American journal of physiology. Cell physiology最新文献

{"title":"Human deep subcutaneous adipose tissue is enriched for inflammatory and tissue remodeling pathways.","authors":"Kahoko Yamada, Yoshitaka Kubota, Kentaro Kosaka, Yoshihisa Yamaji, Shinsuke Akita, Hideki Tokumoto, Masayuki Kuroda, Nobuyuki Mitsukawa","doi":"10.1152/ajpcell.00463.2025","DOIUrl":"10.1152/ajpcell.00463.2025","url":null,"abstract":"<p><p>Subcutaneous superficial adipose tissue (SAT) and deep adipose tissue (DAT) are anatomically separated by the superficial fascia and differ in both function and histological organization. This study presents a comprehensive transcriptomic comparison between SAT and DAT using bulk and single-cell RNA sequencing. Bulk RNA sequencing revealed that DAT is enriched in genes related to inflammation, tissue remodeling, and oxidative stress. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed significant enrichment of inflammatory response, cytokine signaling, and TNF signaling pathways in DAT, indicating a proinflammatory and remodeling-prone environment. Single-ce7ll RNA sequencing identified distinct differences in immune and stromal cell composition. SAT exhibited higher proportions of anti-inflammatory M2 macrophages and CD8/NK cells, whereas DAT showed an increase in oxidative stress-associated Mox macrophages and specific subtypes of fibroblasts and preadipocytes. <i>MT1X</i> and <i>HMOX1</i> expression in FAPs of DAT supports a stress-responsive phenotype, whereas <i>CCN1</i> expression in FAPs of SAT may reflect a role in structural maintenance. In addition, <i>APOE</i> was upregulated in macrophages of DAT, consistent with its known roles in immune modulation and lipid metabolism. These findings highlight cellular and molecular differences between SAT and DAT, suggesting a more active involvement of DAT in inflammation and tissue remodeling.<b>NEW & NOTEWORTHY</b> This study reveals that human deep subcutaneous adipose tissue (DAT) exhibits a distinct proinflammatory and remodeling-prone gene expression profile compared with superficial adipose tissue (SAT). Using both bulk and single-cell RNA sequencing, the researchers identified an increased presence of oxidative stress-associated macrophages and stress-responsive fibroblasts in DAT, suggesting its stronger involvement in systemic inflammation and metabolic dysfunction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1161-C1172"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncoupling protein 3 regulates energy and stress-related pathways in undifferentiated skeletal muscle myoblasts.","authors":"Austin Kindall, Yen Huynh, Jeesun Kim, Stefano Tiziani, John DiGiovanni","doi":"10.1152/ajpcell.00366.2025","DOIUrl":"10.1152/ajpcell.00366.2025","url":null,"abstract":"<p><p>Uncoupling protein 3 (UCP3), a member of the mitochondrial solute carrier family, shares high homology with both UCP1 and UCP2. Its exact functional role has been elusive since its discovery, with previous studies primarily focusing on studying UCP3 function in differentiated skeletal muscle myotubes or whole animal models because basal levels of UCP3 protein are low in undifferentiated myoblasts. In the present study, we demonstrate that UCP3 plays a role in modulating energy and redox stress-related pathways in undifferentiated muscle myoblasts. Although low, UCP3 mRNA and protein levels were detectable in wild-type (WT) myoblasts. Both whole body UCP3 knockout (wKO) and conditional UCP3 knockout (cKO) myoblasts displayed increased activation of AMP-activated protein kinase (phosphorylation of AMPK) and elevated levels of peroxisome proliferator-activated receptor delta/beta (PPARδ/β) and glucose transporter 4 (GLUT4) proteins compared with WT myoblasts. This altered energy signaling was further associated with UCP3 KO myoblasts exhibiting impaired insulin-stimulated glucose uptake, whereas WT cells and UCP3 KO cells expressing WT UCP3 were sensitive to insulin stimulation. Moreover, UCP3 KO myoblasts had an accumulation of fatty acids and upregulation of downstream PPARδ target genes in UCP3 KO cells. Finally, UCP3 KO myoblasts were found to be more sensitive to oxidative stress and hypoxia, due in part to a decrease in the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio compared with WT myoblasts. Collectively, these findings demonstrate that UCP3 is a key modulator of energy sensing and oxidative stress in undifferentiated skeletal muscle myoblasts.<b>NEW & NOTEWORTHY</b> This article provides new information demonstrating that UCP3 plays a role in modulating energy and redox stress-related signaling pathways in proliferative muscle myoblasts. The studies used both UCP3 whole body knockout (KO) myoblasts as well as a novel UCP3 conditional KO mouse generated as part of the current study. Collectively, these findings show that, despite low levels, UCP3 is a key modulator of energy metabolism and oxidative stress in undifferentiated muscle myoblasts.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1108-C1120"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term daily deflazacort decreases membrane permeability and increases maximum force in <i>mdx</i> mice.","authors":"Kristen D Turner, Ying Qian, Dennis R Claflin, Breanne L Newell-Stamper, Angela K Peter, Daniel E Michele, Alan J Russell, Susan V Brooks","doi":"10.1152/ajpcell.00187.2025","DOIUrl":"10.1152/ajpcell.00187.2025","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by the absence of dystrophin, which leads to mechanical instability of the muscle fiber membrane and a predisposition for cell membrane permeability and contraction-induced muscle injury. Deflazacort is an FDA-approved corticosteroid for treating DMD, and treatment of dystrophic mice with deflazacort reduces inflammation and improves muscle regeneration. Whether deflazacort protects from contraction-induced injury in <i>mdx</i> mice is unknown. To address this question, adult <i>mdx</i> mice were administered 1.2 mg/kg deflazacort daily by oral gavage for either 3 or 8-9 wk and compared with both vehicle-treated <i>mdx</i> mice and wild-type controls for various measures of susceptibility to injury. Both 3 and 8-9 wk of deflazacort treatment decreased Evans Blue dye (EBD) accumulation in vivo compared with vehicle-treated controls, but the reduction was substantially greater (58% vs. 26%) following shorter-term treatment. Furthermore, for dorsiflexor muscles evaluated in situ, 3 wk deflazacort treatment dramatically increased isometric force production, and the force decline induced by a single lengthening contraction was reduced more than 50% compared with vehicle-treated controls. Using ex vivo lumbrical muscle preparations, we found that levels of intercontraction calcium accumulation significantly correlated with force decline during repeated isometric contractions in all deflazacort-treated mice, and a trend for lower aberrant calcium accumulation was seen following 3 wk of treatment. Given that some protective effects were reduced or not present in a preclinical model of DMD with longer-term steroid treatment, these data provide important evidence for the beneficial use of short-term deflazacort.<b>NEW & NOTEWORTHY</b> Mechanical instability of muscle fiber membranes is a hallmark feature of Duchenne muscular dystrophy (DMD). Glucocorticoids are commonly prescribed in DMD; however, effects on contraction-induced injury and associated mechanisms remain unclear. Here, 3 wk deflazacort in <i>mdx</i> mice substantially reduced Evans Blue dye uptake and the lengthening contraction-induced force decline in vivo and resulted in a strong trend toward blunted calcium uptake during damaging contractions ex vivo. These findings indicate that short-term deflazacort protects from contraction-induced injury.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1214-C1225"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of tenomodulin in the tendon repair process.","authors":"Yao Jiang, Girish Pattappa, Dasheng Lin, Giovanna Della Porta, Maximilian Rudert, Chisa Shukunami, Denitsa Docheva","doi":"10.1152/ajpcell.00461.2025","DOIUrl":"10.1152/ajpcell.00461.2025","url":null,"abstract":"<p><p>Tendons and ligaments are essential connective tissues that attach muscle to bone and bone to bone, thus enabling the storage and transfer of kinetic energy under high-intensity and repetitive conditions. The incidence of tendon and ligament injuries caused by sports has shown an increasing trend over the years, as the population's participation in daily sporting activities continues to rise. Moreover, during the late gestational and postnatal stages, the tendon repair mechanism shifts from complete regeneration to a repair process that is characterized by some scar tissue formation. Current understanding of tendon recovery has shifted from initially focusing on local cell proliferation and extracellular matrix (ECM) synthesis at the injury sites to emphasizing dynamic matrix remodeling, cell heterogeneity, and the integrated regulation of multiple signaling pathways. Tenomodulin (<i>TNMD</i>) is a key regulator of tendon maturation, differentiation, and remodeling, and is recognized as a crucial marker for the tendon lineage. The review aims to systematically consolidate the role of <i>TNMD</i> in tendon repair process. A comprehensive analysis of the <i>TNMD</i> gene and protein structure and its function in different stages of the tendon repair process is presented. In addition, the review addresses the potential therapeutic applications of <i>TNMD</i>, providing both a theoretical framework and an experimental foundation for the development of translational strategies in tendon and ligament clinical practice.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1075-C1084"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thrombopoietin mitigates neuronal death by enhancing mitophagy and suppressing NLRP3 inflammasome activation under oxygen-glucose deprivation conditions.","authors":"Liang Li, Yu Zhang, Junyan Zhong, Huimin Kong, Yong Liu, Hui Chen, Xiaoyi Fang, Zhiyuan Zhong, Hongman Xue, Mo Yang, Chun Chen","doi":"10.1152/ajpcell.00847.2024","DOIUrl":"10.1152/ajpcell.00847.2024","url":null,"abstract":"<p><p>Thrombopoietin (TPO), a principal hematopoietic cytokine, regulates the development and proliferation of megakaryocytes and platelets. Our previous research demonstrated TPO's neuroprotective role against hypoxic-ischemic brain injury in rats. Yet, the underlying mechanisms remain unclear. This study reveals that A20 [tumor necrosis factor alpha (TNF-α)-induced protein 3 (Tnfaip3)] significantly contributes to TPO's neuroprotective effect by enhancing mitophagy in neurons. TPO reduces cell death under oxygen-glucose deprivation (OGD) conditions. Mechanistically, TPO induces the TNF-α and NF-κB signaling pathways to increase A20 expression, thereby promoting mitophagy, diminishing reactive oxygen species (ROS) production, and stabilizing mitochondrial membrane potential (MMP). A20 maintains mitochondrial dynamics and mitigates OGD-induced excessive mitochondrial fission. Furthermore, A20 suppresses NLRP3 inflammasome activation by enhancing mitophagy. This study elucidates a novel mechanism of TPO's neuroprotection, distinct from its hematological effects, supporting its potential therapeutic application in treating neurological injuries.<b>NEW & NOTEWORTHY</b> TPO, known for its role in megakaryocytes development and platelets production, also protects neurons from damage caused by oxygen and glucose deprivation. Thrombopoietin (TPO) boosts the A20 protein, which enhances the cell's mitophagy for damaged mitochondria. This reduces harmful reactive oxygen species (ROS) and inflammation, ultimately promoting neuron survival. This discovery opens new avenues for using TPO to treat neurological injuries.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1173-C1187"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smooth signals: computational insights into autonomic vascular control.","authors":"Gonzalo Hernandez-Hernandez, Colleen E Clancy","doi":"10.1152/ajpcell.00591.2025","DOIUrl":"10.1152/ajpcell.00591.2025","url":null,"abstract":"<p><p>The regulation of vascular tone underlies normal cardiovascular homeostasis, ensuring appropriate distribution of blood flow to tissues and maintenance of blood pressure. Computational modeling and simulation constitute a powerful framework for deciphering plausible mechanisms of autonomic signaling in vascular smooth muscle across spatial and temporal scales and allow for the prediction of emergent nonlinear effects of perturbations. Integrative computational modeling approaches are now beginning to inform the precision use of calcium channel blockers, angiotensin II type 1 receptor antagonists, and lipid-modulating therapies in cardiovascular disease. By simulating system-level behavior under physiological and pathological conditions, computational models have the potential to enhance drug discovery, guide individualized treatment strategies, and generate testable hypotheses for experimental validation. This review highlights key molecular mechanisms, emerging modeling tools, and future directions for computational approaches to autonomic signaling in vascular smooth muscle.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1101-C1107"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of IL-1β on pancreatic acinar cells mitochondrial TPP carrier-mediated uptake: inhibition mediated via the intracellular NF-κB signaling pathway.","authors":"Selvaraj Anthonymuthu, Subrata Sabui, Kalidas Ramamoorthy, Yusuf Ali Ahmed, Appakalai N Balamurugan, Hamid M Said","doi":"10.1152/ajpcell.00375.2025","DOIUrl":"10.1152/ajpcell.00375.2025","url":null,"abstract":"<p><p>We investigated the effects of proinflammatory cytokines on carrier-mediated thiamin pyrophosphate (TPP) uptake by pancreatic acinar cells (PACs) mitochondria using mouse-derived pancreatic acinar 266-6 cells (PAC 266-6) and human primary PACs as models. First, we assessed the level of expression of the mitochondrial TPP transporter (MTPPT) mRNA in the pancreatic tissue of patients with chronic pancreatitis and found the level to be significantly lower than that in normal control subjects. We then examined the effects of exposing PACs to IL-1β, IL-6, and TNF-α on mitochondrial TPP uptake and observed significant inhibition by all these proinflammatory cytokines. Focusing on IL-1β (since it showed a more severe effect), we found this proinflammatory cytokine to also cause a significant inhibition in MTPPT protein and mRNA expression, as well as in the activity of the <i>SLC25A19</i> promoter. Effect on the latter, appeared to be mediated via a decrease in the binding affinity of NF-Y (a nuclear factor that drives <i>Slc25a19</i> promoter activity) as well as via epigenetic mechanism/histone-modification were significant reduction in levels of enrichment of the activator markers H3K4-trimethylation and H3K9-acetylation, and an increase in level of enrichment of the repressor marker H3K27-trimethylation were observed. Finally, evidence was obtained suggesting a role for the intracellular NF-κB signaling pathway in mediating the effects of IL-1β on PAC mitochondrial TPP uptake process. These results show that exposure of PACs to IL-1β causes inhibition in mitochondrial TPP uptake, and that this effect is exerted at the level of <i>SLC25A19</i> transcription and is mediated via the NF-κB signaling pathway.<b>NEW & NOTEWORTHY</b> This study demonstrates that exposure of pancreatic acinar cells to IL-1β leads to inhibition in carrier-mediated thiamin pyrophosphate uptake by their mitochondria. This effect appears to be exerted at the level of <i>SLC25A19</i> transcription and is mediated via the NF-κB signaling pathway.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1203-C1213"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"(R)-vanzacaftor potentiates BK_Ca channels in the absence of CFTR correction or potentiation.","authors":"Aaron Kolski-Andreaco, Scott A Hahn, John Sembrat, Adam C Straub, Michael B Butterworth, Daniel C Devor","doi":"10.1152/ajpcell.00654.2025","DOIUrl":"10.1152/ajpcell.00654.2025","url":null,"abstract":"<p><p>We previously demonstrated the CFTR correctors VX-445 (elexacaftor) and S-VX-121 (vanzacaftor) potentiate heterologously expressed BK_Ca channels, as well as in primary human bronchial epithelial cells (HBEs). This potentiation of BK_Ca resulted in altered vasoreactivity and neuronal excitability. We postulated novel compounds could be identified that would potentiate BK_Ca while not affecting CFTR. Herein, we demonstrate that the enantiomer of vanzacaftor, R-VX-121, possesses these attributes. Using Fisher rat thyroid (FRT) cells expressing F508del CFTR, we demonstrate S-VX-121 corrects F508del CFTR when incubated overnight, as assessed by an increase in transepithelial Cl^- current (I_Cl) in response to forskolin, as well as the appearance of band C upon immunoblot (IB). In contrast, R-VX-121 failed to increase I_Cl and induce band C. Importantly, R-VX-121 competed with S-VX-121 to eliminate the correction of F508del CFTR observed during both I_Cl measurements and IB, indicating it associates with CFTR. Neither S- nor R-VX-121 potentiated CFTR, as assessed by changes in I_Cl. Distinct from our CFTR results, both S- and R-VX-121 potentiated BK_Ca in primary HBEs as well as during whole cell patch-clamp recording of heterologously expressed α-BK_Ca. Using wire myography, we demonstrate both S- and R-VX-12 vasodilate preconstricted mouse mesenteric arteries in a paxilline-dependent manner, confirming a role for BK_Ca. In contrast, the CFTR inhibitor, CFTR_inh172 did not alter the effects of S- and R-VX-121 on vasoreactivity, confirming CFTR is not involved in this response. These data demonstrate R-VX-121 represents a novel BK_Ca potentiator that does not modulate CFTR function, suggesting R-VX-121 may be clinically useful as a BK_Ca agonist.<b>NEW & NOTEWORTHY</b> We previously demonstrated that the CFTR correctors, VX-445 and S-VX-121, are BK_Ca channel potentiators. These CFTR correctors altered vasoreactivity and action potential firing frequency effects, which may explain the adverse events (AEs) reported in cystic fibrosis (CF). We now demonstrate that the enantiomer of vanzacaftor, R-VX-121, potentiates BK_Ca, while not correcting or potentiating CFTR. Thus, we have identified a novel BK_Ca potentiator that may be useful in diseases where BK_Ca modulation is therapeutically proposed.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1130-C1138"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The blueprint of neurocardiac crosstalk in arrhythmic syndromes.","authors":"Tania Zaglia, Induja Perumal Vanaja, Anna Guazzo, Marco Mongillo","doi":"10.1152/ajpcell.00558.2025","DOIUrl":"10.1152/ajpcell.00558.2025","url":null,"abstract":"<p><p>Inherited arrhythmogenic syndromes encompass a spectrum of genetic cardiac disorders unified by heightened vulnerability to sympathetic stimulation and risk of sudden cardiac death. Traditionally categorized as either functional (e.g., catecholaminergic polymorphic ventricular tachycardia, CPVT) or structural (e.g., arrhythmogenic cardiomyopathy, ACM), these syndromes are increasingly recognized to share a common reliance on neurocardiac signaling. In this review, we examine CPVT and ACM as representative extremes of the functional-structural continuum, highlighting how sympathetic activation acts not only as an acute arrhythmic trigger but also as a chronic driver of disease progression. We dissect the roles of β-adrenergic signaling, neuropeptide Y (NPY), and regional innervation patterns in shaping myocardial excitability, remodeling, and arrhythmogenesis. While CPVT exemplifies a trigger-dependent, Ca²⁺-driven arrhythmia in structurally normal hearts, ACM demonstrates a substrate-amplified phenotype involving maladaptive autonomic remodeling and neurogenic fibrofatty infiltration. We discuss the emerging relevance of neuromodulatory and peptidergic therapies-including β-blockade, left cardiac sympathetic denervation, and NPY antagonism-and propose an integrated framework for arrhythmia classification and management based on autonomic mechanisms. By reframing inherited arrhythmias as disorders of integrated neural and myocardial physiology, we highlight new opportunities for mechanistic insight, biomarker development, patient stratification, and translational therapy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1038-C1045"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of carnitine palmitoyl transferase 2 in the progression of salt-sensitive hypertension.","authors":"Lashodya V Dissanayake, Brody A Smith, Adrian Zietara, Vladislav Levchenko, Melissa Lowe, Olha Kravtsova, Abigail Shapiro, Gunjan Upadhyay, Ganesh V Halade, Aron M Geurts, Oleg Palygin, Alexander Staruschenko","doi":"10.1152/ajpcell.00485.2025","DOIUrl":"10.1152/ajpcell.00485.2025","url":null,"abstract":"<p><p>Carnitine palmitoyl transferase 2 (CPT2) is a key enzyme in mitochondrial fatty acid oxidation (FAO), a process critical for renal energy homeostasis. Disruption of FAO and accumulation of plasma acylcarnitines (fatty acids conjugated to carnitine) have been implicated in renal and vascular diseases. Although the kidney relies heavily on FAO, the specific renal consequences of CPT2 deficiency remain poorly understood. Clinical data suggest that CPT2 expression may be associated with increased lifespan in patients on antihypertensive therapy, yet a direct link between CPT2 and hypertension has not been established. Our previous work in salt-sensitive (SS) hypertension showed that a high-salt (HS) diet increases FAO while reducing renal acylcarnitine levels. To investigate how CPT2 deficiency affects renal function and metabolic regulation under dietary stress, we generated a novel CPT2-deficient rat model on the Dahl SS background. Homozygous knockouts were embryonically lethal; thus, heterozygous (<i>SS</i>^Cpt2+/-) rats were used for further studies. At baseline, <i>SS</i>^Cpt2+/- rats exhibited lower urinary excretion of tricarboxylic acid cycle metabolites compared with wild-type littermates, suggesting altered mitochondrial metabolism. Under an HS diet, <i>SS</i>^Cpt2+/- rats had no significant differences in blood pressure. However, when faced with a high-salt ketogenic diet, these rats exhibited somewhat contradictory effects, showing lower blood pressure alongside lipid dysregulation and accumulation of long-chain acylcarnitines. Collectively, our findings reveal a complex role for CPT2 in the metabolic and pathophysiological responses to SS hypertension, with implications for renal and cardiovascular outcomes under dietary stress.<b>NEW & NOTEWORTHY</b> Although high-salt diets have been shown to negatively impact cardiovascular health, the ketogenic diet has demonstrated beneficial effects. In the current study, we created a model of CPT2 deficiency on a salt-sensitive background and showed that the combination of both diets has an unexpected effect on a model of fatty acid dysregulation, seemingly reducing the development of hypertension. Our data suggest a complex role for CPT2, extending beyond fatty acid oxidation, in regulating blood pressure.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1188-C1202"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}