Function (Oxford, England)最新文献

{"title":"Bemotrizinol and the Physiology of Photoprotection: A New Opportunity to Reduce Cutaneous Ultraviolet Damage.","authors":"Phillip Holler, George Cotsarelis","doi":"10.1152/function.90019.2026","DOIUrl":"https://doi.org/10.1152/function.90019.2026","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e900192026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119180","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":"ROS scavenging mitigates TNFα-induced endoplasmic reticulum stress and mitochondrial fragmentation in human airway smooth muscle.","authors":"Debanjali Dasgupta, Sanjana Mahadev Bhat, Gary C Sieck","doi":"10.1152/function.036.2026","DOIUrl":"10.1152/function.036.2026","url":null,"abstract":"<p><p>The proinflammatory cytokine tumor necrosis factor alpha (TNFα) mediates airway responses to acute inflammation. Previously, we demonstrated that, in human airway smooth muscle (hASM) cells, TNFα increases reactive oxygen species (ROS) formation. TNFα also selectively activates the inositol-requiring enzyme 1α (pIRE1α^S724 autophosphorylation) endoplasmic reticulum (ER) stress pathway involving splicing of X-box binding protein 1 (XBP1s) and transcriptionally activates cyclin-dependent kinases 1 and 5 (CDK1 and CDK5), promoting dynamin-related protein 1 (DRP1) phosphorylation at serine 616 (pDRP1^S616) and mitochondrial fragmentation. In the present study, we hypothesized that in hASM cells, TNFα-induced ROS triggers pIRE1α^S724/XBP1s ER stress pathway. To test this hypothesis, we examined the impact of the ROS scavenger tempol on TNFα-induced pIRE1α^S724/XBP1s ER stress pathway and downstream signaling mediating mitochondrial fragmentation. Bronchiolar tissue samples were obtained from six patients with no history of smoking or chronic pulmonary disease. The smooth muscle layer was dissected, and hASM cells were dissociated and randomly assigned to four treatment groups: <i>1</i>) vehicle, <i>2</i>) vehicle + TNFα (20 ng/mL, 6 h), <i>3</i>) tempol (500 μM) only, and <i>4</i>) tempol (500 μM) + TNFα (20 ng/mL, 6 h). ROS formation was determined by confocal imaging using MitoSox Red. Mitochondria were labeled with MitoTracker Green and imaged using confocal microscopy. Using Western blot, we demonstrated that tempol reduced cellular ROS formation and mitigated the TNFα-induced increase in pIRE1α^S724, XBP1s, CDK1/5, pDRP1^S616 protein levels and reduced mitochondrial fragmentation. These findings support our hypothesis and indicate a role of ROS in mediating TNFα-induced ER stress and mitochondrial fragmentation.<b>NEW & NOTEWORTHY</b> In human airway smooth muscle cells, TNFα induces reactive oxygen species (ROS) generation and promotes endoplasmic reticulum (ER) stress and mitochondrial fragmentation. Importantly, treatment with the ROS scavenger tempol effectively attenuated TNFα-induced oxidative stress, suppressed ER stress and mitochondrial fragmentation, and improved the intrinsic respiratory capacity and functional efficiency of individual mitochondria. These findings identify oxidative stress as a central mediator linking TNFα signaling to ER stress and mitochondrial fragmentation, highlighting tempol as a potential therapeutic strategy.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0362026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889041","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":"Simulated shift work schedules disrupts circadian rhythms and behavior in mice.","authors":"Jun-Yi Duan, Xiao-Tong Huang, Ai-Yu Duan, Li Ma, Wei Chen, Qun Luo","doi":"10.1152/function.012.2026","DOIUrl":"10.1152/function.012.2026","url":null,"abstract":"<p><p>Shift work has become a major cause of circadian rhythm disruption in modern society. This study investigated the systemic consequences of shift schedules by subjecting mice to different light-dark (LD) cycles: non-24-h cycles (rapidly rotating <i>groups A</i> and <i>B</i>) and 24-h cycles (<i>group C</i> and control group). We performed behavioral tests, serum hormone measurements, transcriptomic analysis of suprachiasmatic nucleus (SCN) genes, and gut microbiome analysis. The results showed that the mice exhibited significant body weight gain after altering LD cycle compared with the control group. In groups exposed to non-24-h cycles, the circadian expression rhythms of core clock genes (<i>Per</i>, <i>Cry</i>, and <i>Bmal1</i>) in the SCN were lost. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that genes in the SCN losing rhythmicity were significantly enriched in metabolic and regulatory pathways, disrupting endocrine and metabolic rhythms and ultimately compromising health. The circadian rhythms of key hormones like melatonin and dopamine were also lost. Concurrently, these central disruptions drove peripheral pathology, including gut microbiota dysbiosis (altered Firmicutes/Bacteroidota ratio, reduced Verrucomicrobia) and a profound loss of gut microbial diurnal oscillations. Behaviorally, this multisystem discord manifested as significantly increased anxiety-like and depression-like behaviors and fatigue (<i>P</i> < 0.05), whereas spatial memory remained intact, indicating selective affective vulnerability. SCN collapse, together with hormonal chaos, desynchronizes the gut microbiome, potentially promoting inflammation and metabolic dysfunction that further disrupts central regulation. These findings provide a physiological foundation for understanding the health consequences of circadian disruption and may help guide the future design of healthier shift work schedules.<b>NEW & NOTEWORTHY</b> Systematic comparison of multiple simulated shift schedules in mice reveals that non-24-h light-dark cycles, but not fixed 24-h shifted cycles, abolish suprachiasmatic nucleus core clock gene (<i>Per</i>, <i>Cry</i>, <i>Bmal1</i>) rhythms, disrupt melatonin and dopamine, and desynchronize gut microbiota at the phylum level. These central and peripheral disruptions selectively exacerbate anxiety- and depression-like behaviors without impairing spatial memory, revealing a hierarchical disintegration of circadian organization. The findings provide a physiological framework for evidence-based shift scheduling.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0122026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13581034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148426976","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":"Positive allosteric modulator of SERCA pump NDC-1171 attenuates cardiac functional decline in mouse model of Duchenne muscular dystrophy.","authors":"Niharika Narra, Alyssa M Richards, Conner C Earl, Abigail D Cox, Russell Dahl, Wendy A Koss, Craig J Goergen","doi":"10.1152/function.018.2026","DOIUrl":"10.1152/function.018.2026","url":null,"abstract":"<p><p>Progressive cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Dysregulation of calcium handling has been implicated in cardiomyopathy progression in DMD. Here we describe a therapeutic approach to improve calcium homeostasis in a mouse model of DMD using the novel therapeutic NDC-1171, which is a positive allosteric modulator of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump. We synthesized NDC-1171 and treated 4-wk-old D2.<i>mdx</i> mice (<i>n</i> = 9) via oral gavage. The drug was administered 3 times per week for 8 wk at 40 mg/kg. A group of D2.<i>mdx</i> mice (<i>n</i> = 9) and a group of DBA/2J mice (<i>n</i> = 9; background strain) received a vehicle on the same schedule. We used ultrasound to assess left ventricular function, followed by a treadmill exhaustion test and a 4-paw grip strength test to assess skeletal muscle function. NDC-1171 attenuated cardiac functional decline in D2.<i>mdx</i> mice. At 16 wk of age, left ventricular ejection fraction (LVEF) was significantly preserved in mice treated with NDC-1171 (57.7 ± 0.5%) compared with mice treated with a vehicle (50.7 ± 0.9%, <i>P</i> < 0.05), though it remained lower than background strain controls (62.4 ± 0.6%). In contrast, functional behavior testing revealed no significant improvement in skeletal muscle function with treatment. These data suggest that treatment with the SERCA pump modulator NDC-1171 helps preserve cardiac function in a murine model of DMD, even as skeletal muscle function was impaired. Future work will be needed to determine whether the benefits of this novel SERCA activator translate to large animal and clinical studies, but these initial results are promising and could help guide development of future treatments for pediatric patients with muscular dystrophy.<b>NEW & NOTEWORTHY</b> Dysregulated calcium handling contributes to cardiomyopathy in Duchenne muscular dystrophy, yet effective cardiac therapies remain limited. This study tested whether pharmacological activation of the SERCA pump with the novel modulator NDC-1171 could preserve cardiac function in a severe D2.<i>mdx</i> mouse model. The results show that NDC-1171 attenuates the decline in left ventricular systolic function without improving skeletal muscle performance or fibrosis, indicating that SERCA activation supports cardiac-specific functional benefits in dystrophic disease.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0182026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148922038","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":"Maternal kidney adaptation and function in pregnancy: review and perspectives.","authors":"Jessica F Hebert, Kevin Burfeind, Michael P Hutchens","doi":"10.1152/function.044.2026","DOIUrl":"10.1152/function.044.2026","url":null,"abstract":"<p><p>Pregnancy imposes considerable physiological demands on the maternal kidney, requiring coordinated structural, hemodynamic, and molecular adaptations to maintain homeostasis and support fetal development. This review synthesizes renal changes throughout normal and abnormal gestation, emphasizing the dynamic interactions among maternal, placental, and fetal systems. These adaptations are driven by integrated hormonal pathways, including the renin-angiotensin system and vasodilatory mediators, as well as emerging mechanotransductive processes that enable the kidney to sense and respond to increased flow and pressure. Bidirectional signaling between the placenta and maternal kidney aligns maternal physiology with fetal demand. Dysregulation of these processes leads to complications such as preeclampsia, gestational hypertension, and pregnancy-associated acute kidney injury, with lasting consequences for maternal and offspring health. Key gaps remain in defining kidney and placental interactions, renal immune and mechanosensory roles, and accurate biomarkers of renal function in pregnancy. Advancing research in these areas is critical to improving diagnosis and outcomes in renal and pregnancy-related disorders.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0442026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956749","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":"Evidence that myoglobin Po₂ is a noninvasive measure of in vivo skeletal muscle mitochondrial Po₂ during exercise in humans.","authors":"Ryan M Broxterman, Bradley A Ruple, Peter D Wagner, Russell S Richardson","doi":"10.1152/function.022.2026","DOIUrl":"10.1152/function.022.2026","url":null,"abstract":"<p><p>Muscle mitochondrial partial pressure of oxygen ([Formula: see text]) is a key determinant of skeletal muscle oxygen consumption ([Formula: see text]), metabolism, gene regulation, and adaptation in health and disease. Yet [Formula: see text] remains difficult to measure directly in vivo in humans during exercise. Myoglobin-associated Po₂ ([Formula: see text]), measured noninvasively using proton magnetic resonance spectroscopy, may provide a measure of [Formula: see text] during maximal exercise in humans because Mb is coupled to mitochondrial oxygen availability, and [Formula: see text] falls in the low Po₂ range expected for [Formula: see text] in vivo. However, it remains unknown whether [Formula: see text] during maximal exercise varies systematically with muscle maximal oxygen consumption ([Formula: see text]), as would be expected if [Formula: see text] reflects [Formula: see text] in vivo. We analyzed data from five initially sedentary males before and after 8 weeks of single-leg knee-extensor exercise (KE) training. During maximal KE under 0.12, 0.21, and 1.00 fractions of inspired oxygen ([Formula: see text]), we measured [Formula: see text] using myoglobin desaturation measured by proton magnetic resonance spectroscopy and muscle [Formula: see text] from leg blood flow and the arterial-femoral venous O₂ content difference. Across [Formula: see text] conditions, muscle [Formula: see text] varied systematically with [Formula: see text] both before and after training, consistent with O₂-dependent mitochondrial respiration. When interpreted within a canonical hyperbolic framework, the [Formula: see text]-[Formula: see text] relationship yielded low apparent mitochondrial P₅₀ values that were broadly consistent with values reported for human skeletal muscle-isolated mitochondria studied in vitro. A complementary linear P₅₀ analysis that did not assume a hyperbolic relationship supported the same interpretation. Together, these findings provide data-supported, proof-of-concept evidence that [Formula: see text] reflects in vivo [Formula: see text] during maximal exercise in humans. <b>NEW & NOTEWORTHY</b> Direct measurement of mitochondrial partial pressure of oxygen ([Formula: see text]) in exercising human skeletal muscle remains difficult. By integrating noninvasive myoglobin Po₂ ([Formula: see text]) and invasive maximal muscle oxygen consumption ([Formula: see text]) measurements across graded oxygen availability, we found that [Formula: see text] behaves as expected for [Formula: see text] during maximal exercise in humans. These findings provide proof-of-concept evidence that [Formula: see text] reflects [Formula: see text] in vivo, potentially enabling new insights into metabolism, hypoxia-sensitive signaling, and exercise capacity in health and disease.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0222026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888881","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":"A DIAMETER AND HEMODYNAMIC REGULATION MODEL UTILIZING AN ARTERIOLAR NETWORK STRUCTURAL MODEL AND EXPERIMENT-BASED MACHINE LEARNING.","authors":"Yuki Bao, Brayden D Halvorson, Sarah A Mattonen, Daniel Goldman, Jefferson C Frisbee","doi":"10.1152/function.045.2026","DOIUrl":"https://doi.org/10.1152/function.045.2026","url":null,"abstract":"<p><p>Arteriolar regulation is central to maintaining adequate tissue perfusion, and its disruption can lead to adverse health outcomes. However, mechanisms governing vessel responses to complex environmental conditions within a network context remain uncertain. This study presents computational simulations of arteriolar network responses to various combinations and intensities of five physiologically significant stimuli: metabolic (via adenosine), adrenergic (via norepinephrine), oxygen, myogenic (intralumenal pressure), and blood flow/shear stress. Individual vessel diameter adaptations are predicted using machine learning models trained on extensive experimental data of arteriolar responses to stimuli combinations in rat skeletal muscle. After evaluating multiple single vessel modeling pipelines, a high-performing machine learning vessel model (R² > 0.9) was applied to an initially static (i.e., non-regulating) network to obtain a novel steady-state network regulation model. The initial static arteriolar network was obtained via a previously described experimentally validated constrained constructive optimization (CCO) approach. Regulated network characteristics are analyzed based on diameter distribution and over a range of hemodynamic properties (volumetric blood flow, red blood cell flow, tube and discharge hematocrit) relevant to tissue health. These simulations support a range of research objectives, allowing user adjustments to network properties (e.g., vessel density), tissue shape/size, and environmental conditions (i.e., varying intensities and combinations of the five vasoactive stimuli). The methodology in this study promotes accessible modeling and holds application in disease research or therapy developments, as well as permitting further theoretical development such as time-dependent network regulation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0452026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119147","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":"Pairing ampakine with brief hypoxia evokes phrenic neuroplasticity via a spinal NMDA receptor-mediated mechanism.","authors":"Prajwal P Thakre, Sabhya Rana, Raphael R Perim, Gordon S Mitchell, David D Fuller","doi":"10.1152/function.019.2026","DOIUrl":"10.1152/function.019.2026","url":null,"abstract":"<p><p>Brief hypoxic episodes drive neuroplasticity in animal models and humans. Pretreatment with an allosteric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (R) modulator (\"ampakine\") enables a single hypoxic exposure to induce sustained increases in phrenic motor activity [\"phrenic motor facilitation\" (pMF)]. Phrenic nerve activity was recorded in anesthetized rats to determine whether the ampakine-hypoxia (A-H) combination is unique in its ability to evoke pMF and to determine its underlying mechanisms. Pairing ampakine CX717 with brief moderate or severe hypercapnia failed to produce pMF. Pairing doxapram, a respiratory stimulant, with hypoxia did not produce pMF. We then sequentially tested the hypotheses that A-H-induced pMF requires spinal serotonin, adenosine, or NMDA receptor activation. Cervical intrathecal delivery of serotonin (methysergide) or adenosine 2 A receptor (MSX-3) antagonists before A-H failed to prevent pMF. In contrast, the NMDA-R blocker MK-801 prevented pMF when administered before but not after A-H. Finally, as a step in the translational pathway, we tested the safety and efficacy of acute A-H exposure in unanesthetized rats with indwelling diaphragm electromyogram (EMG) wires after cervical spinal cord injury (SCI). A-H was well tolerated, and at 3 mo after SCI, increased diaphragm EMG output. We conclude that the mechanism driving sustained increases in phrenic motor output after A-H is independent of spinal adenosine or serotonin receptor activation, but requires spinal NMDA-R activation for the induction, but not maintenance, of A-H pMF. Ampakine pretreatment may be useful to increase the efficacy of hypoxia-based rehabilitation paradigms after SCI, particularly since clinical trials report a substantial number of \"low responders.\"<b>NEW & NOTEWORTHY</b> Rehabilitation paradigms using brief hypoxia exposure can improve recovery after spinal cord injury. A low dose of ampakines, which enhance AMPA neurotransmission, coupled with brief hypoxia (A-H), uniquely evokes respiratory neuroplasticity (\"phrenic motor facilitation\" or pMF) <i>via</i> a mechanism that requires spinal NMDA, but not serotonin or adenosine receptor activation. A-H also increased diaphragm activation in rats with chronic SCI, suggesting that the A-H pairing may be useful in neurorehabilitation.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0192026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474642","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":"Ampakine-hypoxia pairing reveals a novel NMDA-dependent respiratory neuroplasticity.","authors":"Pauline Michel-Flutot, Kun-Ze Lee, Stéphane Vinit","doi":"10.1152/function.047.2026","DOIUrl":"10.1152/function.047.2026","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0472026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474637","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":"Type 1 diabetes differentially disrupts right and left ventricular daily rhythms.","authors":"Sharanya S Bettadapura, Samantha J Torres, Marjie P Schmitt, Brandon L Roberts, Danielle R Bruns","doi":"10.1152/function.041.2026","DOIUrl":"10.1152/function.041.2026","url":null,"abstract":"<p><p>Circadian rhythms are endogenous ∼24-h cycles that regulate cardiovascular physiology. Although circadian regulation of the left ventricle (LV) is well established, whether the right ventricle (RV) exhibits intrinsic rhythmicity is not known. Here, we provide the first evidence that the healthy RV exhibits robust rhythms in function and molecular gene expression. Cardiovascular disease is the leading cause of mortality in type 1 diabetes (T1D). T1D disrupts circadian rhythms, yet how T1D alters chamber-specific circadian control remains unclear. We investigated RV and LV function and gene expression across the 24-h light-dark cycle in male streptozotocin-induced T1D and control mice. Echocardiographic assessment of diabetes-induced remodeling at ZT0-4 and ZT12-16 [zeitgeber time (ZT)] revealed time-dependent functional impairment, including reversal of the normal diurnal heart rate pattern. T1D impaired day-night RV and LV systolic function, with loss of day-night difference in LV ejection fraction and impaired active period RV stroke volume. Cosinor analysis of RV and LV gene expression demonstrated preserved 24-h rhythmicity of core clock genes <i>Arntl1</i> and <i>Per2</i> in both ventricles with T1D, whereas the clock output genes <i>Nr1d1</i> and <i>Dbp</i> had dampened amplitude in the RV but amplified expression in the T1D LV. These findings demonstrate that T1D differentially disrupts circadian regulation of the RV and LV, with selective vulnerability of the clock-controlled output genes despite preservation of the core oscillator. Chamber-specific circadian remodeling may contribute to the elevated cardiovascular risk in T1D and has implications for the timing of diagnostic and therapeutic interventions.<b>NEW & NOTEWORTHY</b> This study provides the first evidence that the healthy right ventricle (RV), like the left ventricle (LV), possesses an intrinsic circadian clock with robust 24-h rhythmicity. Using a mouse model of type 1 diabetes, we show that diabetes does not uniformly suppress cardiac clocks but instead differentially rewires RV and LV rhythms, dampening clock-output gene amplitude in the RV while amplifying it in the LV. Together, we reveal chamber-specific circadian vulnerability with implications for diabetic cardiomyopathy and chronotherapy.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0412026"},"PeriodicalIF":3.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148690472","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}