C Goad, Christin F Rickman, Samuel E Velasquez, Jaycob D Warfel","doi":"10.3389/fphys.2024.1468369","DOIUrl":"10.3389/fphys.2024.1468369","url":null,"abstract":"<p><strong>Introduction: </strong>Metabolic flexibility is the ability of a system to switch between metabolic substrates. Human and murine skeletal muscle tissues and cells with decreased activity of the regulatory RNA-binding protein, human antigen R (HuR), have decreased capacity for fat oxidation, and thus decreased metabolic flexibility. In this study, we aimed to assess the preference for carbohydrates in mice lacking HuR in skeletal muscle.</p><p><strong>Methods: </strong>Experiments were performed on weight-matched control and HuR knockout mice of both sexes. Palmitate and pyruvate oxidation were performed in mouse muscle following the release of ¹⁴CO₂. <i>In vivo</i> glucose and lipid uptake were assayed in mouse tissue following nonmetabolizable ³H-2-deoxyglucose or ¹⁴C-bromopalmitate injection. Transcriptomic analyses were performed in the skeletal muscle of all mice, followed by qPCR validation of select genes. Serum lactate and glucose levels were measured in mice <i>via</i> tail nick, and the muscle glycogen level was measured through colorimetric assay. Indirect calorimetry was used to measure respiratory exchange ratios.</p><p><strong>Results: </strong>Male muscle-specific HuR knockout mice showed increased glucose uptake relative to controls, specifically in skeletal muscle, and have increased muscle glycogen content. These mice also displayed greater respiratory exchange ratios than controls. None of these differences were noted in females. Transcriptomics showed far more differences between male and female mice than between control and HuR knockout mice. However, differential gene expression between male and female mice was diminished by 50% following the removal of HuR. Male HuR knockout mouse skeletal muscle had increased glycolytic gene expression relative to controls but showed no difference relative to females of the same genotype. Both palmitate and pyruvate oxidation were decreased in the skeletal muscle of male HuR knockout mice relative to controls, and serum lactate levels were increased. No notable differences were seen in females between genotypes.</p><p><strong>Discussion: </strong>The increase in the markers of glucose utilization with decreased HuR activity in male mice may indicate a switch toward glycolysis as compensation for decreased fat oxidation. These results continue to highlight a sex dependence on HuR as a driver of fat oxidation in mouse skeletal muscle while also indicating that muscle itself shows greater ambiguity between males and females following the removal of HuR.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"15 ","pages":"1468369"},"PeriodicalIF":3.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Th1/Th17 and Th2 cytokines on lipid metabolism in differentiated keratinocytes.","authors":"Alessia Cavallo, Emanuela Camera, Miriam Maiellaro, Grazia Bottillo, Sarah Mosca, Daniela Kovacs, Enrica Flori, Giorgia Cardinali","doi":"10.3389/fphys.2025.1387128","DOIUrl":"10.3389/fphys.2025.1387128","url":null,"abstract":"<p><strong>Introduction: </strong>Abnormalities of keratinocyte differentiation and impairment of permeability barrier are features of inflammatory skin diseases driven by Th1/Th17 and Th2 immune response, such as psoriasis and atopic dermatitis. We aimed at identifying the signature of the Th1/Th17 and Th2 environments on keratinocytes, focusing on the expression of genes involved in the lipid metabolism and profiles of abundance of lipid metabolites.</p><p><strong>Methods: </strong>Human immortalized keratinocytes in prodifferentiative conditions induced by increasing calcium concentration, and 3D epidermal equivalents were treated with mixtures either of TNF-α and IL-17A plus Th1-related cytokines (IL-1α, IL-6) or of Th2 cytokines (IL-4, IL-13). The expression of genes involved in epidermal differentiation and lipid metabolism was evaluated by RT-PCR at 2, 4 and 7 days of treatment. The protein levels of early and late keratinocyte differentiation markers were assessed. The lipid composition was investigated by GCMS and LCMS.</p><p><strong>Results: </strong>Both Th1/Th17 and Th2 cytokine mixtures changed the expression of genes involved in the metabolism of fatty acids (FAs), i.e., FAS, FADS2, SCD1, and ALOX12B. Th1/ Th17 downregulated the ELOVL3 gene, which is implicated in the FAs elongation, while the mRNA levels of ABCA12 and HMGCR, genes involved in lipids transport and cholesterol synthesis, respectively, were decreased with both cytokine mixtures. DEGS1 and DEGS2, key enzymes in the ceramide synthesis, were downregulated and upregulated in the Th1/Th17 and Th2 environments, respectively. The mRNA expression of CERS3, which synthesizes ceramides containing long chain FAs, was increased by Th1/Th17 cytokines. Both Th1/ Th17 and Th2 cytokine mixtures lowered the CERS6 mRNA levels in differentiated keratinocytes. Effects specific to Th1/Th17 or Th2 cytokines were observed on freely extractable cell lipids. Th1/Th17 cytokines significantly inhibited the high calcium-induced synthesis of phospholipids (PCs, PEs, SMs), and short-chain ceramides, while the synthesis of ceramides with medium to long carbon chains was upregulated. Th2 cytokines caused a generalized decrement of free FAs, including long-chain ones. In contrast to 2D cultures, the 3D epidermal equivalents allowed the identification of altered profiles of acyland hexosyl-ceramides.</p><p><strong>Conclusion: </strong>The different effects exerted by Th1/Th17 and Th2 cytokines support, at least in part, the features of lipid barrier alterations specific to psoriasis or atopic dermatitis.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1387128"},"PeriodicalIF":3.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term microgravity effects simulation does not affect fNIRS measures of cerebral oxygenation changes induced by cognitive load.","authors":"Vsevolod Peysakhovich, Thibault Kiehl, Lucia Vicente Martinez, Laure Boyer, Mickaël Causse, Alexis Paillet, Anne Pavy-Le Traon","doi":"10.3389/fphys.2025.1425302","DOIUrl":"10.3389/fphys.2025.1425302","url":null,"abstract":"<p><p>In the past decade, there has been a surge in interest in space exploration studies, particularly due to the prospect of exploring distant planets such as Mars. However, long-duration space missions may pose cognitive challenges resulting from spaceflight-induced perceptual and motor changes, prolonged cephalic fluid shifts, and high cognitive load. One method for monitoring cognitive activity is functional near-infrared spectroscopy (fNIRS), a technique not yet tested under prolonged microgravity conditions beyond parabolic flight periods. Since fNIRS relies on cerebral oxygenation levels, should we adjust it for the fluid shift? To address this, the study explores the impact of simulated microgravity on cerebral oxygenation measures using fNIRS during a cognitive task, employing head-down tilt at different inclination levels and the Toulouse N-back Task (assessing memory and mental calculation) with varying difficulty levels. Eighteen subjects participated in the experiment. The results indicated that increasing difficulty levels of the cognitive task led to decreased accuracy, longer response times, and higher perceived difficulty scores. The inclination levels did not affect task performance. Increased difficulty was also concomitant with increasing HbO and decreasing HbR concentrations unaffected by the head-down tilt angle variations. These promising findings suggest that fNIRS measures could be used under microgravity conditions to measure cognitive load without correction for fluid shift.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1425302"},"PeriodicalIF":3.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between the lactate-to-albumin ratio (LAR) index and risk of acute kidney injury in critically ill patients with sepsis: analysis of the MIMIC-IV database.","authors":"Yiming Hua, Ning Ding, Huaizhi Jing, Yifei Xie, Hao Wu, Yue Wu, Beidi Lan","doi":"10.3389/fphys.2025.1469866","DOIUrl":"10.3389/fphys.2025.1469866","url":null,"abstract":"<p><strong>Background: </strong>Lactate-to-albumin ratio (LAR) is an emergency predictive indicator of sepsis-related mortality. An elevated LAR is associated with poor outcomes in critically ill patients. However, its predictive value for acute kidney injury (AKI) in patients with sepsis remains unclear. Therefore, this study aimed to investigate the relationship between LAR and AKI in patients with sepsis.</p><p><strong>Methods: </strong>The study population was derived from the Medical Information Mart for Intensive Care-IV (2.0) database and stratified into quartiles based on the LAR. The primary endpoint was the occurrence of AKI. The secondary endpoints were the use of renal replacement therapy (RRT) and in-hospital mortality. Kaplan-Meier survival analysis and Cox proportional hazards models were used to assess the association between the LAR index and risk of AKI in patients with sepsis.</p><p><strong>Results: </strong>In this study, 5,222 patients with sepsis were included, of whom 3,029 were male (58%). Kaplan-Meier survival analysis demonstrated significant differences in the cumulative incidence of AKI and cumulative usage rate of RRT among patients with sepsis based on the quartiles of the LAR index. Additionally, Cox proportional hazards analysis adjusted for confounding factors showed a significant association between the LAR index and incidence of AKI in patients with sepsis.</p><p><strong>Conclusion: </strong>Our study indicated that a high LAR index can serve as an independent predictor of AKI in patients with sepsis.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1469866"},"PeriodicalIF":3.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differences between macrovascular and microvascular functions in pregnant women with chronic hypertension or preeclampsia: new insights into maternal vascular health.","authors":"Julyane N S Kaihara, Hellen Cristiane Grepi Okano, Eduardo Carvalho de Arruda Veiga, Gustavo Moleiro Tallarico, Carlos Alan Dias-Junior, Ricardo Carvalho Cavalli, Valeria Cristina Sandrim","doi":"10.3389/fphys.2025.1536437","DOIUrl":"10.3389/fphys.2025.1536437","url":null,"abstract":"<p><strong>Introduction: </strong>Hypertensive disorders of pregnancy, including chronic hypertension (CH) and preeclampsia (PE), stand as prominent global contributors to maternal and perinatal morbidity and mortality. Endothelial dysfunction plays a central role in the pathophysiology of these conditions. This dysfunction impacts blood flow and the regulation of vascular response, potentially leading to alterations in the remodeling of blood vessels. Nitric oxide bioavailability, a key regulator of vascular tone, is often diminished in endothelial dysfunction, with nitrite levels serving as a surrogate marker. Methods such as pulse wave velocity (PWV) and peripheral arterial tonometry provide valuable insights into vascular health in large and small vessels, respectively, in hypertensive pregnancies. Among these, peripheral arterial tonometry stands out as a less explored technique in research. This study aimed to evaluate potential alterations in the macrovascular arterial stiffness and the microvascular endothelial function among pregnant women diagnosed with CH or PE compared to healthy pregnant (HP) women. Additionally, we aimed to correlate these vascular parameters with demographic and clinical data.</p><p><strong>Methods: </strong>The study enrolled 24 HP women, 24 with CH during pregnancy, and 24 with PE who underwent evaluations of large-artery stiffness via PWV assessments and peripheral arterial tonometry via natural logarithm of the reactive hyperemia index (lnRHI) assessments.</p><p><strong>Results: </strong>Patients with CH and PE exhibited higher large-artery stiffness than HP, although the lnRHI values remained comparable across all groups. Furthermore, PWV values demonstrated a direct correlation or tendency toward a positive correlation with systolic and diastolic blood pressures (SBP and DBP) in all groups. However, PWV and nitrite concentrations were not correlated. Notably, microvascular function was positively correlated with SBP and DBP in PE, but not in CH or HP. The correlation between lnRHI and nitrite concentrations was observed in the PE group.</p><p><strong>Conclusion: </strong>Thus, our findings indicate that, while HDPs have demonstrated increased large-artery stiffness in comparison to HP, the microvasculature analyzed by peripheral arterial tonometry was similar among all three groups. Interestingly, the correlation patterns in the nitrite levels, blood pressure, and microvascular function differed in the PE and CH groups.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1536437"},"PeriodicalIF":3.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Web-based machine learning application for interpretable prediction of prolonged length of stay after lumbar spinal stenosis surgery: a retrospective cohort study with explainable AI.","authors":"Paierhati Yasheng, Alimujiang Yusufu, Yasenjiang Yimiti, Haopeng Luan, Cong Peng, Xinghua Song","doi":"10.3389/fphys.2025.1542240","DOIUrl":"10.3389/fphys.2025.1542240","url":null,"abstract":"<p><strong>Objectives: </strong>Lumbar spinal stenosis (LSS) is an increasingly important issue related to back pain in elderly patients, resulting in significant socioeconomic burdens. Postoperative complications and socioeconomic effects are evaluated using the clinical parameter of hospital length of stay (LOS). This study aimed to develop a machine learning-based tool that can calculate the risk of prolonged length of stay (PLOS) after surgery and interpret the results.</p><p><strong>Methods: </strong>Patients were registered from the spine surgery department in our hospital. Hospital stays greater than or equal to the 75th percentile for LOS was considered extended PLOS after spine surgery. We screened the variables using the least absolute shrinkage and selection operator (LASSO) and permutation importance value and selected nine features. We then performed hyperparameter selection via grid search with nested cross-validation. Receiver operating characteristics curve, calibration curve and decision curve analysis was carried out to assess model performance. The result of the final selected model was interpreted using Shapley Additive exPlanations (SHAP), and Local Interpretable Model-agnostic Explanations (LIME) were used for model interpretation. To facilitate model utilization, a web application was deployed.</p><p><strong>Results: </strong>A total of 540 patients were involved, and several features were finally selected. The final optimal random forest (RF) model achieved an area under the curve (ROC) of 0.93 on the training set and 0.83 on the test set. Based on both SHAP and LIME analyses, intraoperative blood loss emerged as the most significant contributor to the outcome.</p><p><strong>Conclusion: </strong>Machine learning in association with SHAP and LIME can provide a clear explanation of personalized risk prediction, and spine surgeons can gain a perceptual grasp of the impact of important model components. Utilization and future clinical research of our RF model are made simple and accessible through the web application.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1542240"},"PeriodicalIF":3.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caveolin and oxidative stress in cardiac pathology.","authors":"Lauren Zadorozny, Jiayue Du, Neil Supanekar, Karthik Annamalai, Qing Yu, Meijing Wang","doi":"10.3389/fphys.2025.1550647","DOIUrl":"10.3389/fphys.2025.1550647","url":null,"abstract":"<p><p>Caveolins interact with signaling molecules within caveolae and subcellular membranes. Dysregulation of caveolin function and protein abundance contributes to cardiac pathophysiological processes, driving the development and progression of heart disease. Reactive oxygen species (ROS) play a critical role in maintaining cellular homeostasis and are key contributors to the pathophysiological mechanisms of cardiovascular disorders. Caveolins have been shown to modulate oxidative stress and regulate redox homeostasis. However, the specific roles of caveolins, particularly caveolin-1 and caveolin-3, in regulating ROS production during cardiac pathology remain unclear. This mini-review article highlights the correlation between caveolins and oxidative stress in maintaining cardiovascular health and modulating cardiac diseases, specifically in myocardial ischemia, heart failure, diabetes-induced metabolic cardiomyopathy, and septic cardiomyopathy. A deeper understanding of caveolin-mediated mechanisms may pave the way for innovative therapeutic approaches to treat cardiovascular diseases.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1550647"},"PeriodicalIF":3.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of gluteal muscle central activation in individuals with and without patellofemoral pain.","authors":"Kai-Yu Ho, Michael Carpio, John Donohue, Jacob Kissman, Jing Nong Liang","doi":"10.3389/fphys.2025.1535141","DOIUrl":"10.3389/fphys.2025.1535141","url":null,"abstract":"<p><p>Patellofemoral pain (PFP) is often linked to knee valgus during weight-bearing activities, commonly attributed to gluteal muscle weakness. However, recent research suggests that central nervous system adaptations may also influence muscle function and movement patterns in individuals with PFP. This study compared the central activation ratio (CAR) of the gluteus medius and gluteus maximus between individuals with and without PFP, and assessed the associations between gluteal CAR, frontal plane projection angle of the trunk and lower extremity, and knee function. Twelve individuals without PFP and 10 individuals with PFP participated. We tested CAR of the gluteal muscles with a superimposed burst protocol during a maximum voluntary isometric contraction and evaluated frontal plane kinematics of the trunk and lower extremities during five single leg tasks. Participants with PFP also completed the Anterior Knee Pain Scale (AKPS). Independent t-tests compared CAR between groups, and Pearson correlation coefficients evaluated the associations between CAR, frontal plane kinematics, and AKPS. Individuals with PFP tended to have lower gluteus maximus CAR, though the difference was not statistically significant (PFP: 90.8% ± 7.0%, Control: 94.4% ± 3.0%; p = 0.067). CAR of both the gluteus maximus (R = 0.790, p = 0.003) and gluteus medius (R = 0.584, p = 0.038) were significantly correlated with AKPS scores, and gluteus maximus CAR was associated with trunk lean angle during single leg landing (R = 0.533, p = 0.006). Our data suggest that higher gluteal CAR is associated with better function in individuals with PFP. Lower gluteus maximus CAR contributes to ipsilateral trunk lean during single leg landing, potentially to reduce external hip moments and muscle demand.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1535141"},"PeriodicalIF":3.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress in understanding Legg-Calvé-Perthes disease etiology from a molecular and cellular biology perspective.","authors":"Xinda Zheng, Zhuqing Dong, Xiaofei Ding, Qian Huang, Shengping Tang, Yuchen Zhang, Boxiang Li, Shijie Liao","doi":"10.3389/fphys.2025.1514302","DOIUrl":"10.3389/fphys.2025.1514302","url":null,"abstract":"<p><p>Legg-Calvé-Perthes disease (LCPD) is a hip disease caused by ischemia of the femoral epiphysis in children, which occurs in children aged 4-8 years (mean 6.5 years), with a male-to-female ratio of about 4:1. The disease has been reported for more than 100 years, but its etiology has not been elucidated. In recent years, a considerable amount of research has been carried out on the etiology of the disease, and the development of the disease is believed to involve a variety of molecular biological alterations, such as the <i>COL2A1</i> mutation, which may be one of the causes of necrotic collapses of the epiphyseal cartilage matrix in LCPD. Tissue factor V Leiden mutation and insulin-like growth factor (IGF-1) abnormalities have also been reported in LCPD, but most theories need further confirmation. The in-depth study of LCPD cell biology has facilitated the suggestion regarding structural and/or functional abnormalities of microvascular endothelial cells in LCPD. This conjecture is supported by epidemiological and clinical evidence. Abnormal activation of osteoclasts, ischemic damage to epiphyseal cartilage, and activation of the bone marrow immune system all play important roles in the onset and progression of the disease. In this paper, we review the previous basic studies on LCPD and give an overview from the molecular biology and cell biology perspectives.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"16 ","pages":"1514302"},"PeriodicalIF":3.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss-of-function mitochondrial DNA polymerase gamma variants cause vascular smooth muscle cells to secrete a diffusible mitogenic factor.","authors":"Samantha Rothwell, Irvin Ng, Sophia Shalchy-Tabrizi, Pola Kalinowski, Omnia M Taha, Italia Paris, Angelica Baniqued, Lisa Lin, Michelle M Mezei, Anna Lehman, Lisa M Julian, Damon Poburko","doi":"10.3389/fphys.2024.1488248","DOIUrl":"10.3389/fphys.2024.1488248","url":null,"abstract":"<p><strong>Introduction: </strong>Mitochondrial dysfunction promotes vascular aging and disease through diverse mechanisms beyond metabolic supply, including calcium and radical signaling and inflammation. Mitochondrial DNA (mtDNA) replication by the POLG-encoded mitochondrial DNA polymerase (POLG) is critical for mitochondrial health. Loss-of-function POLG variants are associated with a predisposition to hypertension. We hypothesized that impaired POLG, through reduced mtDNA copy number or other mechanisms, would promote smooth muscle hypertrophy or hyperplasia that drives vascular remodeling associated with hypertension.</p><p><strong>Methods: </strong>We characterized the effect of over-expressing POLG variants that were previously observed in a cohort of hypertensive patients (p.Tyr955Cys, p.Arg964Cys, p.Asn1098Ile, and p.Arg1138Cys) in A7r5 cells.</p><p><strong>Results: </strong>AlphaFold modeling of the POLG holoenzyme complexed with DNA predicted changes in the catalytic site in the p.Tyr955Cys and p.Asn1098Ile variants, while p.Arg964Cys and p.Arg1138Cys showed minimal effects. The POLG variants reduced mtDNA copy number, assessed by immunofluorescence and droplet digital PCR, by up to 27% in the order p.Tyr955Cys > p.Arg964Cys > p.Asn1098Ile > p.Arg1138Cys relative to wild-type-transfected cultures. Loss of mtDNA was reduced in cultures grown in low serum and glucose media, but the cell density was increased in the same rank order in both 10% serum and 1% serum. POLG constructs contained a Myc epitope, the counterstaining for which showed that the mtDNA copy number was reduced in both transfected cells and untransfected neighbors. Live-cell imaging of mitochondrial membrane potential with TMRM and radical oxygen species production with MitoSOX showed little effect of the POLG variants. POLG variants had little effect on oxygen consumption, assessed by Seahorse assay. Live-cell imaging growth analyses again showed increased growth in A7r5 cells transfected with p.Tyr955Cys but a decreased growth with p.Arg1138Cys, while p.Tyr955Cys increased growth of HeLa cells. Conditioned media from HeLa cells transfected with POLG variants reduced doubling times in naïve cultures. Pharmacologically, wedelolactone and MitoTEMPOL, but not indomethacin or PD98059, suppressed the mitogenic effects of p.Tyr955Cys and p.Arg964Cys in A7r5 cells.</p><p><strong>Discussion: </strong>We conclude that POLG dysfunction induces secretion of a mitogenic signal from A7r5 and HeLa cells even when changes in mtDNA copy number are below the limit of detection. Such mitogenic stimulation could stimulate hypertrophic remodeling that could contribute to drug-resistant hypertension in patient populations with loss-of-function POLG variants.</p>","PeriodicalId":12477,"journal":{"name":"Frontiers in Physiology","volume":"15 ","pages":"1488248"},"PeriodicalIF":3.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}