Acta Physiologica (Oxford, England)[JOURNAL]
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200 papers
Binding the Problem: Galectin-3's Emerging Role in Advanced Glycation End Product Dynamics.
Kulow VA
Acta Physiol (Oxf) · 2025 Dec · PMID 41243879 · Publisher ↗
Abstract loading — click title to view on PubMed.
A 12-Week Strength Training Improves Mitochondrial Respiration, HO Emission and Skeletal Muscle Integrity in Women With Myotonic Dystrophy Type 1.
Marcangeli V, Girard-Côté L, Di Leo V … +11 more , Roussel MP, Lawless C, Charest O, Argaw A, Dulac M, Hajj-Boutros G, Morais JA, Vincent A, Gouspillou G, Leduc-Gaudet JP, Duchesne E
Acta Physiol (Oxf) · 2025 Dec · PMID 41241935 · Full text
BACKGROUND: Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK gene, causing the accumulation of toxic RNA that sequesters RNA-binding proteins. Clinically, DM1 is characterized by progressive...
BACKGROUND: Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK gene, causing the accumulation of toxic RNA that sequesters RNA-binding proteins. Clinically, DM1 is characterized by progressive muscle weakness and atrophy, resulting in reduced physical capacity and quality of life. Recent evidence implicates mitochondrial dysfunction in DM1 pathophysiology. While aerobic exercise has been shown to improve skeletal muscle and mitochondrial health in individuals with DM1, the benefits of strength training remain unexplored. OBJECTIVES: We investigated the effects of a 12-week strength training program on mitochondrial respiration, reactive oxygen species (ROS) production and muscle integrity in women with DM1. METHODS: Vastus lateralis muscle biopsies were collected pre- and post-training in participants with DM1 and once in unaffected/untrained individuals. Mitochondrial respiration and hydrogen peroxide emission (marker of ROS production) were assessed in permeabilized myofibers, while OXPHOS protein contents were quantified by immunoblotting and immunofluorescence. Markers of myofiber denervation (NCAM+) and integrity (centrally located myonuclei, damaged laminin, nuclear clumps) were assessed on histological sections. RESULTS: At baseline, DM1 participants exhibited lower mitochondrial respiration compared to unaffected individuals. Strength training significantly improved mitochondrial respiration and content in DM1 participants. At baseline, absolute ROS production was lower, while ROS production normalized to oxygen consumption (free radical leak) was higher, in DM1. Histological signs of denervation and altered muscle integrity were observed. Strength training partially normalized mitochondrial free radical leak and restored some markers of myofiber integrity. CONCLUSION: Collectively, our results indicate that strength training enhances mitochondrial health and improves myofiber integrity in women with DM1.
Factors Influencing Blood Lactate Concentration During Exercise: A Narrative Review With a Lactate Shuttle Perspective.
Benítez-Muñoz JA, Cupeiro R
Acta Physiol (Oxf) · 2025 Dec · PMID 41241931 · Full text
AIM: Blood lactate concentration ([La]), usually measured in mmol/L, is one of the most frequently measured parameters during clinical exercise tests as well as during performance assessments of athletes. Therefore, the...
AIM: Blood lactate concentration ([La]), usually measured in mmol/L, is one of the most frequently measured parameters during clinical exercise tests as well as during performance assessments of athletes. Therefore, the purpose of this review is to examine the methodological and biological factors that influence [La] in order to improve the accuracy and interpretation of its measurement during clinical, research, and athletic testing. METHODS: A narrative review of the scientific literature was conducted, focusing on studies addressing the biological as well as methodological variables that may affect the measurement of [La]. RESULTS: According to the lactate shuttle theory, blood [La] depends on production, transport, and consumption. Both methodological and biological factors can substantially alter these processes and, subsequently, [La], potentially leading to misinterpretation when comparing data across sessions or individuals. CONCLUSION: Since lactate is commonly measured in research, medical, and training testing, it is important to understand these factors to avoid misinterpretation. The main recommendation is to control all these factors when measuring [La] and to carry out the measurements under the same conditions when monitoring the evolution of a specific person or comparing different individuals.
Effects of Heat Exposure on Kynurenine Pathway Metabolism-Comparison Between Exertional and Exogenous Heating of the Human Body.
Louvrou V, Eimantas N, Juškevičiūtė E … +4 more , Solianik R, Brazaitis M, Engberg G, Erhardt S
Acta Physiol (Oxf) · 2025 Dec · PMID 41217979 · Full text
BACKGROUND: The kynurenine pathway (KP) plays a pivotal role in many diseases that involve distinct pathological mechanisms. OBJECTIVES: Since KP metabolites are potential disease biomarkers, it is crucial to investigate...
BACKGROUND: The kynurenine pathway (KP) plays a pivotal role in many diseases that involve distinct pathological mechanisms. OBJECTIVES: Since KP metabolites are potential disease biomarkers, it is crucial to investigate their fluctuations under physiological conditions. As the KP is stress-responsive, this study examines how peripheral KP metabolites change with core temperature increases induced by two different modalities. METHODS: In this randomized cross-over study, 11 young healthy males were subjected to (a) exogenous heating via hot water immersion (44°C, EXO), and (b) exertional heating via exercise (EXE), until rectal temperature (T) reached 39°C, followed by a recovery phase. Blood samples were collected at baseline and at every 0.5°C T increment during both the heating and recovery phases. Plasma levels of KP metabolites, stress, and metabolic markers were measured. Correlation analyses between kynurenine pathway metabolites and stress markers were computed over the course of the trials. RESULTS: EXE and EXO trials induced the KP, but to different extents. Most plasma KP metabolite concentrations (kynurenic acid, picolinic acid, 3-hydrokynurenine, quinolinic acid) increased. Stress markers were elevated in both trials. Changes in KP metabolites, stress, and metabolic markers were not persistent, and returned to baseline following recovery. CONCLUSION: An elevation in body temperature by heat exposure or exercise increases peripheral concentration of several KP metabolites that return to baseline upon trial cessation, suggesting that KP enzymes are adaptable to physiological stressors.
Maternal Diet-Induced Excess Adiposity in Mice Disrupts Mid-Gestation Decidual Immune and Vascular Homeostasis Without Impairing Spiral Artery Remodeling.
Bellissimo CJ, Yeo E, Ribeiro TA … +9 more , Jazwiec PA, Ellewela C, Bains J, Lewis AE, Kennedy KM, Ashkar AA, Beristain AG, Bowdish DME, Sloboda DM
Acta Physiol (Oxf) · 2025 Dec · PMID 41217975 · Full text
AIM: Maternal excess adiposity (i.e., overweight/obesity) is linked to impaired uteroplacental perfusion, compromised placental development, and increased risk of adverse pregnancy outcomes. Inflammation and immune dysre...
AIM: Maternal excess adiposity (i.e., overweight/obesity) is linked to impaired uteroplacental perfusion, compromised placental development, and increased risk of adverse pregnancy outcomes. Inflammation and immune dysregulation accompanying excess adiposity may disrupt leukocyte-mediated tissue remodeling and immunoregulation, contributing to placental dysfunction. However, the impacts of excess adiposity on populations of innate lymphoid cells and macrophages orchestrating these processes, and on the decidual microenvironment, remain understudied. Here, we used a mouse model of high-fat, high-sucrose (HFHS) diet-feeding to study the impacts of excess adiposity on decidual immune dynamics during placental development. METHODS: Uteroplacental tissues were collected at mid-gestation (E10.5) from mice fed a control chow (CON) or HFHS diet before and during pregnancy. Multicolour flow cytometry was used to profile decidual leukocyte composition. Spiral artery remodeling was measured using (immuno)histochemistry. Multiplex immunoassays were used to compare systemic and decidual cytokine and growth factor levels. Comparative gene expression was measured in placental tissues using a NanoString nCounter array. RESULTS: HFHS pregnancies had elevated decidual leukocyte abundance, with increased tissue-resident and conventional-like NK cells, and MHC-II macrophages. This was not associated with abnormal spiral artery remodeling but coincided with increased decidual proinflammatory cytokine and chemokine expression, and greater elevations in mediators of angiogenesis, endothelial activation, and coagulation. Despite this, placental gene expression was largely unaltered at mid-gestation. CONCLUSION: These findings point towards decidual vascular inflammation and dysregulated angiogenesis during early placentation in pregnancies complicated by excess adiposity. This may stem from or induce shifts in resident immune cells, contributing to later placental dysfunction.
Role of the Choroid Plexus Kir7.1 Channel in the Regulation of Mouse Cerebrospinal Fluid K Concentration.
Henao JC, Burgos J, Vera E … +4 more , Ruminot I, Cid LP, Cornejo I, Sepúlveda FV
Acta Physiol (Oxf) · 2025 Dec · PMID 41212743 · Publisher ↗
AIM: K channel Kir7.1 is prominently expressed at the apical membrane of the choroid plexus epithelium (CPE) together with the Na-K-ATPase pump and cotransporter NKCC1. Its unusual independence of extracellular K ([K]) s...
AIM: K channel Kir7.1 is prominently expressed at the apical membrane of the choroid plexus epithelium (CPE) together with the Na-K-ATPase pump and cotransporter NKCC1. Its unusual independence of extracellular K ([K]) suggests a key role in regulating cerebrospinal fluid (CSF) K concentration ([K]). We tested this hypothesis by exploring the effect of Kir7.1 inactivation or modification of its K-dependence in mice. METHODS: We generate conditional Kir7.1 knockout (cKO) and knockin mice carrying the M125R mutation altering Kir7.1 K-dependence. We study the electrical properties of CPE cells in vitro as well as in vivo CSF secretion and [K]. CPE NKCC1 activity, expression and phosphorylation status were also evaluated. RESULTS: Kir7.1 identified as the primary [K]-independent conductance in CPE cells, critically contributes to their membrane potential. CPE cells from Kir7.1-M125R mice exhibited a K conductance with direct dependence on [K]. While CSF secretion rates were unaltered in both cKO Kir7.1 and M125R animals, [K] was significantly decreased in cKO mice and increased in M125R mutants. Unexpectedly, NKCC1 activity was strongly inhibited in Kir7.1 cKO CPE despite unaltered expression and phosphorylation levels, but remained unaffected in M125R cells. CONCLUSIONS: Kir7.1 imparts high K permeability and defines the membrane potential of CPE cells. Its unusual [K]-independent conductance underpins its important role in the regulation of [K]. Moreover, Kir7.1 appears crucial for NKCC1 function, likely these two proteins forming part of an apical complex with the Na-K-ATPase. Given the continuity of CSF with brain interstitial space, Kir7.1-mediated control of [K] might influence neuronal excitability.
Unique Role of Proximal Tubule Dipeptidyl Peptidase 4 on Blood Pressure, Renal Sodium Handling, and Na/H Exchanger Isoform 3 Phosphorylation.
Martins FL, Ribeiro-Silva JC, de Jesus EF … +2 more , Nistala R, Girardi ACC
Acta Physiol (Oxf) · 2025 Dec · PMID 41187974 · Full text
BACKGROUND: Dipeptidyl peptidase 4 (DPP4) is a transmembrane serine exopeptidase highly expressed in the proximal tubule (PT). While its enzymatic role is well characterized, its non-enzymatic functions remain unclear. D...
BACKGROUND: Dipeptidyl peptidase 4 (DPP4) is a transmembrane serine exopeptidase highly expressed in the proximal tubule (PT). While its enzymatic role is well characterized, its non-enzymatic functions remain unclear. DPP4 physically associates with the Na/H exchanger isoform 3 (NHE3), and DPP4 inhibitors promote natriuresis; however, the mechanisms by which DPP4 regulates NHE3 and its role in blood pressure (BP) regulation remain controversial. We hypothesized that PT DPP4 promotes sodium reabsorption and attenuates pressure-natriuresis by preventing NHE3 phosphorylation at serine 552 (pS552). METHODS: We generated PT-specific Dpp4 knockout mice (Dpp4) and examined the effects of PT-specific and global Dpp4 deletion (Dpp4) on systolic blood pressure (SBP), natriuresis, and NHE3 phosphorylation at baseline and following acute angiotensin II (Ang II) infusion in male and female mice. RESULTS: Both Dpp4 and Dpp4 showed enhanced diuretic and natriuretic responses to saline loading, with higher renal pS552-NHE3, and unchanged baseline SBP. Ang II elevated DPP4 activity in controls but not in Dpp4 mice, suggesting that PT DPP4, rather than DPP4 in other nephron segments, is regulated by Ang II under these experimental conditions. Ang II increased SBP in all groups, but the pressor response was significantly attenuated in both Dpp4 and Dpp4 mice, paralleling sustained pS552-NHE3 elevation. CONCLUSION: These findings demonstrate that DPP4 modulates NHE3 activity by preventing pS552-NHE3 accumulation, promoting an anti-natriuretic effect. In the absence of PT DPP4, these mechanisms are disrupted, reducing Ang II sensitivity, maintaining high pS552-NHE3 levels, and likely enhancing pressure-natriuresis, underscoring the role of PT DPP4 in modulating signaling mechanisms governing renal function.
Mechanisms That Prevent Vascular Leakage During Leukocyte Extravasation.
de Haan SJ, van Buul JD
Acta Physiol (Oxf) · 2025 Dec · PMID 41176691 · Full text
BACKGROUND: Inflammation is the response of the immune system against harmful stimuli in tissues. Leukocyte extravasation or TransEndothelial Migration (TEM) is a crucial step during inflammation, in which leukocytes mig...
BACKGROUND: Inflammation is the response of the immune system against harmful stimuli in tissues. Leukocyte extravasation or TransEndothelial Migration (TEM) is a crucial step during inflammation, in which leukocytes migrate over the endothelial barrier toward the damaged tissue. OBJECTIVE: Historically, it was believed that leukocyte TEM directly causes excessive vascular leakage, resulting in tissue edema. However, it is now clear that leukocyte TEM and vascular leakage are uncoupled events with different spatiotemporal regulation. Moreover, several mechanisms have been identified that prevent vascular leakage during leukocyte TEM. CONCLUSION: Here we summarize the different mechanisms that are responsible for limiting the leakage during the transmigration event and explore their clinical relevance in developing targeted therapeutics for controlling vascular leakage in inflammatory diseases.
Mitochondrial Dysfunction Contributes to Decompensation in a Zebrafish Model of Isoproterenol-Induced Heart Failure.
Vicente M, García-Blázquez A, Martínez-Sielva A … +4 more , Salgado-Almario J, Jordán J, Domingo B, Llopis J
Acta Physiol (Oxf) · 2025 Dec · PMID 41170837 · Full text
AIM: Heart failure is a clinical syndrome where the heart's structural or functional impairment leads to inadequate blood flow to meet the body's metabolic demands. Mitochondrial dysfunction is increasingly recognized as...
AIM: Heart failure is a clinical syndrome where the heart's structural or functional impairment leads to inadequate blood flow to meet the body's metabolic demands. Mitochondrial dysfunction is increasingly recognized as a central contributor underlying the contractile impairment observed in the failing heart. This study aimed to explore the interplay between calcium dynamics, cardiac mechanical performance, and mitochondrial ATP production during the progression of heart failure in zebrafish larvae exposed to chronic isoproterenol stimulation. METHODS: Heart failure was induced by treating zebrafish larvae with 100 μM isoproterenol from 3 to 14 days postfertilization (dpf). Cardiac calcium transients, contractility, and mitochondrial ATP levels were assessed in vivo using transgenic lines expressing specific fluorescent biosensors. Additionally, transcriptomic analysis by RNA sequencing was performed on hearts collected at 14 dpf following prolonged isoproterenol exposure. RESULTS: After 4 days of isoproterenol treatment (7 dpf), larvae exhibited ventricular dilation, reduced calcium levels, and diminished contractile force (p < 0.0001), although cardiac output remained intact. In contrast, extended treatment (11 days; 14 dpf) led to decompensated heart failure, characterized by a significant decline in cardiac output (p < 0.0001). Mitochondrial ATP levels were preserved at 7 dpf but dropped markedly at 14 dpf (p < 0.0001). Transcriptomic profiling at this later stage revealed downregulation of key functions (p < 0.05) involved in mitochondrial energy metabolism and energy transfer. CONCLUSION: In this model, heart dysfunction was initially evidenced by cardiac dilation. At 4 days of isoproterenol treatment, calcium levels and contractility decreased. Subsequently, decompensation coincided with a collapse in mitochondrial ATP production.
Caloric Restriction Substantially Improves Glucose Regulation in Mice With Hnf1a-Deficient Beta-Cells.
Sharmine S, Legøy TA, Unger L … +3 more , Paulo JA, Ghila L, Chera S
Acta Physiol (Oxf) · 2025 Dec · PMID 41165340 · Publisher ↗
AIM: HNF1A-MODY, the most prevalent form of monogenic diabetes, displays incomplete penetrance, indicating the involvement of other environmental and genetic factors in the disease etiology. Currently, it is largely unkn...
AIM: HNF1A-MODY, the most prevalent form of monogenic diabetes, displays incomplete penetrance, indicating the involvement of other environmental and genetic factors in the disease etiology. Currently, it is largely unknown what the influence of environmental factors, such as toxins or diet, is on HNF1A-MODY onset and progression. Here we address this issue by exploring the impact of diet on islet and insulin-secreting beta-cells in the context of HNF1A mutation. METHODS: Transgenic mice allowing the specific Hnf1a mutation in insulin-secreting beta-cells were exposed to four distinct dietary regimens including combinations of high-fat diet and caloric restriction. In vitro stem cell islets bearing the HNF1A heterozygous mutation and their isogenic controls were used for validation in humans. The readouts included physiological tests, immunofluorescence, proteomics, bulk, and single-cell transcriptomics. RESULTS: Hnf1a-deficient beta-cells exhibited high sensitivity to dietary cues. Exposure to a high-fat diet exacerbated the glucose regulation defects, while caloric restriction significantly improved blood glucose levels in vivo, without perturbing islet architecture. The high-throughput methods identified changes in the Hnf1a-deficient beta-cells proteome landscape, involving conserved critical regulators of metabolic and growth processes, such as the Carbohydrate Response Element Binding Protein (Chrebp/Mlxipl) and ATP citrate lyase (Acly) among others. CONCLUSIONS: This study hallmarks the important impact of diet on Hnf1a-deficient beta-cells, stemming new therapeutic perspectives, such as future diet management approaches.
Estrogen and Estrogen Receptors in Cardioimmunology: Implications in Physiology, Pathophysiology, and Therapeutic Strategies.
Hou H, Adzika GK
Acta Physiol (Oxf) · 2025 Dec · PMID 41163516 · Publisher ↗
Estrogen (E2) and estrogen receptors (ERs) play vital roles in conferring cardioprotection by modulating several immunological homeostatic responses in cardiovascular tissues. Over the recent decades, the role of inflamm...
Estrogen (E2) and estrogen receptors (ERs) play vital roles in conferring cardioprotection by modulating several immunological homeostatic responses in cardiovascular tissues. Over the recent decades, the role of inflammatory responses as a tangential component impacting cardiac function and disease are being appreciated and investigated to elucidate the underlying pathomechanisms, identify and develop therapeutic strategies; thus, the emergence of the multi-disciplinary field-cardioimmunology. Here, after summarizing expressions and functionalities of ERs in cellular constituents of the cardiovascular system, we discuss synergistic estrogenic signaling mechanisms preserving cardiovascular function and immune homeostasis. Next, we review studies implicating E2 and ERs in inflammation-driven cardiovascular disease initiation and progression and highlight therapeutic strategies and clinical implications to foster further research into promoting cardiovascular health.
Is Predisposition to T2D Impacted by Polymorphisms in Genes Involved in Insulin Signaling and Cellular Bioenergetics?
Pati B, Jastroch M, Bal NC
Acta Physiol (Oxf) · 2025 Dec · PMID 41163347 · Publisher ↗
BACKGROUND: Type 2 diabetes (T2D) represents a growing global health challenge, with its prevalence and associated metabolic complications rising sharply over the past two decades. Although the pathogenesis of T2D is com...
BACKGROUND: Type 2 diabetes (T2D) represents a growing global health challenge, with its prevalence and associated metabolic complications rising sharply over the past two decades. Although the pathogenesis of T2D is complex and influenced by lifestyle and (micro)environmental factors, genetic constituents have been considered major predisposing factors. Recent literature shows significant individual variations in both the progression of T2D and the efficacy of antidiabetic drugs. These individual variations are expected to emanate from the inherent genetic make-up and potential epigenetic modifications by environmental factors. HYPOTHESIS: It has been proposed that altered metabolism (including cellular bioenergetic mechanisms) provides protection from T2D. Moreover, several researchers have proposed that proteins regulating cellular bioenergetics, for example, involved in adaptive thermogenesis, represent good targets to counter T2D. Therefore, we thoroughly searched the literature on genetic variability associated with T2D in this review. RESULTS: We could only find genes involved in (1) insulin secretion (INS, PDX1, ABCC8, KCNJ11, KCNQ1, CDKAL1, IGFBP2) and (2) cellular bioenergetics in insulin-responsive tissues (INSR, IRS, AKT, SLC2A4, TBC1D4, PPP1R3A, LEP, LEPR, ADIPOQ, TCF7L2, PPAR-γ, SLC30A8). Specific attention is given to diverse ethnic populations, in particular Indian subgroups where these genetic factors may display clearer association to T2D. CONCLUSION: By emphasizing genetic predispositions, this review highlights the lack of studies on the genetic association of cellular bioenergetics proteins in T2D pathogenesis. It also underscores the potential for early detection, personalized management, and the development of targeted therapies for individuals with T2D across different genetic profiles.
Immunological Protein Signature During Acute Exercise.
Wenzel C, Walzik D, Wences T … +5 more , Trebing S, Meyer K, Groll A, Zimmer P, Joisten N
Acta Physiol (Oxf) · 2025 Dec · PMID 41163346 · Full text
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Exploring Desmin as a Potential Modifier in Duchenne Muscular Dystrophy-Associated Cardiomyopathy.
Guennec BE, Hovhannisyan Y, Revet G … +10 more , Polat S, Hassani M, Mougenot N, Barthelemy I, Blot S, Cieniewski-Bernard C, Ferry A, Kordeli E, Li Z, Agbulut O
Acta Physiol (Oxf) · 2025 Dec · PMID 41163301 · Full text
AIM: Duchenne muscular dystrophy (DMD), a rare X-linked genetic disorder, is affecting skeletal and cardiac muscles due to the loss of the dystrophin protein. Modifier proteins, whose expression is altered in DMD patient...
AIM: Duchenne muscular dystrophy (DMD), a rare X-linked genetic disorder, is affecting skeletal and cardiac muscles due to the loss of the dystrophin protein. Modifier proteins, whose expression is altered in DMD patients, may influence disease progression. Desmin, a muscle-specific intermediate filament protein, is increased in the skeletal muscle of mdx mice, a murine model of DMD with a mild phenotype. Here, we inquired whether desmin acts as a modifier in DMD-associated cardiomyopathy. METHODS: Soluble and insoluble desmin levels were quantified in the hearts of two mdx mouse models (B10.mdx and D2.mdx), and GRMD dystrophic dogs. The expression of desmin-regulatory proteins was also assessed in mdx mice. To assess the impact of desmin levels on the phenotype, we generated mdx mice either desmin-deficient (mdx-Des) or with reduced levels of desmin by introducing a heterozygous desmin knock-out allele (mdx-Des). Phenotypic analyses included cardiac function assessment and histological evaluation. RESULTS: In mdx mice, desmin was elevated in its insoluble, phosphorylated, and presumably filamentous form, while GRMD dogs with a severe DMD-like phenotype showed no such increase. Desmin deficiency in mdx mice led to severely aggravated dystrophic features, including cardiac dysfunction and increased fibrosis. Moreover, partial desmin reduction in mdx-Des mice led to the abrogation of insoluble desmin increase and worsened the mild mdx dystrophic phenotype. CONCLUSION: Increased filamentous desmin appears to be protective in mdx mouse hearts and may modulate the severity of DMD cardiomyopathy. These findings support a modifier role for desmin and highlight this protein as a potential therapeutic target for DMD.
Twenty-Four Hour Rhythms in Cardiovascular Physiology.
Thomsen MB
Acta Physiol (Oxf) · 2025 Nov · PMID 41104853 · Full text
Many physiological parameters, such as heart rate and blood pressure, display pronounced daily rhythms, with significant differences between day and night levels. The ability to anticipate the 24 h cycle of ambient light...
Many physiological parameters, such as heart rate and blood pressure, display pronounced daily rhythms, with significant differences between day and night levels. The ability to anticipate the 24 h cycle of ambient light confers an adaptive advantage, allowing organisms to prepare for periods of activity and rest. Considering chronophysiology is essential when designing, conducting, and interpreting laboratory experiments because of the often considerable amplitude of the rhythms. This review introduces a straightforward mathematical tool to detect 24 h rhythms in physiological datasets. Next, the review examines 24-h diurnal rhythms in heart rate, QT interval, and blood pressure, based on telemetry recordings from conscious, freely moving mice. These examples illustrate how long-term, continuous monitoring of physiological parameters enables precise characterization of daily cycles when present. Furthermore, the large datasets obtained through methods such as telemetry make it possible to determine whether the observed rhythms are dependent on heart rate. Circadian and diurnal rhythms play an essential role in cardiovascular physiology, influencing key parameters such as heart rate and blood pressure. Considering chronophysiology is therefore essential when designing, conducting, and interpreting physiological studies.
Cardiomyocyte-Specific Deletion of Sirtuin 5 Accelerates the Development of Heart Failure Upon Dysregulating Purine Metabolism.
Byrne NJ, Koentges C, Pfeil K … +24 more , Lueg JC, Bakshi S, Tarkhnishvili A, Vosko I, Gollmer J, Birkle LC, Rathner T, Birkle S, Tang S, Rau C, Hoffmann MM, Odening KE, Barnes S, Wilson LS, Ljubojevic-Holzer S, Wallner M, von Lewinski D, Rainer P, Sedej S, Sourij H, Bode C, Wende AR, Zirlik A, Bugger H
Acta Physiol (Oxf) · 2025 Nov · PMID 41104836 · Full text
AIM: Sirtuin 5 (SIRT5), a mitochondrial NAD-dependent deacylase, regulates fundamental cellular pathways, including energy substrate metabolism. The current study is designed to better elucidate the role of SIRT5 in the...
AIM: Sirtuin 5 (SIRT5), a mitochondrial NAD-dependent deacylase, regulates fundamental cellular pathways, including energy substrate metabolism. The current study is designed to better elucidate the role of SIRT5 in the development of heart failure (HF). METHODS: Mice with cardiomyocyte-specific deletion (cSirt5) or overexpression (cSirt5-Tg) of SIRT5 were generated and subjected to chronic pressure overload by transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography, isolated heart perfusions, and histology. MS-based metabolomics and bulk RNA sequencing were used to explore metabolic and molecular signatures. RESULTS: cSirt5-Tg mice had similar cardiac structure and function compared to control mice, whereas cSirt5 mice displayed exacerbated cardiac dilation and dysfunction following TAC, measured both in vivo by echocardiography and ex vivo in isolated heart perfusions. Metabolomics revealed accumulation of inosine and hypoxanthine, and depletion of adenosine, adenine, AMP, and ADP in cSirt5 hearts and following TAC, indicating dysregulation of purine metabolism. RNA-sequencing uncovered upregulation of purine-nucleoside phosphorylase and 5' nucleotidase, and downregulation of adenosine kinase (ADK) in cSirt5 hearts following TAC, indicating dysregulation at the interface of adenosine nucleotide salvage and purine degradation in the absence of SIRT5. Analyses of left ventricular tissue of patients with HF revealed reduced SIRT5 expression correlating with reduced ADK expression. CONCLUSION: Loss of SIRT5 in cardiomyocytes aggravates cardiac remodeling and dysfunction in response to chronic pressure overload, involving ATP precursor depletion due to transcriptional dysregulation of cardiac purine metabolism.
Fentanyl Disrupts Vagal Control of Airway Tone to Induce Transient Obstruction.
Parks RR, Andersen MJ, Hatfield ML … +1 more , Burgraff NJ
Acta Physiol (Oxf) · 2025 Nov · PMID 41090325 · Full text
AIM: Opioid-induced respiratory depression (OIRD) is the primary cause of death in opioid overdose, resulting from both suppressed respiratory rhythm and increased airway and thoracic rigidity that compromise ventilation...
AIM: Opioid-induced respiratory depression (OIRD) is the primary cause of death in opioid overdose, resulting from both suppressed respiratory rhythm and increased airway and thoracic rigidity that compromise ventilation and resuscitation. While the effect(s) of opioids on central rhythm-generating circuits are well documented, the mechanisms leading to airway obstruction remain poorly understood. Here, we investigated the hypothesis that enhanced vagal parasympathetic output contributes to fentanyl-induced airway disruption. METHODS: In urethane-anesthetized mice, diaphragm electromyography (EMG), respiratory airflow, and vagus nerve activity were recorded in-vivo before and after intraperitoneal fentanyl administration (500 μg/kg). The effects of bilateral vagotomy, atropine administration, and intracisternal naloxone were evaluated to determine the contribution of vagal pathways and central opioid receptor mechanisms. RESULTS: Fentanyl caused a characteristic slowing of respiratory rate accompanied by a compensatory increase in tidal volume, but also produced a transient delay between diaphragm activation and airflow onset, consistent with airway obstruction. This delay was abolished by bilateral vagotomy or atropine and reversed by intracisternal naloxone, implicating central vagal mechanisms. Vagal electroneurograms showed increased tonic multiunit activity and enhanced large-amplitude single-unit firing, particularly within efferent fibers, together with a loss of normal inspiratory phase-locking. The magnitude of tonic vagal activation strongly correlated with the severity of airway disruption. CONCLUSIONS: Fentanyl disrupts respiratory-autonomic integration by enhancing parasympathetic vagal drive, producing a central, opioid receptor-mediated mechanism of airway constriction. Targeting vagal pathways may therefore represent a promising adjunctive strategy for improving airway patency and ventilatory recovery during opioid overdose reversal.
Electrical Remodeling of Pressure Overloaded Rat Heart Is Attenuated if Imposed During Proliferative Cardiac Growth.
Nekvindova E, Hrdlicka J, Boros A … +8 more , Slegrova M, Kvasilova A, Skop V, Halberstat J, Holzerova K, Neckar J, Sedmera D, Olejnickova V
Acta Physiol (Oxf) · 2025 Nov · PMID 41090321 · Full text
AIM: Left ventricular pressure overload (LVPO) in adults is associated with adverse electrical remodeling, characterized by reduced conduction velocity (CV). However, the progression of LVPO differs when imposed during t...
AIM: Left ventricular pressure overload (LVPO) in adults is associated with adverse electrical remodeling, characterized by reduced conduction velocity (CV). However, the progression of LVPO differs when imposed during the proliferative phase of cardiac development. It remains unknown how increased cardiomyocyte proliferation affects LVPO electrical remodeling. METHODS: CV maturation from rat postnatal day (PD) 1 to PD90 and analyzed underlying connexin 43 (Cx43) profile. Pressure overload was induced by abdominal aortic constriction (AAC) in rats during the proliferative phase of cardiac growth (PD2). Animals subjected to AAC during the non-proliferative heart growth (AAC-PD6) and Sham-operated rats served as controls. Electrical remodeling was assessed at PD21 using ECG, optical mapping, western blots, immunofluorescence, and lipidomic analysis, complemented by functional analyses through echocardiography. RESULTS: Pressure overload led to a 2.5-fold increase in heart weight compared to Sham in both AAC groups. A significant increase in relative left ventricular wall thickening was observed in AAC-PD2 rats only. Optical mapping and ECG showed preserved conduction properties in AAC-PD2 animals, whereas the AAC-PD6 group displayed prolonged QRS and significantly reduced longitudinal CV. While total and phosphorylated Cx43 levels were comparable between the AAC groups, AAC-PD2 animals demonstrated higher intercalated disc localization. Furthermore, lipidomic profiling revealed maintained long-chain acylcarnitine (LCAC) levels in AAC-PD2, whereas AAC-PD6 tended toward LCAC accumulation. CONCLUSION: This study provides new insights into the remodeling upon pressure overload during cardiac proliferative growth, demonstrating attenuated electrical alteration by preserved CV and highlighting the role of Cx43 localization and preserved levels of LCACs.
Dietary Nitrate Prevents Cardiac Dysfunction in HFrEF by Improving Hemodynamics, Ameliorating Remodeling, and Resolving Inflammation.
Shimari M, Picozzi G, Boeder A … +7 more , Guimarães DD, Zhuge Z, Lundberg JO, Carlstrom M, Lund LH, Andersson DC, Pironti G
Acta Physiol (Oxf) · 2025 Nov · PMID 41081419 · Full text
AIMS: Impaired cardiac function, reduced nitric oxide (NO) bioavailability, and inflammation are key contributors to the pathogenesis and progression of heart failure with reduced ejection fraction (HFrEF). This study ai...
AIMS: Impaired cardiac function, reduced nitric oxide (NO) bioavailability, and inflammation are key contributors to the pathogenesis and progression of heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate whether dietary inorganic nitrate supplementation can attenuate cardiac dysfunction and adverse remodeling in HFrEF by enhancing NO signaling. METHODS: Two mouse models of HFrEF, induced by myocardial infarction (MI) or transverse aortic constriction (TAC), were treated with dietary nitrate or a control diet for 4-6 weeks, initiating the treatment on day 3 after myocardial injury. Echocardiography and pressure volume (PV) loop analysis were employed to assess cardiac function and hemodynamics. Histology staining was performed to assess the degree of cardiac fibrosis. Myograph experiments were conducted to assess aortic vasorelaxation. Biomarkers related to hypertrophy, fibrosis, and inflammation were analyzed in cardiac tissues through Q-PCR analysis and immunofluorescence staining. RESULTS: In HFrEF mice, long-term inorganic nitrate treatment increased systolic and diastolic function, enhanced vascular relaxation, and reduced both replacement and reactive fibrosis. In the nitrate group, cardiac gene expression showed downregulation of hypertrophy-, fibrosis-, and inflammation-related markers, alongside upregulation of anti-inflammatory markers associated with M1-to-M2 macrophage polarization. Immunofluorescence confirmed reduced fibrosis and increased anti-inflammatory protein biomarkers associated with increased serum nitrate and cardiac cGMP levels. CONCLUSIONS: Early initiation of dietary nitrate supplementation after myocardial injury enhances cardiac and vascular function, reduces fibrosis and inflammation, and holds promise as a cardioprotective strategy to reduce the progression of HFrEF through NO-signaling.
Transduction Mechanisms for Cold Temperature in Mouse Trigeminal and Vagal Ganglion Neurons Innervating Different Peripheral Organs.
Gers-Barlag K, Del Campo AG, Hernández-Ortego P … +2 more , Quintero E, Viana F
Acta Physiol (Oxf) · 2025 Nov · PMID 41036646 · Full text
AIM: To elucidate the molecular mechanism of cold sensing by visceral sensory endings, a side-by-side characterization of cold-sensitive (CS) neurons in adult mouse trigeminal (TG) and vagal ganglia (VG) was performed. M...
AIM: To elucidate the molecular mechanism of cold sensing by visceral sensory endings, a side-by-side characterization of cold-sensitive (CS) neurons in adult mouse trigeminal (TG) and vagal ganglia (VG) was performed. METHODS: A combination of physiological, pharmacological, molecular, and genetic tools was employed on trigeminal and vagal neurons. RESULTS: CS neurons are more abundant in VG, and the majority co-express TRPA1. Cold-evoked responses are severely blunted in Trpa1 KO mice. In contrast, TRPM8 deletion or pharmacological TRPM8 blockade had little impact on VG cold sensitivity. In Trpm8 reporter mice, VG TRPM8 expression was restricted to the rostral jugular ganglion. In vivo labeling of airway-innervating VG neurons demonstrated their enhanced cold sensitivity and higher TRPA1 expression compared to neurons innervating the stomach wall. In contrast, the majority of CS TG neurons co-express TRPM8 markers, and their cold sensitivity is reduced after TRPM8 deletion or blockade. However, pharmacological or genetic ablation of TRPA1 confirmed its contribution to high-threshold cold sensitivity in TG, suggestive of a role in noxious cold sensing. In both ganglia, a fraction of CS neurons responded to cooling by a mechanism independent of TRPA1 or TRPM8. Blocking potassium channels enhanced cold sensitivity independently of the specific transducer mechanism, suggestive of a common excitability brake mechanism. CONCLUSIONS: The study highlights the differential contribution of TRPM8 and TRPA1 channels to cold sensitivity in somatic and visceral ganglia, establishing a critical role of TRPA1 channels in visceral cold transduction. Finally, cold sensitivity seems fine-tuned to the specific physiological needs of different organs.
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