American Journal Of Physiology. Cell Physiology[JOURNAL]
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200 papers
The roles of Tenascin C in kidney diseases.
Caspers T, Boor P, Klinkhammer BM
Am J Physiol Cell Physiol · 2026 Feb · PMID 41419123 · Publisher ↗
Tenascin C (TNC), an extracellular matrix glycoprotein, is crucial for embryonic development and tissue repair, inflammation, extracellular matrix remodeling, and fibrosis, particularly in kidney diseases. Although its e...
Tenascin C (TNC), an extracellular matrix glycoprotein, is crucial for embryonic development and tissue repair, inflammation, extracellular matrix remodeling, and fibrosis, particularly in kidney diseases. Although its expression is typically low in healthy adult kidneys, TNC is upregulated in various kidney disease conditions, including acute kidney injury (AKI) and chronic kidney disease (CKD). TNC influences fibroblast activation, and elevated TNC levels correlate with CKD severity, highlighting its potential as a biomarker for diagnosis and monitoring of fibrogenesis. TNC's multifaceted role offers opportunities for therapeutic interventions. Here, we provide an overview of TNC's structural and functional attributes, its regulatory mechanisms, and its multifactorial role in kidney disease development and progression. We also discuss recent approaches aiming to use TNC as a target for diagnostic and therapeutic purposes.
Retinoic acid promotes expression of inflammatory factors in proliferative adult human heart cells.
Gans IM, Lessard AJ, Ryzhov SV … +2 more , Vary CP, Sawyer DB
Am J Physiol Cell Physiol · 2026 Feb · PMID 41412446 · Full text
Retinoid signaling is increased in the hearts of patients with coronary artery disease and during acute myocardial infarction (MI). The effects of retinoids on cardiac repair after injury remain incompletely understood....
Retinoid signaling is increased in the hearts of patients with coronary artery disease and during acute myocardial infarction (MI). The effects of retinoids on cardiac repair after injury remain incompletely understood. Our laboratory has derived proliferative cardiac cell clones from adult human left ventricle biopsies and is investigating how these cells might participate in cardiac repair in heart failure. We treated clones isolated from unique individuals with retinoic acid (RA) and performed unbiased proteomics, bioinformatic analyses, and targeted follow-up experiments to identify and confirm RA-regulated factors and processes. RA increased the expression of well-known proinflammatory proteins including interleukin-1 (IL1A and B) and inducible cyclooxygenase 2 (COX2), while decreasing the expression of extracellular matrix (ECM) factors such as thrombospondin 1 and collagens. Additionally, we found that basal expression of retinoid metabolizing enzymes (e.g., ALDH1A3) significantly correlated with expression of cytokines and inflammatory mediators including IL1A/B and COX2 across clones from different donors. Secretion of IL1B by clones was found to respond to physiological and pharmacological doses of RA, and monocyte migration in vitro responded to secretions from RA-treated clones. Our findings suggest a mechanism by which retinoids promote inflammation and contribute to adverse cardiac remodeling in the injured heart, providing a potential avenue to regulate myocardial inflammation and remodeling processes. Within the injured heart, cells are exposed to elevated retinoic acid signaling resulting from mobilized stores of its precursor, vitamin A, and increased cardiac expression of synthesizing enzymes. This study investigated the effects of retinoic acid, a potent regulator of cell fate and function, on human proliferative cardiac cell clones derived from left ventricle biopsies. The results show an increase in inflammatory factor secretion, immune cell activation, and decreased extracellular matrix expression.
Precise dynamic control of tissue oxygenation during brain slice electrophysiology.
Jurado A, Pérez-González AP, Farré R … +3 more , Gozal D, Gasull X, Almendros I
Am J Physiol Cell Physiol · 2026 Feb · PMID 41407307 · Publisher ↗
Precise oxygen regulation is essential for maintaining neuronal integrity in ex vivo brain slice electrophysiology, yet conventional chambers provide poorly defined oxygenation. This limitation is particularly problemati...
Precise oxygen regulation is essential for maintaining neuronal integrity in ex vivo brain slice electrophysiology, yet conventional chambers provide poorly defined oxygenation. This limitation is particularly problematic when model neurological disorders are characterized by transient or intermittent hypoxia (IH), such as transient ischemic attacks and sleep apnea. We aimed to develop a versatile oxyslice recording chamber (ORC), enabling real-time monitoring of neural activity with rapid, precise oxygen modulation during standard recordings. A polydimethylsiloxane (PDMS)-based ORC comprising a gas-permeable membrane that separates the recording and gas chambers was developed, allowing rapid and uniform oxygen exchange. The device integrates seamlessly into standard electrophysiological setups and operates at low perfusion rates. Tissue oxygenation was measured, and hippocampal slices were exposed to continuous hypoxia (CH, 3% or 1% O) and IH (6-1% O cycles every 30 s) while recording field excitatory postsynaptic potentials (fEPSPs) in the hippocampal CA1 region. The ORC achieved precise, reproducible control of oxygen at the cellular level. Both CH and IH induced hypoxia severity-dependent reductions in fEPSP slopes, fully reversed upon reoxygenation. Severe CH (1% O) reduced the fEPSP slope by ∼60%, whereas IH reduced it by ∼40%, indicating a partial mitigation during reoxygenation phases. This novel ORC provides a robust, adaptable method for real-time oxygen modulation in ex vivo neuronal standard recordings. Its ability to model continuous and intermittent hypoxia at physiological oxygen tensions fills a major gap in current electrophysiological methodologies, opening new opportunities for mechanistic studies of hypoxia-driven dysfunction and therapeutic discovery. This study presents the oxyslice recording chamber (ORC), a simple and reproducible system for precise oxygen control during brain slice recordings. The ORC has been developed to be easily constructed and implemented in any electrophysiology laboratory. As a proof of concept, we reproduced continuous hypoxia (transient ischemic stroke) and intermittent hypoxia (sleep apnea), revealing distinct and reversible changes in hippocampal function applicable to various hypoxia-related conditions and brain regions.
Skeletal muscle methylome-transcriptome disruptions during the onset and progression of colorectal cancer-induced cachexia.
Cabrera AR, Jones RG, Shrems ER … +5 more , Morena F, Wen Y, Washington TA, Murach KA, Greene NP
Am J Physiol Cell Physiol · 2026 Jan · PMID 41385570 · Full text
Cancer cachexia is a wasting condition, primarily affecting skeletal muscle, impairing patients' quality of life, prognosis, and survival. The molecular triggers are incompletely defined, but given prior evidence for epi...
Cancer cachexia is a wasting condition, primarily affecting skeletal muscle, impairing patients' quality of life, prognosis, and survival. The molecular triggers are incompletely defined, but given prior evidence for epigenetic plasticity in muscle, we speculate that dysregulated DNA methylation plays a role in muscle transcriptional alterations mediating cachexia severity. We aimed to describe and integrate the cachexia methylome and transcriptome. We used a time course approach in a mild cachexia model (colon-26, C26) coupled with a severe cachexia genetic model () in both biological sexes to assess the methylome across degrees of cachexia pathology. The muscle methylome and transcriptome were analyzed separately and subsequently integrated using a computational technique to infer epigenetic control of gene expression. Male mice exhibited widespread disruptions to the transcriptome across time points, whereas females were more protected; in severe pathophysiologic phenotypes, the magnitude of change was similar between sexes. A conserved set of inflammation-related genes was dysregulated across cachexia progression and sex, including , , and . Epigenetic alterations in both sexes emerged in promoter regions as early as 10 days post-tumor implant in C26, despite a lack of physiologic phenotype and before the transcriptome disruptions. Our integration analysis suggests methylome alterations as a mechanism of cachexia pathophysiology in severe phenotypes. A conserved feature across -omics layers, sexes, and conditions was dysregulated and neurodegeneration-related pathways, which may indicate cachexia-mediated denervation. Overall, we provide evidence for the role of epigenetics in cachexia progression and severity and a valuable resource to the cachexia research communities. Using multi-omics integration, we establish that DNA methylation status likely influences the muscle transcriptome during cancer cachexia, affecting pathways commonly disrupted in cachexia including those associated with neurodegeneration and metabolism. Epigenetic dysregulation occurs early and progresses during the onset and establishment of cancer cachexia, highlighting DNA methylation as a potential therapeutic target to slow or mitigate disease progression.
Plectin associates with focal adhesions and contributes to cytoskeletal organization and mechanical properties of astrocytes.
Furlani B, Potokar M, Pozo Devoto VM … +4 more , Pérez-Sala D, Wiche G, Zorec R, Jorgačevski J
Am J Physiol Cell Physiol · 2026 Feb · PMID 41379572 · Publisher ↗
Reactive astrogliosis, a hallmark of central nervous system pathologies, involves a spectrum of astrocyte responses, including morphological remodeling and the upregulation of intermediate filaments such as vimentin and...
Reactive astrogliosis, a hallmark of central nervous system pathologies, involves a spectrum of astrocyte responses, including morphological remodeling and the upregulation of intermediate filaments such as vimentin and glial fibrillary acidic protein (GFAP). Changes in astrocyte shape are driven by cytoskeletal dynamics and are important for interactions with the surrounding microenvironment. Focal adhesions (FAs), which serve as physical and signaling links between the cytoskeleton and the extracellular matrix, play a central role in these structural adaptations. Here, we identify plectin, a versatile cytoskeletal linker, as an important modulator of FA-associated processes in cultured mouse astrocytes. We demonstrate that plectin localizes to FAs in astrocytes, and its deficiency is associated with changes in their number, maturation, and turnover. Plectin also displays polarization within FAs, depending on their maturation state, and it contributes to the recruitment of key cytoskeletal elements, particularly vimentin, to FAs. In plectin-deficient astrocytes, the vimentin and GFAP network exhibits impaired connectivity, accompanied by altered viscoelastic properties of the cells. Compared with astrocytes maintained in serum-free neurobasal medium, astrocytes cultured in serum-containing medium, which resemble reactive astrocytes, exhibit elevated plectin levels along with an increased number and size of FAs, supporting the involvement of plectin in pathological conditions. Plectin contributes to FA dynamics in astrocytes and exhibits spatial polarization within individual FAs as revealed by superresolution microscopy (SIM and STED). Atomic force microscopy demonstrated that plectin deficiency alters cell viscoelasticity, unveiling the role of plectin in the mechanical properties of astrocytes. Plectin expression, along with the FA protein vinculin, is upregulated in astrocytes cultured under serum-containing conditions-an in vitro model of reactive astrocytes-compared with serum-free, native-like conditions.
Endotrophin as a biomarker and mediator in cardiovascular-kidney-metabolic syndrome: current insights and remaining questions.
Genovese F, Karsdal M, Devos H … +3 more , Bager C, Nuñez J, Bayes-Genis A
Am J Physiol Cell Physiol · 2026 Feb · PMID 41364548 · Publisher ↗
Endotrophin, a biologically active fragment derived from the α3 chain of collagen type VI, has emerged as both a risk biomarker and a potential pathogenic factor in cardiovascular-kidney-metabolic (CKM) syndrome. Over th...
Endotrophin, a biologically active fragment derived from the α3 chain of collagen type VI, has emerged as both a risk biomarker and a potential pathogenic factor in cardiovascular-kidney-metabolic (CKM) syndrome. Over the past decade, research has shed light on its role in various noncommunicable diseases, emphasizing its signaling properties and diagnostic potential. Despite these advances, significant gaps remain in our understanding of how endotrophin contributes to CKM pathophysiology and whether targeting it therapeutically could modify disease progression. This narrative review synthesizes current evidence on endotrophin biological functions and clinical associations, drawing from both experimental and clinical studies. In addition, it identifies critical areas where further investigation is required, including the molecular mechanisms linking endotrophin to CKM-related tissue dysfunction and its causal role in disease development. By mapping current knowledge and highlighting research priorities, this review aims to advance the field toward a more complete understanding of endotrophin as a potential therapeutic target.
A human cardiomyocyte-based cellular model mimicking cardiac ischemia.
Vartanian-Grimaldi JS, Agbulut O
Am J Physiol Cell Physiol · 2026 Jan · PMID 41364545 · Publisher ↗
Ischemic heart disease, the most common form of heart disease worldwide, is caused by a lack of oxygen and nutrients in the heart due to the narrowing of coronary arteries. Research in this field is mostly limited to ani...
Ischemic heart disease, the most common form of heart disease worldwide, is caused by a lack of oxygen and nutrients in the heart due to the narrowing of coronary arteries. Research in this field is mostly limited to animal models, but the development of cellular models could significantly accelerate the discovery of novel therapeutic molecules to protect cardiomyocytes from ischemic stress. To address this limitation, this study focused on developing an in vitro model of ischemic stress using human cardiomyocytes derived from induced pluripotent stem cells. After differentiating induced pluripotent stem cells into cardiomyocytes, the cells, cultured either in monolayers or as a spheroid, were exposed to an ischemic environment characterized by oxygen and nutrient deprivation. Specifically, we reduced the oxygen concentration to 1% using a hypoxia chamber and the glucose concentration to 65 mg/L to trigger the onset of cardiac ischemia. Twenty-four hours later, the stressed cardiomyocytes were treated with tumor necrosis factor alpha (TNF-α, 20 ng/mL) and interleukin 6 (IL-6, 20 ng/mL) to also mimic the inflammatory environment. The cells were then analyzed at various timepoints following exposure to ischemic stress. Our results showed that this novel ischemia model induces progressive cellular toxicity characterized by increased apoptosis, double-stranded DNA breaks, and overall cell death. These effects are accompanied by mitochondrial and metabolic dysfunction, loss of cardiomyocyte contractile function, and numerous morphological alterations, including reduced cell and nuclei size and disorganization of the α-actinin network. In conclusion, our results highlight that this model offers a valuable platform for understanding the mechanistic underpinnings of cardiomyocyte ischemic stress and holds promise for screening novel therapeutic molecules aimed at protecting cardiomyocytes. Furthermore, by reducing reliance on animal models, it adheres to the reduction, replacement, and refinement (3Rs) ethical principles. In this study, we developed a novel in vitro model of cardiac ischemia using cardiomyocytes derived from induced pluripotent stem cells. Cells were exposed to oxygen and nutrient deprivation, followed by proinflammatory cytokines to mimic postischemic inflammation. This approach reproduces key features of ischemic injury, including mitochondrial dysfunction, impaired contractility, and morphological changes. The model provides a valuable tool for studying cardiac pathophysiology and testing therapeutic strategies while reducing reliance on animal models.
The astrocytic engine: Na,K-ATPase at the nexus of brain function and malfunction.
Verkhratsky A, Hansen LMB, Staehr C … +1 more , Matchkov VV
Am J Physiol Cell Physiol · 2026 Jan · PMID 41364026 · Publisher ↗
Astrocytes are fundamental for brain homeostasis and act as dynamic signaling elements within the central nervous system. By maintaining ionic balance, neurotransmitter turnover, and metabolic support, they sustain neuro...
Astrocytes are fundamental for brain homeostasis and act as dynamic signaling elements within the central nervous system. By maintaining ionic balance, neurotransmitter turnover, and metabolic support, they sustain neuronal excitability and network stability. Ionic excitability of astrocytes is mediated primarily by fluctuations of intracellular Na, K, Ca, and Cl ions. Central to these processes is the Na,K-ATPase, which maintains transmembrane Na and K gradients, driving secondary active transport, including uptake of neurotransmitters such as glutamate, γ-aminobutyric acid, and their precursors glutamine and L-serine. Astrocytic Na changes rapidly coordinate neuronal activity with glial homeostasis via -methyl-d-aspartate receptor signaling, whereas K clearance is primarily mediated by the Na,K-ATPase α isoform, preventing neuronal hyperexcitability. The Na,K-ATPase also contributes to neurovascular coupling, linking synaptic activity to local vasodilation through Ca- and K-dependent signaling in astrocytic endfeet. Beyond ion transport, the Na,K-ATPase serves as a signaling hub, engaging intracellular kinase signaling pathways, including Src and phosphoinositide 3-kinase kinases, thereby modulating astrocyte morphology, metabolism, and stress responses. Dysfunctions of astrocytic Na,K-ATPase isoforms are implicated in multiple neuronal pathologies, including seizures, familial hemiplegic migraine, neurodegeneration, and neuroinflammatory disorders. These pathologies reflect primarily loss-of-function mechanisms, altered ion homeostasis, and reactive oxygen species or inflammatory signaling. Understanding the isoform- and cell-type-specific functions of the Na,K-ATPase across the neurovascular unit will be crucial for future development of targeted therapies aimed to restore ion homeostasis and signaling in the diseased brain.
Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.
Yadav A, Schmitt S, Ma W … +2 more , Mobley JA, Thalacker-Mercer AE
Am J Physiol Cell Physiol · 2026 Jan · PMID 41348587 · Publisher ↗
Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration/development, especially under physiological stress like aging or catabolic conditions. Gln availabilit...
Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration/development, especially under physiological stress like aging or catabolic conditions. Gln availability regulates MPC proliferation by modulating intracellular metabolic and epigenetic states. Gln deficiency reduces cell viability, induces G0/G1 cell cycle arrest, and downregulates MyoD expression, collectively inhibiting myogenesis in human primary myoblasts (human skeletal muscle myoblast) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of tricarboxylic acid cycle enzyme, α-ketoglutarate dehydrogenase complex, components (i.e., DLST and OGDH), elevates histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions ( locus). These changes establish a direct link between Gln availability and an epigenetic-metabolic axis crucial for myogenic gene regulation. Thus, extracellular Gln acts as a key regulator of MPC proliferation through metabolic-mediated control of chromatin state. This study revealed that extracellular Gln regulates MPC proliferation through metabolic-epigenetic axis. Gln deficiency impairs myogenesis, enhances the nuclear localization of TCA cycle enzyme, increases histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions. These findings establish Gln as a critical modulator of chromatin state via intermediary metabolic mediators during myogenesis.
Effects of acidosis and inorganic phosphate on Ca sensitivity of young and older adult skeletal muscle fibers.
Teigen LE, Zepeda CS, Dobrzycki I … +3 more , Hunter SK, Fitts RH, Sundberg CW
Am J Physiol Cell Physiol · 2026 Jan · PMID 41348575 · Full text
The cellular mechanisms for the age-related loss in skeletal muscle contractile function and increased fatigability are unresolved. We previously observed that the depressive effects of fatiguing levels of hydrogen (H; p...
The cellular mechanisms for the age-related loss in skeletal muscle contractile function and increased fatigability are unresolved. We previously observed that the depressive effects of fatiguing levels of hydrogen (H; pH 6.8, 6.6, and 6.2) and inorganic phosphate (P; 12, 20, and 30 mM) did not differ in myofibers from young compared with older adults. However, these studies used saturating Ca, while fatigue during high-intensity contractions in vivo also likely involves a decrease in myoplasmic free Ca. Thus, we compared the Ca sensitivity of myofibers from 10 young (22.1 ± 3.6; 5 women) and 13 older (71.7 ± 5.5; 7 women) adults in conditions mimicking quiescent (pH 7 + 4 mM P) and fatigued (pH 6.2 + 30 mM P) muscle. Fast fiber cross-sectional area was ∼35% smaller in older (4,859 ± 2,116 µm) compared with young (7,446 ± 2,399 µm, = 0.002), which corresponded with lower maximal absolute force (P) in both quiescent (old = 0.75 ± 0.30 mN; young = 1.13 ± 0.32 mN; = 0.002) and fatigue conditions (old = 0.35 ± 0.14 mN; young = 0.52 ± 0.16 mN; = 0.002). There were no differences in fast fiber size-specific P, indicating the age-related decline in force was due to differences in fiber size. Elevated H and P shifted the force-pCa relationship to the right, confirming nonhuman studies that these metabolites contribute to fatigue by depressing the sensitivity of the myofilaments to Ca. However, Ca sensitivity was not different with age or sex in either condition, and the metabolite-induced shift in the force-pCa relationship did not differ with age in either the slow ( = 0.507) or fast ( = 0.115) fibers. These data suggest the age-related increase in fatigability of limb muscles cannot be explained by an increased sensitivity of the myofibers to elevated H and P in maximal or submaximal Ca. This study reports the effects of elevated H and P on Ca sensitivity of human skeletal muscle fibers and determines whether the effects of these metabolites are altered by aging in submaximal Ca. The metabolites markedly depressed Ca sensitivity in human muscle fibers, but there was no effect of age or sex. These data suggest that Ca sensitivity is preserved with age in conditions that mimic both quiescent and fatigued muscle.
Eccentric overload training promotes serial sarcomerogenesis to a greater extent than conventional resistance training.
Rilling A, Hinks A, Kirkup AQ … +2 more , Franchi MV, Power GA
Am J Physiol Cell Physiol · 2026 Feb · PMID 41343154 · Publisher ↗
Eccentric exercise has been shown to increase serial sarcomere number (SSN) through sarcomerogenesis in both animal and human models. However, eccentric contractions rarely occur in isolation and are often used in conjun...
Eccentric exercise has been shown to increase serial sarcomere number (SSN) through sarcomerogenesis in both animal and human models. However, eccentric contractions rarely occur in isolation and are often used in conjunction with concentric movements, limiting the ability to evoke a maximal eccentric contraction. Eccentric overload training provides an increased eccentric stimulus, yet its impact on muscle morphology and mechanics is not widely understood. We compared the effects of eccentric overload training (ECC) and conventional resistance training (CONV) on morphological [SSN, fascicle length (FL), sarcomere length (SL), physiological cross-sectional area (PCSA), wet weight] and mechanical changes (torque, normalized torque, power, passive torque) pre- to post-training. Nineteen Sprague-Dawley ( = 10; ECC = 9; CONV) male and female rats (13-14 wk, 317 g) completed 4 wk (3× week) of training. SSN increased with training by 17% in the soleus ( < 0.001) and 6% in the medial gastrocnemius ( = 0.021) in the ECC group, compared with 2% and 4% in the CONV group. Peak plantar flexion torque increased ∼27% in the ECC and ∼21% in the CONV group ( < 0.001) but did not differ between groups ( = 0.318). There was a 26% increase in normalized torque for the ECC, as compared with 2.5% in the CONV group at 90°, demonstrating an interaction of training × group ( < 0.001). Power increased ∼9%, with an interaction of sex × training × group ( = 0.021) driven by increases in torque at peak power in the ECC male group. These findings indicate that overload training provided a more robust stimulus for longitudinal muscle remodeling than conventional resistance training. Eccentric overload training promotes greater sarcomerogenesis than conventional resistance training in male and female rats.
Autophagy and GLUT1 trafficking: an overview of molecular mechanisms.
Petrosino S, Grumati P
Am J Physiol Cell Physiol · 2026 Jan · PMID 41309058 · Publisher ↗
Autophagy is a catabolic process that enables cellular metabolic adaptation in response to nutrient deprivation. It facilitates the degradation of proteins and cellular components within lysosomes to generate essential m...
Autophagy is a catabolic process that enables cellular metabolic adaptation in response to nutrient deprivation. It facilitates the degradation of proteins and cellular components within lysosomes to generate essential metabolites. The glucose transporter 1 (GLUT1) is among the proteins that can undergo autophagy-mediated degradation in response to metabolic stimuli. GLUT1 is essential for cellular glucose supply in several tissues. Notably, GLUT1 facilitates glucose transport across the blood-brain barrier, creating a concentration gradient from the bloodstream into the brain's interstitial fluid. The presence of GLUT1, at the plasma membrane, is the first step in initiating glucose uptake and driving glycolysis inside the cell. Glycolysis can be initiated in response to several stimuli, including glucose availability, autophagy inhibition, and growth factor accessibility. In this review, we highlight recently described mechanisms that govern the subcellular distribution of GLUT1 with a focus on autophagy-mediated trafficking. Understanding how autophagy coordinates GLUT1 sorting in response to metabolic demands may uncover novel therapeutic targets for metabolic disorders characterized by dysregulated GLUT1 trafficking.
SERPINE1 drives molecular synergies in colorectal cancer.
Nuha N, Higgins SP, Czekay RP … +4 more , Higgins CE, Guo L, Lee H, Higgins PJ
Am J Physiol Cell Physiol · 2026 Jan · PMID 41297032 · Publisher ↗
Colorectal cancer is a complex disease shaped by genetic changes and cross talk among tumor cells, stromal factors, and infiltrating cellular elements within the tumor environment. In this review, we explore an integrati...
Colorectal cancer is a complex disease shaped by genetic changes and cross talk among tumor cells, stromal factors, and infiltrating cellular elements within the tumor environment. In this review, we explore an integrative network of genes and their encoded proteins that play significant roles in colorectal cancer progression. Among the most clinically relevant and frequently implicated factors in digestive system cancer is the prominent protumorigenic serine protease inhibitor SERPINE1 (also known as plasminogen activator inhibitor-1 or PAI-1). This SERPIN impacts critical pathways that regulate extracellular matrix remodeling, neoplastic and immune cell migration, tumor cell survival, metastasis, and drug resistance, and plays a major role in shaping the neoplastic inflammatory microenvironment. As a result of this multifaceted function, PAI-1 correlates with high-risk scores and poor patient outcomes in various malignancies including colorectal cancer. Recent bioinformatic approaches provide new insights on how PAI-1 contributes to tumor progression and patient prognosis. This review provides a unified framework for understanding this disease at the molecular level and highlights promising targets for future therapies and diagnosis.
Comprehensive transcriptomic analysis identifies Lrg1 as a potential therapeutic target for preventing muscle atrophy in cancer cachexia.
Lee H, Kim A, Son K … +5 more , Choi A, Cha S, Shin H, Kim NS, Lee H
Am J Physiol Cell Physiol · 2026 Jan · PMID 41289601 · Publisher ↗
Cancer cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting and systemic inflammation, primarily observed in patients with advanced-stage cancer. Cachexia severely impacts patients' qu...
Cancer cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting and systemic inflammation, primarily observed in patients with advanced-stage cancer. Cachexia severely impacts patients' quality of life and even increases mortality rates; however, effective therapeutic interventions remain elusive. To identify key mediators of muscle atrophy, we integrated >100 bulk and single-cell transcriptomic datasets from diverse murine cachexia models, including colorectal, lung, and pancreatic cancer. This analysis identified leucine-rich α-2-glycoprotein 1 (), as consistently upregulated in skeletal muscle endothelial cells across cachexia models and progressively increased during disease progression. Functional studies demonstrated that recombinant Lrg1 induced myotube atrophy in vitro, accompanied by reduced fusion index, shortened myotube length, and increased expression of the atrogenes such as MAFbx and MuRF1. Neutralization of Lrg1 or pharmacological inhibition of Stat3 prevented these effects. Our findings nominate Lrg1 as a candidate biomarker and potential therapeutic target for preventing skeletal muscle wasting in cancer cachexia. This study reports the first omics-based characterization of the CT-26 cancer cachexia model and shows transcriptomic concordance with other models. Integrative bulk and single-cell analyses identified as a gene highly expressed in endothelial cells and associated with muscle wasting. Functional assays indicated that extracellular Lrg1 activates Stat3 and induces myotube atrophy, whereas its neutralization or Stat3 inhibition prevented these effects. Lrg1 may therefore serve as a biomarker and therapeutic target in cancer cachexia.
Remodeling of sarcoplasmic reticulum Ca uptake in cardiac Purkinje cells after ischemic myocardial infarction in various large mammalian species and humans.
Stuyvers BD, Guo Y, Dun W … +13 more , Boyden PA, Amin R, Wiede L, Doré J, Hopkinson Z, Ter Keurs HEDJ, Haissaguerre M, Hocini M, Brette F, Bernus O, Chaigne S, Quesson B, Vigmond E
Am J Physiol Cell Physiol · 2026 Jan · PMID 41289600 · Publisher ↗
After myocardial infarction (MI), increased spontaneous sarcoplasmic reticulum (SR)-Ca releases depolarize the membrane and trigger action potentials (APs) in cardiac Purkinje cells (Pcells). This abnormal Ca-activity is...
After myocardial infarction (MI), increased spontaneous sarcoplasmic reticulum (SR)-Ca releases depolarize the membrane and trigger action potentials (APs) in cardiac Purkinje cells (Pcells). This abnormal Ca-activity is involved in ventricular fibrillation. Spontaneous Ca-transients analysis suggested that intensification of SR-Ca uptake accounts for the abnormal SR-Ca release in post-MI Pcells. Increased SR-Ca-pump (SERCA) density, phospholamban (PLB)-dependent Ca-pump activation, and modification of the pump Ca-transport properties can mediate an increase in SR-Ca uptake. We examined whether Pcells of ischemic hearts show signs of these alterations, hence supporting the hypothesis of post-MI increase in SR-Ca-uptake. Pcells were prepared from hearts with and without MI in dogs, sheep, pigs, and humans. The distribution of SR-Ca pumps and phosphorylated forms of PLB, pPLBSer16 and pPLBThr17, was captured by specific immunofluorescence and confocal microscopy. Protein and transcript levels of sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2) subisoforms were measured in Purkinje fibers and myocardium by Western blot (WB) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. In normal hearts, Ca pumps and PLB antibodies colocalized throughout Pcells. After MI, Ca pump staining exhibited larger intensity in peripheral compared with central regions of Pcells. Phosphorylated PLB staining was unchanged, indicating no alteration of the pump-β-adrenergic regulation after MI. Expression of the regular cardiac pump, SERCA2a, was preserved. However, the emergence of another pump, SERCA2b, was found after MI. The addition of SERCA2b to the existing SERCA2a expression increased the total pump density, which was consistent with an augmentation of SR-Ca-uptake in Pcells after MI. After MI, the peripheral region of Pcells seems to express the SERCA2b pump subisoform, which is consistent with larger pump density and intensification of SR-Ca uptake. A gradient in the density of SR-Ca pumps appears from the center to the periphery of Purkinje cells (Pcells) after MI. We found that this post-MI rearrangement could result from the peripheral expression of SERCA2b pump, which is absent in healthy hearts. The additional expression of SERCA2b to the existing cardiac pump SERCA2a, and possibly more efficient Ca-transport properties of SERCA2b, are consistent with the proarrhythmic elevation of SR-Ca uptake previously proposed in Pcells after MI.
In vivo inhibition of miR-125b-5p modulates monocyte trafficking through the CCR7 receptor and reduces atherosclerosis.
Mallén A, Rotllan N, Griñán R … +11 more , Varela C, Bertolino E, Paloschi V, Maegdefessel L, Escolà-Gil JC, Aran JM, Sbraga F, Blasco-Lucas A, Torras J, Navarro E, Hueso M
Am J Physiol Cell Physiol · 2026 Jan · PMID 41289597 · Publisher ↗
Monocytes and regulatory noncoding RNAs play a crucial role in the development of atherosclerosis (ATH). We have previously shown that miR-125b-5p was upregulated in aortic macrophages, and the aim of this paper was to f...
Monocytes and regulatory noncoding RNAs play a crucial role in the development of atherosclerosis (ATH). We have previously shown that miR-125b-5p was upregulated in aortic macrophages, and the aim of this paper was to further study the "in vivo" impact of miR-125b-5p in ATH progression. Eight-weeks-old mice, fed with a high-fat diet for 14 wk, were treated with a miR-125b-5p mimic, with its specific antagonist (antagomiR-125b), with a control scrambled sequence (control oligonucleotide SC) or with a control vehicle with phosphate-buffered saline (PBS) for 4 wk. Treatment with the miR-125b-5p mimic increased plaque sizes, macrophage infiltration, and NF-κB activation compared to PBS control, independently of cholesterol levels. In contrast, treatment with a specific antagomir produced opposite effects and increased the number of M2 macrophages. Finally, the miR-125b-5p mimic was found to reduce expression of the chemokine receptor CCR7 in the human monocyte cell line THP-1 cells, and the mouse macrophage-like cell line RAW264.7 cells, as well as in the aortas and livers of mice, whereas the antagomiR-125b increased CCR7 expression. Reduced CCR7 expression was also observed in the aorta of patients with coronary artery disease. miR-125b-5p mimic increased inflammation and ATH progression. Targeting miR-125b-5p with a specific antagomir reduced plaque size and macrophage infiltration and increased expression of the chemokine receptor CCR7. These results support a role for miR-125b-5p in the upregulation of CCR7 expression and monocyte trafficking, thus restricting vascular inflammation in ATH progression. Our study investigates the role of inflammation and monocyte trafficking in atherosclerosis (ATH). We show that miR-125b-5p increases plaque inflammation and downregulates CCR7. Targeting miR-125b-5p with a specific antagomir restores CCR7 expression, enhances macrophage migration, and reduces both the inflammation and plaque size. The miR-125b-5p/CCR7 axis in ATH progression was further validated in a cohort of patients, suggesting that modulating this pathway may offer a novel therapeutic strategy.
Noncoding RNA molecules mediating skeletal muscle mitochondrial function and their potential applications in exercise molecular physiology: a systematic review.
Chavez-Guevara IA, Vázquez-Lorente H, Herrera-Quintana L … +4 more , Rubio-Valles M, López LC, Plaza-Díaz J, Amaro-Gahete FJ
Am J Physiol Cell Physiol · 2026 Jan · PMID 41289594 · Publisher ↗
This systematic review investigates the role of noncoding RNAs (ncRNAs), including miRNAs, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and transfer RNAs, in regulating mitochondrial biogenesis, dynamics, oxi...
This systematic review investigates the role of noncoding RNAs (ncRNAs), including miRNAs, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and transfer RNAs, in regulating mitochondrial biogenesis, dynamics, oxidative phosphorylation, and mitophagy in skeletal muscle and the potential applications of these ncRNAs in exercise molecular physiology. We conducted a comprehensive search in PubMed, Scopus, and Web of Science databases, identifying 45 relevant studies out of 2,378 records. The main findings indicate that miRNAs such as miR-128, miR-133a, miR-696, and miR-499 are critical regulators of mitochondrial function. Moreover, lncRNAs (lncEDCH1 and lncRNA-H19) and circRNA (circ-PTPN4) significantly influence mitochondrial biogenesis and function. Exercise interventions were shown to modulate the expression of these ncRNAs, particularly miR-133a and miR-696, leading to enhanced mitochondrial biogenesis and function. The review highlights the potential of these ncRNAs as biomarkers and therapeutic targets for improving mitochondrial function and treating metabolic and mitochondrial disorders. Further research is needed to explore the muscle-specific and exercise-modality-specific effects of ncRNAs to develop personalized interventions. Understanding the complex regulatory mechanisms of ncRNAs in mitochondrial adaptations can pave the way for innovative therapeutic strategies in exercise molecular physiology and metabolic health.
Distinct roles of glycocalyx components in regulating endothelial functions in a perfused three-dimensional human endothelium-on-a-chip.
Tanawattanasuntorn T, Phungsom A, Muta K … +3 more , Lokakaew J, Chotiwan N, Ketsawatsomkron P
Am J Physiol Cell Physiol · 2026 Jan · PMID 41285157 · Publisher ↗
Increased degradation of the endothelial glycocalyx (EGX) is associated with cardiovascular disease. However, whether EGX impairment drives endothelial dysfunction or reflects disease severity remains unclear. Prior stud...
Increased degradation of the endothelial glycocalyx (EGX) is associated with cardiovascular disease. However, whether EGX impairment drives endothelial dysfunction or reflects disease severity remains unclear. Prior studies investigating EGX function primarily used two-dimensional (2-D) endothelial cell cultures, which poorly mimic the endothelial microenvironment, particularly lacking luminal shear flow. To address these limitations, we leveraged a three-dimensional (3-D) human endothelium-on-a-chip to examine the roles of EGX components, namely heparan sulfate (HS) and sialic acid (SA), in regulating vascular permeability and monocyte adhesion. EGX expression was markedly higher in perfused 3-D human umbilical vein endothelial cells (HUVECs) cultures than in 2-D cultures. In 3-D HUVECs, tumor necrosis factor-alpha, a disruptor of endothelial function, did not reduce EGX expression, whereas dengue nonstructural protein 1 downregulated EGX. In 3-D HUVECs, HS degradation by heparinase III significantly increased endothelial permeability to 70-kDa fluorescein isothiocyanate-dextran without inducing cytotoxicity, whereas SA cleavage by neuraminidase reduced vascular permeability. Interestingly, neither HS nor SA cleavage affected 3-D human coronary artery endothelial cells (HCAECs) permeability. However, neuraminidase treatment significantly increased monocyte adhesion in both 3-D HUVECs and HCAECs, an effect not observed in heparinase III-treated 3-D endothelium from either vessel bed. These findings demonstrate that HS and SA play distinct roles in regulating endothelial barrier function and vascular inflammation in 3-D human endothelium. Using a perfused 3-D human endothelium-on-a-chip, we investigated the endothelial glycocalyx (EGX) in vascular regulation. EGX degradation was linked to endothelial dysfunction induced by dengue NS1, but not by TNF-α. In HUVECs, heparan sulfate (HS) degradation increased permeability, whereas sialic acid (SA) cleavage had the opposite effect. SA degradation, but not HS, enhanced monocyte adhesion in HUVECs and human coronary ECs. This study highlights distinct, component-specific roles of HS and SA in regulating vascular function.
Adipose tissue releases nucleosides.
Zhang J, Le T, Ruiz-Torres V … +17 more , Cohen M, Paharkova V, Abt E, Alnajjar HS, Tan J, Rashid K, Jones AE, Ball AB, Divakaruni AS, Paszkiewicz RL, Bandaru P, Mack JJ, Ashby JW, Kim J, Li G, Radu CG, Mittelman SD
Am J Physiol Cell Physiol · 2026 Jan · PMID 41269663 · Full text
It remains unclear how excess adipose tissue in obesity leads to inflammation, insulin resistance, and other comorbidities. Extracellular nucleosides can induce inflammation through the activation of immune cell toll-lik...
It remains unclear how excess adipose tissue in obesity leads to inflammation, insulin resistance, and other comorbidities. Extracellular nucleosides can induce inflammation through the activation of immune cell toll-like and purinergic receptors. The present study quantified nucleoside release from adipocytes and adipose tissue. Cultured mouse adipocytes released many nucleosides used in RNA/DNA. Adipose tissue from obese mice released more nucleosides than that from control nonobese mice ex vivo and had higher interstitial fluid concentrations in vivo. Consistent with the mouse study, human adipose tissue also showed significant release of adenosine/deoxyadenosine, guanosine/deoxyguanosine, and uridine ex vivo. Adipocytes release nucleosides in part through the equilibrative nucleoside transporter 1, though other pathways also appear to contribute to extracellular nucleoside concentrations. Extracellular nucleosides induce adipose tissue expression of inflammatory cytokines , , and . These data uncover a previously unknown phenomenon of adipocyte release of nucleosides, which contribute to adipose tissue inflammation in obesity. Adipose tissue inflammation contributes to the morbidity and mortality of obesity. Adipocytes are known to release uridine and adenosine, but information on other nucleosides is lacking. As nucleosides can induce inflammation, we characterized nucleoside release from mouse and human adipose tissue. Adipose tissue released adenosine/deoxyadenosine, guanosine/deoxyguanosine, and uridine ex vivo. Nucleoside secretion was associated with adipose tissue expression of inflammatory cytokines. This represents a new mechanism by which obese adipose tissue may develop inflammation.
Cardiovascular-kidney-metabolic syndrome: prevalence, risks, disease trajectories, and early-stage management.
Gunnarsson S, Vito O, Unwin RJ
Am J Physiol Cell Physiol · 2026 Jan · PMID 41269265 · Publisher ↗
Cardiovascular-kidney-metabolic (CKM) syndrome affects approximately 90% of US adults, arising from the convergence of metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD). These conditio...
Cardiovascular-kidney-metabolic (CKM) syndrome affects approximately 90% of US adults, arising from the convergence of metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD). These conditions create self-reinforcing cycles of multiorgan damage, substantially increasing mortality risk. The American Heart Association's 2023 staging framework stratifies CKM from stage 0 (no risk factors) through stage 4 (clinical CVD with persistent metabolic dysfunction), informing stage-specific interventions. This review synthesizes current evidence on CKM epidemiology, pathophysiology, and disease trajectories. Population-based studies reveal that stage 2 (metabolic risk factors or early CKD) represents the most prevalent category, affecting nearly half of adults in Western cohorts. Progression occurs in 34% of stage 1 individuals, with each stage transition conferring an incrementally higher cardiovascular mortality risk. We describe the biological cascade linking dysfunctional adiposity, insulin resistance, and endothelial dysfunction to renal and cardiac damage, emphasizing bidirectional organ cross talk and the emerging role of hepatic pathology [metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH)] in CKM progression. Finally, we examine stage-specific interventions, from lifestyle modification and weight-loss pharmacotherapy (GLP-1 agonists and dual agonists) in early stages to multidrug cardiorenal protection [sodium-glucose cotransporter-2 (SGLT2) inhibitors and renin-angiotensin-aldosterone system (RAAS) blockade] in advanced disease. This framework allows targeted risk stratification and evidence-based management to interrupt CKM trajectories and improve population health outcomes.
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