AIM: In the process of muscle growth and repair, microRNAs (miRNAs) serve as a critical factor in spatiotemporal regulation. Nevertheless, the molecular regulatory mechanisms underlying muscle regeneration remain largely...AIM: In the process of muscle growth and repair, microRNAs (miRNAs) serve as a critical factor in spatiotemporal regulation. Nevertheless, the molecular regulatory mechanisms underlying muscle regeneration remain largely unknown. METHODS: Exosomes from control and miR-126-knockdown BMSCs were isolated via ultracentrifugation. A mouse muscle injury model was established using 1.2% barium chloride in gastrocnemius muscles. Injured tissues received local injections of BMSC exosomes or AAV-miR-126. Gene expression was analyzed by qRT-PCR/Western blot. Tissue morphology and repair were assessed via H&E staining, while regeneration markers were evaluated through immunostaining. RESULTS: Here, we identified miR-126-5p in BMSC-derived exosomes as a positive regulator of muscle regeneration. These exosomes promoted the proliferation and maturation of myoblasts and facilitated the regeneration of skeletal muscle in male C57BL/6J mice. FBXO32 was confirmed as the downstream target of exosomal miR-126-5p to regulate skeletal muscle regeneration, and it ubiquitinated and degraded myogenic differentiation 1 (MyoD). Notably, miR-126-5p knockdown from BMSC-derived exosomes significantly inhibited proliferation and differentiation of Pax7 SCs and muscle regeneration, whereas adeno-associated virus (AAV)-mediated overexpression of miR-126-5p accelerated these processes. Specifically, the BMSC-derived exosomes delivered miR-126-5p to skeletal muscle, thus decreasing the expression of FBXO32, in turn increasing MyoD expression, finally significantly promoting satellite cell differentiation and skeletal muscle regeneration. CONCLUSIONS: BMSC-derived exosomes could promote skeletal muscle injury repair through miR-126-5p, and thus miR-126-5p may act as a molecular therapeutic target of skeletal muscle diseases. Elucidating functional mechanisms of exosomes and miRNA is of great significance for developing new biotherapy strategies for skeletal muscle disease.
Acta Physiol (Oxf)
· 2025 Nov · PMID 41017344
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INTRODUCTION: Pregnancy is a time of significant maternal physiological change to meet the metabolic demands of the feto-placental unit. In cases of pregnancy complications, mal-adaptive physiological responses may occur...INTRODUCTION: Pregnancy is a time of significant maternal physiological change to meet the metabolic demands of the feto-placental unit. In cases of pregnancy complications, mal-adaptive physiological responses may occur, potentially impacting the health of both mother and fetus. Moreover, some maternal changes may persist beyond delivery. Although the clinical symptoms of preeclampsia (PE) and gestational diabetes mellitus (GDM) usually resolve post-partum, growing evidence suggests that these conditions confer a lifelong increased risk of cardiometabolic disease in affected women. This review aimed to summarize epidemiological evidence linking PE and GDM to future maternal cardiometabolic disorders, explore potential underlying mechanisms based on animal and small-scale human studies, and discuss implications for future research and postpartum clinical care. METHODS: Targeted PubMed searches were conducted to search for relevant publications. RESULTS: Data suggest that pregnancy complications may both reveal an underlying predisposition to cardiometabolic disease and induce lasting physiological changes that contribute to future health risks. Notably, women with a history of PE may have a 3-4-fold increased risk of cardiovascular disease, while those with prior GDM may face up to a 10-fold higher risk of developing type 2 diabetes. CONCLUSION: Pregnancy offers a valuable window into a woman's future health, presenting a unique opportunity for preventative medicine for up to half of the world's population.
AIM: In the adult brain, GABA exerts either depolarizing or hyperpolarizing effects on neuronal membranes, depending on neuron type, subcellular location, and neuronal activity. Depolarizing GABA typically inhibits neuro...AIM: In the adult brain, GABA exerts either depolarizing or hyperpolarizing effects on neuronal membranes, depending on neuron type, subcellular location, and neuronal activity. Depolarizing GABA typically inhibits neurons through shunting, which is mediated by increased membrane conductance upon GABA receptor activation; however, it can also excite neurons by recruiting voltage-dependent conductances. The net influence of these opposing actions of depolarizing GABA on glutamatergic synaptic inputs remains incompletely understood. We aimed to examine the spatiotemporal characteristics of membrane polarization and shunting mediated by GABA receptors and assess their functional impact on the integration of GABAergic and glutamatergic inputs along dendrites. METHODS: Using whole-cell current-clamp recordings in CA1 pyramidal neurons and dentate gyrus granule cells (GCs) from rat hippocampal slices, we mimicked GABAergic and glutamatergic inputs with local GABA puff and glutamate spot-uncaging, respectively. A mathematical model further quantified the relative effects of local shunting and polarization. RESULTS: Depolarizing GABAergic postsynaptic responses (GPSRs) exhibited biphasic actions, exerting inhibitory effects at the synapse through shunting, and excitatory effects distally, where depolarization predominated. The excitatory component also persisted longer than the shunting inhibition. In contrast, hyperpolarizing GPSRs remained consistently inhibitory across both spatial and temporal dimensions. CONCLUSIONS: These findings highlight the complex spatiotemporal interplay between shunting and membrane polarization mediated by GABAergic inputs, providing new insights into dendritic computation and neuronal network dynamics.
Gaudry MJ, Bundgaard A, Kutschke M
… +5 more, Ostatek K, Dela Rosa MAS, Crichton PG, Reznick J, Jastroch M
Acta Physiol (Oxf)
· 2025 Oct · PMID 40990116
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AIM: Uncoupling protein 1 (UCP1) is the crucial protein for non-shivering thermogenesis in placental mammals, but the molecular mechanism of thermogenic proton transport is still unknown. Its histidine pair motif (H145 a...AIM: Uncoupling protein 1 (UCP1) is the crucial protein for non-shivering thermogenesis in placental mammals, but the molecular mechanism of thermogenic proton transport is still unknown. Its histidine pair motif (H145 and H147) has been claimed as a critical element for proton translocation, leading to the paradigmatic "cofactor model" of the UCP1 thermogenic mechanism. The histidine pair motif is mutated (H145Q) in the naked mole-rat (NMR, Heterocephalus glaber) UCP1, suggesting disrupted thermogenic function in line with NMR's poor thermoregulatory abilities. Here, we investigated the functionality NMR versus mouse UCP1 to scrutinized the importance of the histidine pair motif. METHODS: Respiratory analyses for UCP1 function were performed in isolated brown adipose tissue mitochondria from NMR and mouse. The histidine pair motif of NMR UCP1 was manipulated through mutations, ectopically overexpressed in HEK293 cells and subjected to plate-based respirometry for functional comparison. RESULTS: Isolated BAT mitochondria of NMRs display guanosine diphosphate-sensitive respiration, indicative of thermogenically competent UCP1. Overexpressed wildtype NMR UCP1 demonstrates proton leak activity comparable to mouse UCP1. Neither restoration of the histidine pair motif nor full ablation of the motif through a double mutation affects UCP1-dependent respiration. CONCLUSIONS: The UCP1 variant of the NMR, a warm-adapted fossorial species, excludes the histidine pair motif as crucial for UCP1 thermogenic function. Collectively, we show that functional investigation into natural sequence variation of UCP1 not only casts new light on the thermophysiology of NMRs but also represents a powerful tool to delineate structure-function relationships underlying the enigmatic thermogenic proton transport of UCP1.
Acta Physiol (Oxf)
· 2025 Oct · PMID 40928049
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BACKGROUND: The cerebral circulation is continuously challenged by intravascular micrometer-sized particles that become trapped microvascular-emboli. These particles may include micro-thrombi, stiffened erythrocytes, and...BACKGROUND: The cerebral circulation is continuously challenged by intravascular micrometer-sized particles that become trapped microvascular-emboli. These particles may include micro-thrombi, stiffened erythrocytes, and leukocytes, while also fat particles, air, and microplastics may cause microvascular embolism. REVIEW SCOPE: In this narrative review, we discuss these embolization processes and their acute and chronic consequences. These relate to the local flow interruption as well as the direct interaction with the endothelium. In addition, we address the clearing processes, including local thrombolysis and extravasation, or angiophagy, of the emboli. CONCLUSION: A continuous balance exists between embolic events and their resolution under normal conditions. Increased micro-embolic rates, as occur in e.g., atrial fibrillation, or decreased clearing, possibly related to endothelial cell dysfunction, disturb this balance. This could lead to continuing loss of capillaries, micro-infarcts, and cognitive decline.
He Y, Zhang H, Zhang Q
… +5 more, Sun Z, Sun X, Xia L, Zheng L, Wang L
Acta Physiol (Oxf)
· 2025 Sep · PMID 40844176
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AIM: The aim of this study is to determine the possible role of N-methyl-D-aspartate receptor (NMDAR) dysregulation in the ischemic electrical remodeling observed in patients with myocardial infarction (MI) and elucidate...AIM: The aim of this study is to determine the possible role of N-methyl-D-aspartate receptor (NMDAR) dysregulation in the ischemic electrical remodeling observed in patients with myocardial infarction (MI) and elucidate the underlying mechanisms. METHODS: Human heart tissue was obtained from the border of the infarct and remote zones of patients with ischemic heart disease, and mouse heart tissue was obtained from the peri-infarct zone. NMDAR expression was detected using immunofluorescence (IF) and Western blotting (WB). Spontaneous ventricular arrhythmias (VAs) in mice were detected using electrocardiogram backpacks. Electrical remodeling post-MI was detected using patch clamp recordings, quantitative real-time polymerase chain reactions, IF, and WB. Mechanistic studies were performed using bioinformatic analysis, plasmid and small interfering RNA transfection, lentiviral packaging, and site-directed mutagenesis. RESULTS: NMDAR is highly expressed in patients with ischemic heart disease and mice with MI. NMDAR inhibition reduces the occurrence of VAs. Mechanistically, NMDAR activation promotes electrophysiological remodeling, as characterized by decreased Nav1.5, Kv11.1, Kv4.2, Kv7.1, Kir2.1, and Cav1.2 expression in patients with ischemic heart disease and mice with MI and rescues these ion channels dysregulation in mice with MI to varying degrees by NMDAR inhibition. Decreased Nav1.5 expression and inward sodium current density were attenuated by NMDAR inhibition in primary rat cardiomyocytes. Moreover, NMDAR activation upregulates T-Box Transcription Factor 3 (TBX3) post-translationally, further downregulating Nav1.5 transcriptionally. Furthermore, AKT1 is the predominant isoform in the ventricular myocardium upstream of TBX3 and mediates NMDAR-induced TBX3 upregulation in cardiomyocytes. CONCLUSION: NMDAR activation contributes to MI-induced VAs by regulating the AKT1-TBX3-Nav1.5 axis, providing novel therapeutic strategies for treating ischemic arrhythmias.
Tasbihi E, Gladytz T, Millward JM
… +3 more, Cantow K, Seeliger E, Niendorf T
Acta Physiol (Oxf)
· 2025 Sep · PMID 40843986
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AIM: The renal tubular volume fraction (TVF) fluctuates under physiological conditions, and is altered in several renal diseases. Tools that enable noninvasive assessment of TVF are currently lacking. Magnetic Resonance...AIM: The renal tubular volume fraction (TVF) fluctuates under physiological conditions, and is altered in several renal diseases. Tools that enable noninvasive assessment of TVF are currently lacking. Magnetic Resonance (MR) TVF cartography is a novel approach for unraveling renal (patho-)physiology. Here, we employ MR-TVF cartography to monitor changes in response to the diuretic furosemide, and examine its role for the interpretation of renal oxygenation assessed by mapping the MRI relaxation time T*. We hypothesize that furosemide increases TVF. METHODS: In anesthetized rats (n = 7) the MRI relaxation times T, T*, T' and kidney size were obtained before/following an i.v. bolus of furosemide using a 9.4 Tesla MRI scanner. Spectral analysis of the T signal decay was performed to estimate the number of T components in renal tissue. TVF cartographies were calculated using voxel-wise bi-exponential fit of the T decay. Near Infrared Spectroscopy (NIRS, n = 9) was used to assess the total hemoglobin concentration (HbT) as a surrogate of renal blood volume. RESULTS: Furosemide induced changes in renal MRI and NIRS parameters relative to baseline: TVF = 31.1%, TVF = 30.7%, T = 13.0% and T = 20.6%. HbT was reduced by 2.7%. HbT declined by 8.6%. Kidney size showed a modest increase of 2.9%. T* and T´ rose by 20.5% and 20.2%. T* and T´ remained unchanged. T* and TVF were strongly correlated in the outer medulla and moderately in the cortex. CONCLUSION: MR-TVF cartography is highly relevant for elucidating mechanisms of renal (patho-)physiology, including the role of renal oxygenation assessed by MRI mapping of renal T*.
Muralikrishnan AS, Biasin V, Zabini D
… +1 more, Osto E
Acta Physiol (Oxf)
· 2025 Sep · PMID 40838278
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BACKGROUND AND AIMS: Vascular dysfunction, driven by endothelial impairment, arterial stiffness, inflammation, and immune activation, contributes to cardiometabolic disorders such as hypertension and atherosclerosis. Sex...BACKGROUND AND AIMS: Vascular dysfunction, driven by endothelial impairment, arterial stiffness, inflammation, and immune activation, contributes to cardiometabolic disorders such as hypertension and atherosclerosis. Sex differences and sex hormones influence the progression of vascular and immune dysfunction. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), regulate glucose homeostasis and also impact vascular and immuno-metabolic health. This review examines their roles in these processes, with emphasis on sex-specific effects. METHODS: A narrative review of preclinical and clinical studies assessing GLP-1 and GIP actions on vascular function, immune regulation, and metabolism, and their modulation by sex and sex hormones. RESULTS: Incretins improve endothelial function, reduce vascular inflammation, and modulate immune-metabolic crosstalk, processes often impaired in cardiometabolic disease. Sex differences affect incretin secretion, signalling, and therapeutic responses, though underlying mechanisms remain unclear. CONCLUSIONS: Incretin hormones are promising targets for improving vascular and immune-metabolic health in cardiometabolic disorders. Understanding sex-specific mechanisms will be essential for optimizing incretin-based therapies.
Moore LG, Wesolowski SR, Lorca RA
… +1 more, Julian CG
Acta Physiol (Oxf)
· 2025 Sep · PMID 40827403
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Adenosine monophosphate-activated protein kinase (AMPK) serves to match perfusion with metabolism. Since pregnancy necessitates significant changes in both perfusion and metabolism for supporting fetal growth, surprising...Adenosine monophosphate-activated protein kinase (AMPK) serves to match perfusion with metabolism. Since pregnancy necessitates significant changes in both perfusion and metabolism for supporting fetal growth, surprising is that AMPK has received scant attention during pregnancy, perhaps due to the complexity of its actions and multiple maternal, placental, and fetal targets. Here we review human as well as experimental animal studies documenting AMPK activation's broad-ranging maternal effects. Emphasized are those affecting vascular control and blood flow to the uteroplacental circulation under conditions of chronic hypoxia. Time and dosage-dependent effects on the placenta and the fetus are also reviewed, revealing that AMPK activation affects all three-maternal, placental, and fetal-pregnancy compartments. We point to the need for an integrated study of AMPK's effects in each compartment during normal as well as fetal growth-restricted (FGR) pregnancies. Since there are currently no therapies for FGR apart from early delivery, whereas there are drugs or nutritional substances activating AMPK approved for human use, such agents may represent new treatments. However, understanding their molecular mechanisms and specific actions in pregnancy compartments is required before conducting such trials.