Function (Oxford, England)最新文献

{"title":"A curious case of hepatic ketogenesis regulating voluntary exercise behavior and the skeletal muscle metabolic proteome.","authors":"Daniel S Lark","doi":"10.1152/function.90009.2026","DOIUrl":"https://doi.org/10.1152/function.90009.2026","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031531","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":"Alcohol and calorie-dense diets modulate immune phenotype and metabolic health in simian immunodeficiency virus infection.","authors":"Liz Simon, Megan Mire, Patrick M McTernan, Eden M Gallegos, Larry Coleman, Robert W Siggins, Adam C Caro, Carol L Baker, Patricia E Molina","doi":"10.1152/function.033.2026","DOIUrl":"10.1152/function.033.2026","url":null,"abstract":"<p><p>Alcohol misuse and calorie-dense diets, especially those rich in sugar and fat, independently increase comorbidity risk among people with HIV. The objective of this study was to define the combined effects of chronic binge alcohol administration and consumption of a high-fat high-sucrose diet (HFSD) on systemic metabolic, immunologic, and body composition outcomes under controlled conditions in an established nonhuman primate (NHP) model of HIV infection. Male NHPs fed HFSD diet were administered alcohol or vehicle. A subset of animals in the vehicle (VEH) and alcohol groups was infected with simian immunodeficiency virus (SIV) and treated with antiretroviral therapy (ART). ART treatment decreased viral loads, which did not differ between the vehicle- and alcohol-administered NHPs. There was a main effect of alcohol to significantly reduce peripheral CD4⁺ T cell counts and the CD4⁺/CD8⁺ T-cell ratio. Overall body composition was not significantly different between the treatment groups. However, bone mineral density was significantly lower in the alcohol/SIV+ group. Alcohol decreased the acute insulin response to glucose. ART effectively suppressed viral loads in vehicle and alcohol/SIV NHPs. Alcohol produced significant immunological alterations, impaired glucose-insulin dynamics, and decreased bone mineral density. These findings highlight alcohol misuse as a modifiable driver of metabolic and immunologic dysfunction. Our ongoing studies will dissect the tissue-specific effects of alcohol and calorie-dense diets that contribute to the systemic changes.<b>NEW & NOTEWORTHY</b> This study examined the interactions of a calorie-dense diet and alcohol in SIV-infected and SIV-seronegative nonhuman primates on systemic viral loads and immunological and metabolic measures. ART effectively suppressed viral loads, irrespective of alcohol administration. Alcohol produced significant immunological alterations and decreased bone mineral density in SIV infection. Alcohol impaired glucose-insulin dynamics irrespective of SIV infection, highlighting a significant metabolic maladaptation. The results highlight the interaction of diet and alcohol on increasing the risk for comorbidities in HIV.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0332026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13460388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450949","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":"Circadian clock protein Bmal1 regulates respiratory motor plasticity in male rats.","authors":"Aaron A Jones, Alexandria B Marciante, Pierce Berardi, Gordon S Mitchell","doi":"10.1152/function.016.2026","DOIUrl":"10.1152/function.016.2026","url":null,"abstract":"<p><p>Acute intermittent hypoxia (AIH) elicits respiratory motor plasticity in the phrenic, intercostal, and hypoglossal motor pools and has emerged as a promising therapeutic strategy to improve respiratory function in people with neuromuscular disorders that compromise breathing. Although we recently reported that time-of-day regulates moderate ([Formula: see text] ∼40-50 mmHg) AIH-induced respiratory motor plasticity, it is unknown whether diurnal effects on AIH-induced phrenic (pLTF) or ventilatory (vLTF) long-term facilitation are mediated via the endogenous circadian clock versus other factors. Since many biological rhythms are driven by the endogenous clock and clock genes (including the essential clock gene Bmal1) are rhythmically expressed in the phrenic motor system, we hypothesized that the molecular clock within respiratory motor neurons exerts time-of-day effects on pLTF and vLTF in Sprague Dawley rats (3-6 mo old males). Intrapleural injections of small-interfering RNAs (siRNAs) were used to selectively knock down Bmal1 within respiratory motor neurons by ∼30%. AIH consisting of 15, 1-min hypoxic episodes ([Formula: see text] = 0.09) was delivered in the midrest (i.e., light) or midactive (i.e., dark) phases, and pLTF (Δintegrated phrenic burst amplitude) and vLTF (ΔV̇e/V̇co₂) were assessed in rats given siRNAs targeting Bmal1 versus nontargeting controls. In midrest phase, pLTF was reduced, and vLTF was abolished in rats given siBmal1 versus nontargeting siRNA. However, siBmal1 had no significant effect on either pLTF or vLTF in the midactive phase. Thus, the phrenic motor neuron circadian clock regulates AIH-induced respiratory motor plasticity in a time-of-day-dependent manner. It is important to consider circadian biology in future studies of AIH-induced respiratory motor plasticity.<b>NEW & NOTEWORTHY</b> Although diurnal cycle influences respiratory motor plasticity elicited by acute intermittent hypoxia (AIH), it is unknown how endogenous circadian clock mechanisms contribute to time-of-day effects on plasticity. We report that knockdown of the circadian clock protein Bmal1 within respiratory motor neurons attenuates phrenic and ventilatory long-term facilitation in a manner dependent on diurnal phase. Thus, circadian biology is an important consideration for studies of respiratory motor plasticity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0162026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13308673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213461","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":"Layer-specific choroidal vascular adaptation to high-altitude hypoxia revealed by functional OCT at 3,800 m.","authors":"Mohammad Amin Safarzadeh, Jacquie R Baker, Satish R Raj, Usman Alim, Trevor A Day, Nicholas G Jendzjowsky, Richard J A Wilson","doi":"10.1152/function.002.2026","DOIUrl":"10.1152/function.002.2026","url":null,"abstract":"<p><p>Ascent to high-altitude induces systemic and ocular changes that alter vision. The functional responses of the choroidal vasculature at different depths to hypoxia remain incompletely understood. In this study, we used functional optical coherence tomography (f-OCT) to quantify changes in choroidal vascular perfusion density (VPD) across superficial, deep, and total choroidal layers in 16 healthy participants. Imaging was performed at baseline (1,100 m) and during acute (<i>day 2</i>) and prolonged exposure (<i>day 9</i>) to high altitude (3,800 m). Our depth-resolved analysis showed a modest but statistically significant decline in superficial choroidal VPD from baseline to <i>day 2</i> (<i>P</i> = 0.031; Cohen's <i>d</i> = -0.73). In contrast, both deep and total choroidal VPD increased significantly from baseline to <i>day 2</i> (<i>P</i> = 0.002 and <i>P</i> = 0.003, respectively; Cohen's <i>d</i> > 0.9). Changes in superficial, deep, and total choroidal VPD persisted from <i>day 2</i> through <i>day 9</i> at 3,800 m. [Formula: see text] showed a strong negative correlation with deep choroidal (<i>r</i> = -0.655; <i>P</i> = 0.0003) and total choroid VPD (<i>r</i> = -0.566; <i>P</i> = 0.0014), but no significant correlation was observed with the VPD of the superficial layer (<i>r</i> = 0.018; <i>P</i> = 0.93). The strong correlation between VPD and the stimulus index ([Formula: see text]/[Formula: see text]) in the total choroid suggests that hypoxia-induced vasodilation outweighs hypocapnic vasoconstriction, leading to increased perfusion (<i>r</i> = 0.629; <i>P</i> = 0.0003). These findings suggest that deep choroidal hyperperfusion on ascent to high altitude helps sustain outer retinal oxygenation. Depth-resolved choroid imaging may offer new insights into ocular resilience to environmental challenges and provide a valuable tool to monitor spaceflight-related ocular changes associated with neuro-ocular syndrome.<b>NEW & NOTEWORTHY</b> This study reveals that the human choroid mounts a depth-specific vascular response to high-altitude hypoxia. Rather than showing uniform vasodilation, superficial choroidal perfusion decreases, whereas deep choroidal perfusion increases and remains elevated after prolonged altitude exposure. The strong relationship between deep choroidal perfusion and arterial blood gases suggests that hypoxia-driven vasodilation outweighs hypocapnic vasoconstriction. These data highlight functional OCT as a powerful tool for measuring how physiological stress reshapes ocular vascular function and suggest that combining high-altitude exposure with depth-resolved functional OCT may provide a useful terrestrial model for vascular changes relevant to spaceflight-associated neuro-ocular syndrome.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0022026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148151979","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":"Synchronization of the 12-h circatidal rhythm maintains the kidney through repeated cycles of warm reperfusion in the hibernating ground squirrel.","authors":"Austin E Gillen, David J Orlicky, Rui Fu, Swati Jain, Alkesh Jani, Sandra L Martin","doi":"10.1152/function.015.2026","DOIUrl":"10.1152/function.015.2026","url":null,"abstract":"<p><p>The hibernating 13-lined ground squirrel kidney is a unique natural model of resistance to damage caused by cold storage and warm reperfusion. Over months, the kidney is exposed to cycles between multiday periods of torpor with low perfusion at ice-cold temperature and rapid warm reperfusion during arousals. Serum creatinine accumulates during torpor but normalizes during arousal, and animals emerge each spring with functioning kidneys. After confirming a lack of kidney histopathology in sections from 11 animals that had completed 11-22 torpor-arousal cycles, we collected RNA sequencing (RNA-Seq) data from 32 ground squirrel kidneys representing 6 key transitional time points based on seasonal and torpor-arousal cycle physiology. Hibernation state-specific gene expression changes were identified after removing three informative outliers. Both seasonal and torpor-arousal cycle-specific gene expression changes were found. These differentially expressed genes illuminated molecular mechanisms that mitigate damage while supporting full recovery during each ∼12 h rewarming. As with the response to renal ischemia-reperfusion injury in other species, the arousing hibernator induced immediate early genes during warm reperfusion. But, in the hibernator, this response did not precipitate the gene expression program of maladaptive repair that is characterized by cell death, immune system activation, and fibrosis. Rather, it appears that induction of immediate early genes activated a universal 12-h, \"circatidal\" rhythm. The efficient unfolding of this rhythm across each arousal from torpor was facilitated by the seasonally changed background primed for rapid cell division and minimal energy consumption. Adaptive repair was achieved, with proteostasis and cell type-specific function restored, assuring that minor damage did not accumulate.<b>NEW & NOTEWORTHY</b> The hibernator kidney exhibits no damage after 10-22 cycles between prolonged cold exposure and rapid warm reperfusion occurring over several months. As found with kidney damage in other species, each rewarming activates an immediate early gene response. Unique to the hibernator, adaptive repair is completed within 12 h, facilitated by rapid activation of the universal \"circatidal\" rhythm unfolding on a seasonally primed background that assures minimal cell death, rapid cell division, and repair.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0152026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13387086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341440","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":"Constitutive mTORC1 activation in skeletal muscle increases inflammation but is not sufficient to impair glucose tolerance.","authors":"Erik D Marchant, Hanna Kalenta, Sean P Kilroe, Jacquelyn May, Wenjun Z Martini, Korri S Weldon, Zhao Lai, Blake B Rasmussen","doi":"10.1152/function.039.2026","DOIUrl":"10.1152/function.039.2026","url":null,"abstract":"<p><p>Aberrant mechanistic target of rapamycin complex 1 (mTORC1) signaling in skeletal muscle has been implicated in aging and insulin resistance; however, it is not known whether chronic mTORC1 activation directly causes glucose intolerance. We tested the hypothesis that constitutive mTORC1 activation in mouse skeletal muscle impairs glucose homeostasis. Six-month-old female and male mice with tamoxifen-inducible, muscle-specific knockout of the DEP domain containing 5, GATOR1 subcomplex subunit gene (<i>Depdc5</i>), a key component of the GAP activity toward rag 1 (GATOR1) complex and negative regulator of mTORC1, were fed normal chow or Western diet (WD; 45% fat, 17% sucrose) for 12 wk. <i>Depdc5</i> knockout (KO) increased mTORC1 signaling and altered autophagy markers. WD increased body and fat mass and impaired glucose tolerance independent of genotype. KO had minimal effects on fasting glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), glycosylated hemoglobin (HbA1c), or oral glucose tolerance, although female KO mice showed a modest increase in WD-induced weight gain and fasting glucose. Mitochondrial respiration and content were unchanged by KO or WD. KO increased mitochondrial H₂O₂ production capacity but did not drive clear signs of oxidative stress. Transcriptomic analysis revealed robust KO-driven upregulation of genes related to cell division and immune pathways. Consistent with this, KO increased TNF-α and IL-6 protein expression and shifted macrophage polarization toward an M2-like phenotype without altering total macrophage content. Collectively, these findings indicate that chronic activation of mTORC1 in skeletal muscle promotes inflammatory remodeling but is insufficient to impair systemic glucose homeostasis, even under dietary stress.<b>NEW & NOTEWORTHY</b> Chronic skeletal muscle mTORC1 hyperactivation is widely assumed to drive insulin resistance and metabolic decline, yet direct causal evidence remains limited. Using adult-onset <i>Depdc5</i> deletion to constitutively activate mTORC1 via GATOR1 disruption, we show that this is insufficient to impair glucose homeostasis even under a Western diet challenge. Strikingly, glucose tolerance and mitochondrial respiration remained preserved despite inflammation and immune transcriptional reprogramming-challenging the prevailing model of mTORC1-driven metabolic dysfunction in muscle.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0392026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474673","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":"Going with the flow: endothelial dysfunction in type 2 diabetes.","authors":"Luke S Dunaway","doi":"10.1152/function.037.2026","DOIUrl":"10.1152/function.037.2026","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0372026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165875","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":"Cellular senescence links muscle atrophy and posttraumatic osteoarthritis after ACL injury.","authors":"Alexander R Keeble, Allison M Owen, Sara Gonzalez-Velez, Nicholas T Thomas, Camille R Brightwell, Peyton J Balawender, Madeline G O'Daniel, Helena C Weiss, Haley Noehren, Heather Thompson, Karen Sofia Zuluaga-Osorio, Zane T Bates, Lauren Gottlieb, Douglas E Long, Douglas A Harrison, Philip A Kern, Caitlin E Conley, Michael A Samaan, Stephen T Duncan, Austin V Stone, Darren L Johnson, Yuan Wen, Brian Noehren, Cory M Dungan, Christopher S Fry","doi":"10.1152/function.017.2026","DOIUrl":"10.1152/function.017.2026","url":null,"abstract":"<p><p>Traumatic knee injury leads to posttraumatic osteoarthritis (PTOA) and significant skeletal muscle weakness, resulting in chronic disability. The current standard of care frequently fails to prevent musculoskeletal dysfunction, underscoring the need to identify therapeutic mechanisms of PTOA. Using an established preclinical anterior cruciate ligament (ACL) transection model of PTOA and leveraging an innovative SPiDER-senescence-associated β-galactosidase stain to discern senescent cells, we investigated cellular senescence at single-cell resolution and identified anti-inflammatory macrophages as a predominant contributor to the senescent cell burden in both muscle and knee joint after injury. Clearance of senescent cells using the senolytic dasatinib and quercetin (D + Q) mitigated injury-induced muscle atrophy and cartilage degradation, with greater senescent cell clearance within muscle compared with cartilage. We also provide clinical evidence of elevated senescent cell burden in the muscle of patients following ACL injury and with PTOA, which is obstinate to standard of care, highlighting cellular senescence as a strong therapeutic target to improve functional recovery after traumatic joint injury.<b>NEW & NOTEWORTHY</b> Posttraumatic osteoarthritis (PTOA) and disability are consequences of ACL injury, but the cellular effectors that facilitate this process are unknown. Our findings demonstrate increased senescent macrophage burden in the muscle and knee joint in a preclinical ACL injury model, as well as in patients who predict poor muscle quality and weakness. We provide evidence that treatment with senolytics is an effective strategy to improve tissue quality and function and mitigate PTOA severity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0172026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13387088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148335007","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 clear view at altitude: layer-specific control of the choroidal circulation.","authors":"Jui-Lin Fan, Philip R K Turnbull","doi":"10.1152/function.046.2026","DOIUrl":"10.1152/function.046.2026","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":"e0462026"},"PeriodicalIF":3.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13387085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341462","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":"Publisher's note.","authors":"","doi":"10.1152/function.023.2026_NOT","DOIUrl":"10.1152/function.023.2026_NOT","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"7 3","pages":"e0232026"},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13232025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148058583","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}