Function (Oxford, England)最新文献

{"title":"Distinct right ventricular performance in response to acute colchicine treatment in healthy and diseased states.","authors":"Kristen LeBar, Lalida Tantisuwat, Jassia Pang, Adam J Chicco, Naomi C Chesler, Zhijie Wang","doi":"10.1093/function/zqaf021","DOIUrl":"https://doi.org/10.1093/function/zqaf021","url":null,"abstract":"<p><p>Right ventricular (RV) dysfunction is a major contributor to mortality in several cardiopulmonary diseases. However, the understanding of RV pathophysiology falls behind its left counterpart, limiting treatment options for conditions associated with discrete RV dysfunction and failure, such as pulmonary hypertension (PH). Accumulating evidence suggests that colchicine (COL) may have therapeutic benefits in multiple diseases, including PH. The mechanisms by which COL improves cardiovascular function are incompletely understood but may be associated with reductions in myocardial tissue viscoelasticity via microtubule depolymerization as demonstrated in prior ex vivo studies. The aim of this study is to investigate the impact of acute COL treatment on healthy and diseased RV organ function. Healthy and PH rats were anesthetized and catheterized for investigation of RV pressure-volume (PV) relationships before and after intramyocardial injections of COL. Marked RV failure was observed secondary to PH, characterized by elevated pulmonary vascular resistance (PVR), RV pressures and end diastolic PV relation (EDPVR) with reduced RV compliance, preload and stroke volume. COL reversed pathological changes in parameters such as EDPVR, and improved RV preload, compliance, stroke volume and ejection fraction in PH rats. COL also reduced RV systolic pressure and heart rate in PH rats, which may be associated with broader effects of COL (improved PVR) in addition to myocardial viscoelastic reduction. In contrast, no significant effect on cardiopulmonary function was observed in healthy rats. These results highlight a potential contribution of RV viscoelasticity to ventricular dysfunction, implicating tissue viscoelasticity as a therapeutic target for RV failure patients.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The amount of releasable insulin depends on continuous oxidative phosphorylation.","authors":"Carolin Tappe, Manjitha Parambath, Julia Reschke, Ingo Rustenbeck","doi":"10.1093/function/zqaf033","DOIUrl":"https://doi.org/10.1093/function/zqaf033","url":null,"abstract":"<p><p>The consensus or canonical model of glucose-stimulated insulin secretion provides that the metabolism of glucose closes KATP channels by increase of the ATP/ADP ratio and that the ensuing depolarization-induced Ca2+ influx through voltage-dependent Ca2+ channels represents the immediate signal for the onset of exocytosis. However, it has been shown earlier that the depolarization-induced secretion can be suppressed by inhibition of the oxidative phosphorylation, pointing to an energy-requiring step presumably located downstream of Ca2+ influx. Here, we have investigated the relation between oxidative phosphorylation and the insulinotropic effect of K+ depolarization to better localize the energy-requiring step. The specific inhibitor of the mitochondrial F1FO ATPase, oligomycin, concentration-dependently and time-dependently inhibited the insulin secretion elicited by a strong K+ depolarization (40 mM). Perifusion with 4 µg/ml of oligomycin for 20, 10 or 5 min prior to the K+ depolarization reduced the amount of insulin secreted from freshly isolated islets from control value to about 5% with a half-time of 1.6 min. 0.4 µg/ml of oligomycin required more time for comparable effects. Cultured islets were less susceptible to the inhibitory action of oligomycin than fresh islets, corresponding to their significantly higher ATP/ADP ratio. The perifusion with oligomycin prior to the K+ depolarization did not decrease the depolarization-elevated cytosolic Ca2+ concentration and did not affect the resting plasma membrane potential and the extent of depolarization by 40 mM KCl. In conclusion, the exocytotic machinery of the beta cell requires a continuously running oxidative phosphorylation to remain responsive to the Ca2+ signal for granule fusion.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of angiotensin II receptor type 1 abolishes the erythropoietin response to exercise.","authors":"Meihan Guo, David Montero","doi":"10.1093/function/zqaf032","DOIUrl":"https://doi.org/10.1093/function/zqaf032","url":null,"abstract":"<p><p>Beneficial adaptations to exercise depend on the normal function of the endocrine system. Whether commonly prescribed antihypertensive medication inhibits erythropoietin (EPO) production with exercise, a key response to enhance aerobic capacity, remains unknown. Healthy adults (n = 63, 42.3 ± 16.5 yr, 52% ♀) matched by age, sex and physical activity were randomized in a blinded and crossover manner to orally ingest valsartan (angiotensin II type 1 receptor-blockade, AT1-blockade) or placebo (calcium carbonate, PBO) 4 hr before starting the experimental protocol. Before and after 1 hr of moderate cycling exercise, blood samples were taken to measure circulating EPO and EPO-regulating hormones along with blood pressure. Cardiac structure/function and peak pulmonary O2 consumption (VO2peak) were assessed during exercise. AT1-blockade decreased heart volumes (left atrium and ventricle) during exercise compared with PBO, particularly in men (P ≤ 0.036). Whole-body O2 extraction and VO2peak were unaffected by AT1-blockade irrespective of sex (P ≥ 0.325). Before and after exercise, AT1-blockade reduced arterial blood pressures (systolic, diastolic) in both sexes (P < 0.001). A condition × time interaction was detected for circulating EPO (P = 0.002), such that AT1-blockade decreased EPO at 3-hr post-exercise compared with PBO (P ≤ 0.025). The effect of exercise on EPO-regulating hormones (angiotensin II, aldosterone, copeptin) was diminished with AT1-blockade. Sex per se did not influence the endocrine response to AT1-blockade. In conclusion, in a randomized, double-blind and placebo-controlled study design, AT1-blockade abolishes the acute EPO response to exercise in women and men. Antihypertensive medications hindering AT1 signaling may restrict key endocrine responses to exercise.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal muscle stem cell mitochondria are transferred to muscle fibers in response to a hypertrophic stimulus.","authors":"Jensen Goh, Julia G Williams, Sarah E Ogle, Jai K Joshi, Logan N Scott, Benjamin I Burke, Alex R Keeble, Nicholas T Thomas, Christopher S Fry, Ahmed Ismaeel, John J McCarthy","doi":"10.1093/function/zqaf031","DOIUrl":"https://doi.org/10.1093/function/zqaf031","url":null,"abstract":"<p><p>The fusion of skeletal muscle stem cell (MuSC) to myofibers during hypertrophy has exclusively focused on the transfer of the MuSC nucleus, leaving the fate of other MuSC organelles, such as mitochondria, largely unexplored. The objective of this study was to determine if MuSCs transfer their mitochondria upon myofiber fusion in response to a hypertrophic stimulus. To achieve this goal, we specifically labeled MuSC mitochondria with Dendra2 fluorescence by crossing the MuSC-specific CreER (Pax7CreER/CreER) mouse with the Rosa26-Dendra2 mouse to generate the Pax7-Dendra2 mouse. To induce the fusion of MuSC to myofibers, Pax7-Dendra2 mice underwent synergist ablation surgery to induce mechanical overload (MOV) of plantaris muscle for 3, 7 and 14 days. To track MuSC proliferation, a mini-osmotic pump was implanted at the time of MOV to continuously deliver EdU. At the designated time, plantaris muscles were excised and processed for immunohistochemistry to quantify Dendra2 + myofibers. There was a progressive increase in Dendra2-positive fibers across the MOV time course. Three distinct patterns or domains of Dendra2 fluorescence within myofibers were identified and designated as newly fused (NF), crescent (CS) or diffuse (DF). From these Dendra2 + domain types, we inferred MuSC fusion dynamics which indicated MuSC fusion occurred prior to mechanical overload day 3 (MOV-3) and preferentially with Type 2A fibers. Quantification of EdU + myonuclei found the majority of early (MOV < 3 days) MuSC fusion was division-independent, while proliferating MuSCs contributed primarily to later fusion events. The results of this study provide the first evidence that MuSC mitochondria are transferred to myofibers upon fusion during hypertrophy while, unexpectedly, revealing a greater complexity in MuSC fusion than previously recognized.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained accumulation of molecular clock suppressors Period 1 and Period 2 promotes C2C12 myotube atrophy through an autocrine-mediated mechanism with relevance to androgen deprivation-induced limb muscle mass loss.","authors":"Grant R Laskin, Jennifer L Steiner, Wayne A Ayers-Creech, Michael L Rossetti, Kirsten R Dunlap, Cynthia Vied, Choogon Lee, Nicholas P Greene, Dennis K Fix, Orlando Laitano, Kislay Parvatiyar, Bradley S Gordon","doi":"10.1093/function/zqaf030","DOIUrl":"https://doi.org/10.1093/function/zqaf030","url":null,"abstract":"<p><p>Low testosterone in males (hypogonadism) is associated with limb muscle mass loss, yet the underlying mechanisms of muscle mass loss remain largely unknown. We previously showed androgen deprivation disrupted limb muscle molecular clock function, and the disruption coincided with elevated levels of the primary molecular clock suppressor, Period 2 (Per2). The purposes herein were to determine if PER2 overexpression leads to muscle atrophy and if preventing PER2 accumulation blunts limb muscle mass loss in response to androgen deprivation. Here, we identify Per2 as a negative regulator of muscle size. Overexpression of Per2 in differentiated C2C12 myotubes reduced myotube diameter, while deletion of Per2 in male mice partially preserved tibialis anterior (TA) mass following castration. The muscle-sparing effect of Per2 deletion in vivo was specific to the TA despite evidence of molecular clock disruption and mass loss in other muscles. Subsequently, we show overexpression of the other primary clock suppressor, Period 1 (Per1) also reduced myotube diameter in differentiated C2C12 myotubes. Mechanistically, both Per1 and Per2 overexpression in vitro induced muscle atrophy in part by an autocrine-mediated mechanism likely involving inflammation as their overexpression induced an inflammatory gene expression signature and increased cytokine/chemokine secretion. Moreover, incubation of C2C12 myotubes in the media conditioned from Per1 or Per2 overexpressing myotubes reduced myotube diameter. Several inflammatory genes identified in vitro were also altered in the limb muscles in response to androgen deprivation. These findings identify a previously unrecognized role for Per1/2 in regulating skeletal muscle mass with implications for muscle loss during hypogonadism.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Mechanics to Restore Right Ventricular Function: A New Frontier in Pulmonary Arterial Hypertension Therapy.","authors":"Taryn Wilson, Lian Tian","doi":"10.1093/function/zqaf029","DOIUrl":"https://doi.org/10.1093/function/zqaf029","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal Implications of Kappa Opioid Receptor Signaling in Sprague-Dawley Rats.","authors":"Steven Didik, Daria Golosova, Adrian Zietara, Ruslan Bohovyk, Ameneh Ahrari, Vladislav Levchenko, Olha Kravtsova, Krish Taneja, Sherif Khedr, Marharyta Semenikhina, Oleg Palygin, Alexander Staruschenko","doi":"10.1093/function/zqaf028","DOIUrl":"https://doi.org/10.1093/function/zqaf028","url":null,"abstract":"<p><p>Opioid use for pain management and illicit consumption has been associated with adverse cardiovascular and cardiorenal outcomes. Despite these associations, the mechanisms underlying opioid-induced kidney damage remain poorly understood. Recently, we demonstrated that stimulation of kappa opioid receptors (KOR) is implicated in the aggravation of salt-sensitive hypertension, glomerular injury, and podocyte damage through excessive podocyte calcium influx. This study aims to elucidate the KOR signaling and renal outcomes underlying opioid use in Sprague-Dawley (SD) rats. Here, we employed freshly isolated glomeruli from SD male rats and immortalized human podocyte cell cultures to investigate the role of KORs in podocyte calcium regulation and overall glomerular function. A glomerular permeability assay was used to evaluate the impact of KORs on glomerular filter integrity. Additionally, the long-term effects of KOR activation were assessed in vivo by chronic intravenous infusion of selective KOR agonist BRL 52537 in SD rats. We found that acute application of BRL 52537 resulted in increased plasma membrane ion channel activity in immortalized human podocytes. Significant calcium influx in response to BRL 52537 was detected in podocytes of the isolated SD rat glomeruli. Further, glomerular permeability analysis revealed decreases in glomerular volume and impaired glomerular integrity, indicating altered glomerular function. Lastly, prolonged KOR activation in SD rats results in an increase in blood pressure, an elevation of basal calcium levels in podocytes, and albuminuria. In conclusion, this study unveils novel renal physiological outcomes by which opioid-induced KOR activation leads to podocyte and glomerular damage in SD rats.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The microenvironment in focus for male fertility.","authors":"Helle Praetorius","doi":"10.1093/function/zqaf027","DOIUrl":"https://doi.org/10.1093/function/zqaf027","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine-1-Phosphate Receptor 2 Promotes Renal Microvascular Constriction and Kidney Injury Following Renal Ischemia-Reperfusion in Rats.","authors":"Zhengrong Guan, Colton E Remedies, Yanfeng Zhang, Paul W Sanders, Edward W Inscho, Wenguang Feng","doi":"10.1093/function/zqaf024","DOIUrl":"10.1093/function/zqaf024","url":null,"abstract":"<p><p>Ischemia-reperfusion (IR) induced acute kidney injury (AKI) features increased renal vascular resistance, which is predominantly regulated by adjustments in afferent arteriolar diameter. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is a potent vasoconstrictor in afferent arterioles. We hypothesized that IR enhanced afferent arteriolar sensitivity to S1P-induced vasoconstriction, thus contributing to renal microvascular dysfunction and kidney injury in AKI. The impact of IR on afferent arteriolar reactivity to S1P was assessed using the in vitro blood-perfused juxtamedullary nephron preparation in male rats subjected to 60 min of bilateral renal arterial ischemia followed by 24 h of reperfusion. Baseline diameter of afferent arterioles declined significantly following IR. S1P evoked concentration-dependent vasoconstriction in both sham and IR rats. However, the S1P concentration-response curve left-shifted after IR and its EC50 reduced by 8-fold (P < 0.05), suggesting enhanced afferent arteriolar reactivity to S1P. S1P receptor 2 (S1PR2) blockade with JTE-013 increased arteriolar diameter by 38 ± 7% following IR contrasted to a 9 ± 3% increase in sham rats (P < 0.05), indicating that endogenous S1P exerts a significant impact on afferent arteriolar tone after IR. Furthermore, IR upregulated mRNA and protein of S1PR2 in isolated preglomerular microvessels and elevated S1P content in kidney homogenates. Conversely, following IR, vasoresponsiveness to S1PR1 agonist, sphingosine, endothelin-1, norepinephrine, and angiotensin II did not differ from sham controls. JTE-013 treatment reduced plasma creatinine, tubular damage, and kidney ROS accumulation in IR rats. These data establish that IR enhances renal microvascular S1P-S1PR2 signaling and promotes kidney sphingolipid metabolites that could negatively affect kidney tissue perfusion, leading to AKI.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251169","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":"Wheat-based protein slows disease progression in Pkd1 knockout mice.","authors":"Randee Sedaka, Jifeng Huang, Shinobu Yamaguchi, Emily Hallit, Aida Moran-Reyna, Jung- Shan Hsu, Caleb Lovelady, Ayaka Fujihashi, Mohammad Sako, Malgorzata Kasztan, Gloria Benavides, Landon Wilson, Victor Darley-Usmar, Stephen Barnes, Takamitsu Saigusa","doi":"10.1093/function/zqaf026","DOIUrl":"https://doi.org/10.1093/function/zqaf026","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}