American Journal Of Physiology. Cell Physiology[JOURNAL]
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200 papers
Extracellular vesicles in exhaled breath condensate as emerging biomarkers in lung cancer.
Schmidt B, Tambon C, Cortopassi F … +2 more , Bokemeyer C, Saul MJ
Am J Physiol Cell Physiol · 2026 Jul · PMID 42233525 · Publisher ↗
Exhaled breath condensate (EBC) has emerged as a noninvasive liquid biopsy medium that captures aerosolized material from the respiratory tract and may provide insight into local lung biology. Within this matrix, extrace...
Exhaled breath condensate (EBC) has emerged as a noninvasive liquid biopsy medium that captures aerosolized material from the respiratory tract and may provide insight into local lung biology. Within this matrix, extracellular vesicles (EVs) can carry DNA, RNA, proteins, and lipids that reflect cellular origin and may report tumor-associated inflammation, airway remodeling, and microenvironmental changes. This review summarizes current evidence on the molecular composition, origin, and biogenesis of EVs detected in EBC, with emphasis on their potential for early lung cancer detection and longitudinal disease monitoring. Proteomic, transcriptomic, and genomic analyses have identified tumor-associated signatures, including cytokines, driver mutations, and epigenetic alterations, whereas lipidomic profiling may capture oxidative, inflammatory, and metabolic stress. Recent methodological advances in EV enrichment, microfluidics, single-vesicle analytics, and digital assays are improving the sensitivity of low-biomass EBC analyses. However, EBC-derived EV research remains technically challenging, and standardization of collection, EV isolation, molecular analysis, and reporting is essential. Artificial intelligence (AI) and machine learning (ML) may support integration of multiomic and clinical data, particularly when validated in prospective cohorts. Together, these developments position EBC-derived EVs as an emerging, patient-friendly, lung-proximal platform for biomarker discovery and future precision oncology applications, while underscoring the need for source-resolved validation and clinical translation studies.
Model epithelia from rumen organoids.
Khomeijani Farahani S, Liebe F, Manna S … +3 more , Weiß F, Stumpff F, Günzel D
Am J Physiol Cell Physiol · 2026 Jul · PMID 42227983 · Publisher ↗
The ruminal epithelium maintains livestock health by absorbing nutrients while maintaining a tight barrier between the lumen and the plasma space. This study demonstrates that rumen organoid-derived two-dimensional cultu...
The ruminal epithelium maintains livestock health by absorbing nutrients while maintaining a tight barrier between the lumen and the plasma space. This study demonstrates that rumen organoid-derived two-dimensional cultures approximate native tissue architecture and reach greater epithelial purity than primary cultures, particularly at later passages. For the initial transcriptomic and structural comparison, cells isolated from stratum basale by fractional trypsinization were used to generate model epithelia on cell culture inserts either from early-passage primary cultures (∼) or after organoid expansion (∼). Transcriptomic analysis was used to compare the primary culture inserts, the organoid-derived inserts, and the native tissues from which they had been derived. Although both cell culture models yielded epithelial-like growth with barrier formation (transepithelial electrical resistance > 400 Ω·cm), transcriptomic analysis revealed higher expression of fibroblast/mesenchymal stromal extracellular matrix (ECM) markers (, and ) in the inserts from the primary cultures. In addition, ECM-remodeling genes (, and ) were upregulated in primary culture inserts, suggesting increased tissue remodeling activity in conjunction with the expression of inflammatory mediators (, and ). Organoid-derived inserts showed less affected mitochondrial pathways [Cytochrome c oxidase (, ), , , and synthase genes] and ribosomal machinery ( and families), while maintaining epithelial purity with no detectable fibroblast or immune cell contamination. The expression of mRNA for numerous short-chain fatty acid transporters is confirmed, including MCT1, MCT4, DRA, PAT, SMCT1, anion exchanger 2, and . This study establishes organoids as a physiologically relevant model for studying rumen epithelial physiology. This study provides a comprehensive comparison between rumen tissue, primary culture, and organoid-derived cell culture inserts through detailed transcriptomic analysis. Cells grown over multiple passages in organoid culture differentiate into model epithelia that better approximate native tissue architecture and reach greater epithelial purity than primary cultures, particularly at later passages. The establishment of a sustainable organoid system with demonstrated molecular fidelity offers a valuable tool for studying rumen epithelial biology while reducing dependence on native tissue.
Correction for Xiong et al., volume 329, 2025, p. C1624-C1641.
Am J Physiol Cell Physiol · 2026 Jun · PMID 42223954 · Publisher ↗
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Allosteric potentiation of GABA receptor promotes survival and maturation of oligodendroglial cells in vitro via Ca/CaMK/AKT signaling pathway.
Cárdenas-Pérez AG, Ordaz RP, Cisneros-Mejorado AJ … +4 more , De la Monja MJ, Lailson M, Garay E, Arellano RO
Am J Physiol Cell Physiol · 2026 Jul · PMID 42213674 · Publisher ↗
Oligodendrocytes (OLs) and their precursor cells (OPCs) express specific receptors to GABA; however, the direct functional consequences of their activation remain not fully determined. It has been shown that expression o...
Oligodendrocytes (OLs) and their precursor cells (OPCs) express specific receptors to GABA; however, the direct functional consequences of their activation remain not fully determined. It has been shown that expression of functional γ-aminobutyric acid (GABA) type A receptors (GABARs) in OPCs and OLs is controlled by their contact with neurons. This suggests a role for GABAergic signaling in OPC-neuron dialogue establishment and their differentiation toward mature OLs. Here, OPCs (NG2) isolated from rat () optic nerve, maintained in vitro, were used to directly study the functional role of the GABA signal. The oligodendroglial GABAR activity was specifically enhanced using -butyl-β-carboline-3-carboxylate (β-CCB), a potent positive allosteric modulator (PAM). β-CCB effects were compared with those of ganaxolone (Gx), a synthetic allopregnanolone analog and unspecific PAM of GABARs. It was found that medium supplemented with one or both PAMs increased cell survival. This effect was eliminated in the presence of GABAR antagonists, such as gabazine or bicuculline, and it was dependent on intracellular Ca increase, which activated the AKT pathway through Ca-calmodulin-dependent kinases (CaMKs) acting upstream. In addition, a morphometric analysis showed that both PAMs promoted an increase in cellular complexity commonly associated with cell maturation, increasing the average cell area, number, and length of branches per cell, as well as the branch point number. These direct actions on NG2 cells would explain, at least in part, the positive effects that GABAergic signaling stimulation has on the myelination process in several experimental models, both in vitro and in vivo. Oligodendrocyte precursor cells express GABARs and release GABA into the extracellular milieu; however, direct consequences of receptor activation remain unclear. In this work, we demonstrate that positive allosteric modulation of the GABAR increases cell survival in vitro and promotes morphological changes associated with maturation. Both effects are generated by an increase in intracellular Ca and activation of Ca-CaM-dependent kinases signaling pathway, which subsequently promote AKT phosphorylation, triggering antiapoptotic signals.
Molecular signatures of lipid peroxidation in cardiomyopathy: unraveling oxidative mechanisms in cardiac cell dysfunction.
Hajri T, Fungwe TV
Am J Physiol Cell Physiol · 2026 Jul · PMID 42187051 · Publisher ↗
Cardiomyopathy, like other major cardiovascular diseases, is becoming increasingly prevalent and represents a growing public health challenge. Although both genetic and acquired factors contribute to its development, obe...
Cardiomyopathy, like other major cardiovascular diseases, is becoming increasingly prevalent and represents a growing public health challenge. Although both genetic and acquired factors contribute to its development, obesity and diabetes remain among the most significant modifiable risks. These conditions share key pathological features, including oxidative stress, inflammation, and elevated lipid peroxidation, all of which can disrupt cellular metabolism and function. Lipid oxidation products, irrespective of their origin, are characterized by increased oxygenation and hydrophilicity compared with their nonoxidized precursors. These properties confer high chemical reactivity toward cellular macromolecules, enabling the formation of covalent protein adducts that alter protein structure and function. Consequently, accumulation of excess lipid oxidation products initiates cytotoxic processes that disrupt mitochondrial homeostasis, potentially impairing cardiomyocyte function and contributing to broader cardiovascular pathology. Although lipid peroxidation frequently accompanies oxidative stress and inflammation, the mechanistic interrelationships among these processes in cardiomyopathy remain poorly defined. This narrative review synthesizes current evidence on the role of lipid peroxidation in cardiomyopathy, with particular emphasis on emerging insights into its interactions with oxidative stress and inflammatory pathways. Furthermore, it examines the impact of lipid oxidation products on mitochondrial dysfunction and cardiomyocyte viability, as well as their role in promoting cardiac fibroblast activation and myocardial fibrosis, all of which are key processes underlying the initiation and progression of cardiomyopathy.
Autonomic nervous system dysregulation as a driver of atrial fibrillation: pathways, modulators, and therapies.
Saha S, Thorpe J, Hill AP
Am J Physiol Cell Physiol · 2026 Jul · PMID 42172428 · Publisher ↗
Cardiac arrhythmias affect 1%-5% of the global population, with atrial fibrillation (AF) being the most common and clinically relevant. While AF is traditionally linked to electrical and structural remodeling of the atri...
Cardiac arrhythmias affect 1%-5% of the global population, with atrial fibrillation (AF) being the most common and clinically relevant. While AF is traditionally linked to electrical and structural remodeling of the atria, growing evidence highlights a critical yet underexplored contributor: dysfunction of the autonomic nervous system (ANS). The ANS regulates heart rate and rhythm through sympathetic and parasympathetic inputs, and its imbalance can initiate and sustain AF by promoting ectopic activity, shortening refractory periods, and enhancing reentry circuits. Autonomic dysregulation is further impacted by lifestyle and environmental influences. Excessive alcohol intake, chronic stress, sleep deprivation, and extreme physical exertion have all been shown to modulate autonomic activity and elevate the risk of AF. Additionally, social determinants such as socioeconomic status and healthcare access indirectly influence AF susceptibility through chronic activation of neurocardiac stress pathways. Mechanistically, emerging research implicates sympathetic hyperinnervation, neuroinflammation, and dysfunction of intrinsic cardiac ganglionated plexi as key contributors to arrhythmogenic remodeling. However, current animal models often fail to capture the complexity of human neuro-cardiac interactions due to species-specific differences in cardiac anatomy, innervation patterns, and immune responses. Human induced pluripotent stem cell (iPSC)-derived models offer an alternative, patient-specific platform to study ANS-driven mechanisms in AF. This review focuses on the role of the ANS in AF pathophysiology, examining the cellular and molecular mechanisms by which autonomic dysregulation promotes arrhythmia. We explore current therapeutic interventions of autonomic-driven AF and discuss the potential of new models to improve mechanistic insight and therapeutic development.
Moderate forced running exercise induces cartilage adaptation but exacerbates the molecular cartilage phenotype of type IX collagen knockout mice.
Weyers M, Li T, Dreiner M … +8 more , Mählich D, Lorenz C, de Roy L, Zigrino P, Han L, Brachvogel B, Zaucke F, Niehoff A
Am J Physiol Cell Physiol · 2026 Jun · PMID 42154996 · Publisher ↗
Mechanical loading is essential for the assembly and maintenance of the articular cartilage extracellular matrix (ECM), whereas alterations in ECM composition profoundly affect cartilage mechanics and function. Type IX c...
Mechanical loading is essential for the assembly and maintenance of the articular cartilage extracellular matrix (ECM), whereas alterations in ECM composition profoundly affect cartilage mechanics and function. Type IX collagen is a heterotrimeric fibril-associated collagen with interrupted triple helices (FACIT) that is covalently linked to type II collagen. It restricts lateral fibril growth and mediates interactions with other ECM components. Although type IX collagen expression is mechanosensitive and implicated in cartilage mechanotransduction, its precise functional role is not yet fully understood. This study investigated the combined effects of type IX collagen deficiency and moderate mechanical loading on articular and growth plate cartilage. Twelve-week-old female wild-type (WT) and mice were randomly assigned to control (CON) or forced running exercise (EXE) groups ( = 10-12 per group). EXE animals underwent treadmill training for 6 wk (20% incline, 18 m/min, 40 min/day, 5 days/wk). Type IX collagen deficiency resulted in an abnormal growth plate architecture and a reduction of all matrilins and cartilage oligomeric matrix protein (COMP) in articular cartilage. Moderate forced running exercise induced a significant increase ( < 0.05) in cartilage thickness at the lateral femoral condyle and altered ECM composition in mice, without evidence of cartilage degeneration. WT mice showed no comparable structural changes. In conclusion, moderate mechanical loading elicits localized, nondegenerative, structural and molecular adaptations in articular cartilage and only modestly modulates the cartilage phenotype associated with type IX collagen deficiency. These findings suggest a limited, yet context-dependent role of type IX collagen in cartilage mechanoadaptation. Moderate forced running exercise only slightly enhances the cartilage phenotype in aging female type IX collagen knockout mice and induces local, nondegenerative, structural and molecular adaptations in the articular cartilage ECM. Alterations in the cartilage phenotype do not depend on the age of the mice.
Disrupting the feed-forward cycle of RyR1 Ca leak and oxidative stress mitigates doxorubicin-induced skeletal myopathy.
Figueroa LC, Tammineni ER, Marco-Moreno P … +5 more , Vallejo-Illarramendi A, de Munain AL, Sagartzazu-Aizpurua M, Fill M, Manno C
Am J Physiol Cell Physiol · 2026 Jul · PMID 42154967 · Publisher ↗
Doxorubicin (DOX) is a highly effective and widely used chemotherapeutic agent used to treat various types of cancer. Unfortunately, DOX also has some undesirable and off-target effects, particularly debilitating muscle...
Doxorubicin (DOX) is a highly effective and widely used chemotherapeutic agent used to treat various types of cancer. Unfortunately, DOX also has some undesirable and off-target effects, particularly debilitating muscle weakness and fatigue. The mechanism behind this DOX-induced skeletal myotoxicity (DISM) remains unclear. Here, we show that acute DOX exposure, at clinically relevant concentrations, impairs isometric force production and accelerates fatigue in ex vivo murine flexor digitorum brevis (FDB) muscles. Mechanistically, we found that DOX increases the open probability of single RyR1 and disrupts calcium (Ca)-dependent inactivation (CDI). This results in a persistent sarcoplasmic reticulum (SR) Ca leak, elevated basal cytosolic Ca, and abnormal Ca release during action potentials. This abnormal intracellular Ca handling ultimately leads to increased cellular reactive oxygen species (ROS) production, which, in turn, exacerbates the functional instability of RyR1. Interestingly, the cytosolic basal Ca elevation precedes ROS generation, suggesting that it initiates a destructive cross talk between Ca dysregulation and oxidative stress. Furthermore, our study suggests that DOX disrupts the interaction between RyR1 and FKBP12 and that pharmacological stabilization of this complex with the novel triazole compounds MP-001 and MP-034 normalizes RyR1 function, Ca and ROS homeostasis, as well as muscle force and fatigue resistance. Our findings indicate that DISM is initiated by DOX destabilization of the RyR1-FKBP12 complex (abnormal SR Ca leak) and then exacerbated by the Ca-ROS vicious cycle. Limiting RyR1-mediated Ca leak with MP compounds represents a promising therapeutic strategy for anti-DISM, aiming to normalize muscle function in patients undergoing DOX chemotherapy. Doxorubicin (DOX), a widely used chemotherapy agent, causes off-target cytotoxicity in healthy cells and often leads to debilitating skeletal muscle fatigue and weakness. In this study, we examined the effects of DOX on excitation-contraction coupling. From single RyR1 channel properties to muscle force production, we identified the underlying mechanisms of muscle dysfunction. We also evaluated novel small molecules that normalize calcium release, highlighting potential therapeutic strategies to prevent DOX-induced skeletal myopathy (DISM).
Quantitative analysis of skeletal muscle contributions to ECF K homeostasis.
Youn JH, Gili S, Oh Y … +1 more , Higgins J
Am J Physiol Cell Physiol · 2026 Jun · PMID 42141909 · Full text
There is a division of labor between the kidney and extrarenal tissues in extracellular fluid (ECF) K homeostasis. The kidney modulates K excretion to match K intake, maintaining daily K balance, whereas extrarenal tissu...
There is a division of labor between the kidney and extrarenal tissues in extracellular fluid (ECF) K homeostasis. The kidney modulates K excretion to match K intake, maintaining daily K balance, whereas extrarenal tissues, primarily skeletal muscle, regulate K shifts between the ECF and intracellular fluid (ICF). Our recent stable isotope-based modeling study revealed that approximately 98% of the newly administered K tracer in resting rats was taken up by extrarenal tissues rather than excreted by the kidney within 5 h of administration, indicating that K exchange between the ECF and ICF pools occurs extremely rapidly. Emerging evidence also suggests that K influx into skeletal muscle varies linearly with physiological ECF K concentration ([K]). These characteristics, combined with its large ICF pool, give skeletal muscle both a high capacity for buffering ECF K and strong control efficiency in modulating K movements into and out of the ICF. The large K fluxes into skeletal muscle-and their dependence on ECF [K]-position skeletal muscle as a key regulator of ECF K homeostasis, alongside insulin, during acute dietary K intake and in the maintenance of postabsorptive ECF [K]. Furthermore, these features provide a mechanism by which insulin's actions on K fluxes are attenuated to prevent hypokalemia when a low-K diet is consumed. In this mini-review, we present quantitative analyses of skeletal muscle function in both acute and long-term K homeostasis under conditions of altered K intake, highlighting its role as a sensor, reservoir, and regulator of ECF [K].
Discovery of Kv3.1 channel inhibitors reveals VU0521426 as a state-dependent inactivator preferentially active against pathogenic gain-of-function mutants.
Chandrappa RU, Satpute Janve V, Days EL … +1 more , Denton JS
Am J Physiol Cell Physiol · 2026 Jun · PMID 42141755 · Full text
Kv3.1 voltage-gated potassium channels play a critical role in regulating neuronal excitability, and dysregulation driven by gain-of-function (GoF) mutations has been implicated in neurological disease. Although Kv3.1 po...
Kv3.1 voltage-gated potassium channels play a critical role in regulating neuronal excitability, and dysregulation driven by gain-of-function (GoF) mutations has been implicated in neurological disease. Although Kv3.1 potentiators have been at the forefront of drug development as a means to enhance neuronal firing, progress towards small-molecule Kv3.1 inhibitors has been limited. Here, we address this gap with the discovery of novel and structurally diverse Kv3.1 channel inhibitors identified through a high-throughput screening of over 50,000 compounds. Among these, VU426 emerged as the most potent compound with an IC of 4.3 μM. VU426 induces pronounced, state-dependent inhibition of outward K current with sustained depolarization, indicating stabilization of an inactivated channel conformation accessed from the open state. Functional characterization of four GoF mutations (V425M, M430I, V432M, and V434L) in the S6 pore lining domain demonstrated that VU426 exhibits 1.5- to 5-fold enhanced potency toward pathogenic GoF Kv3.1 mutants relative to wild-type channels. Automated patch clamp electrophysiological studies revealed that V432M and V434L mutations embedded deep in the S6 domain had the greatest sensitivity to VU426. Despite its potency, VU426 exhibited limited selectivity for Kv3.1 over related Kv channels. Together, these findings identify novel Kv3.1 inhibitors and highlight a pharmacological strategy for targeting clinically identified pathogenic variants. This study identifies the first structurally diverse collection of small-molecule inhibitors of Kv3.1 potassium channels, highlighting VU426 as a moderately potent, state-dependent inactivator. Notably, VU426 displays enhanced potency against multiple pathogenic gain-of-function Kv3.1 mutants, revealing a mechanism-based strategy for selectively targeting disease-associated channel variants.
Prenatal alcohol exposure-mediated Tet1 upregulation promotes DNA demethylation and elevated transcription at the miR-150 promoter.
Westenskow MR, Amdor AG, Gutierrez R … +2 more , Perales G, Gardiner AS
Am J Physiol Cell Physiol · 2026 Jul · PMID 42132410 · Publisher ↗
Prenatal alcohol exposure (PAE) has a strongly documented effect on the structure and function of brain vasculature including effects on brain microvascular endothelial cell (BMVEC) behavior, impacting appropriate angiog...
Prenatal alcohol exposure (PAE) has a strongly documented effect on the structure and function of brain vasculature including effects on brain microvascular endothelial cell (BMVEC) behavior, impacting appropriate angiogenesis in development. We previously demonstrated that the effects of PAE on BMVEC behavior are partially mediated by the upregulation of miR-150-5p, a negative regulator of angiogenesis. Here, we characterize transcriptional mechanisms by which alcohol exposure results in upregulated miR-150-5p in BMVECs. We provide evidence for increased transcription of the miR-150 gene with alcohol exposure; specifically, we show elevated pri-miR-150 abundance, an altered miR-150 promoter methylation landscape, and overall increased miR-150 promoter activity. The alterations to the methylation landscape prompted investigation of enzymes responsible for DNA methylation dynamics, and we show altered expression of DNA methyltransferase (Dnmt) genes and Tet methylcytosine dioxygenase 1 (Tet1). We also illuminate alterations to the activation of a wide array of transcription factors throughout the nucleus as well as altered association between transcription factors and the miR-150 promoter. Overall, we uncover a novel mechanism of gene expression dysregulation by alcohol exposure in BMVECs through differential transcription factor binding as a result of altered DNA methylation mediated primarily by elevated Tet1. Elevation of miR-150-5p in the brain vasculature during prenatal alcohol exposure occurs partially through increased transcription. This increase in transcription is mediated by the upregulation of Tet1; the elevated TET1 protein partially demethylates the miR-150 promoter into a 5hmC-rich sequence. Consequently, transcription factor binding to the promoter sequence is altered, resulting in increased miR-150 transcription.
The double-edged nature of β-catenin: from multicellular innovation to cancer vulnerability.
Garrido-Faúndez V, Castro-Pereira B, Weil-Echeverría C … +6 more , Sandoval-Baeza F, Sánchez-González VP, Robinson F, Ravasio A, Owen GI, Bertocchi C
Am J Physiol Cell Physiol · 2026 Jun · PMID 42126086 · Publisher ↗
β-Catenin embodies a fundamental paradox of multicellular life. The same molecular system that enabled the emergence of animal multicellularity by coupling cell-cell adhesion to gene regulation also creates a vulnerabili...
β-Catenin embodies a fundamental paradox of multicellular life. The same molecular system that enabled the emergence of animal multicellularity by coupling cell-cell adhesion to gene regulation also creates a vulnerability that can drive cancer when misregulated. As a central regulator of cell physiology, β-catenin integrates cell-cell adhesion, mechanotransduction, and gene expression to coordinate tissue architecture with transcriptional programs controlling proliferation, differentiation, and homeostasis. Phylogenomic analyses indicate that bona fide β-catenins form a metazoan-specific monophyletic clade derived from an ancestral armadillo-repeat scaffold. This conserved superhelical structure generates a single interaction groove that mediates mutually exclusive binding to E-cadherin, adenomatous polyposis coli (APC), and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors. Although this architecture enabled early metazoans to coordinate adhesion, signaling, and morphogenesis, it also introduced an intrinsic regulatory vulnerability. Mutations that disrupt β-catenin degradation stabilize the protein, uncoupling Wnt signaling from its normal regulatory constraints and driving persistent proliferative transcriptional programs. In parallel, emerging structural and biophysical studies reveal conformational plasticity and mechanosensitive properties that enable dynamic partitioning between adhesive and signaling pools. Disruption of these regulatory layers promotes tumor progression, metastasis, immune evasion, and therapy resistance, positioning β-catenin as both a central oncogenic node and a challenging therapeutic target. In this review, we integrate evolutionary, structural, and mechanobiological perspectives to illustrate how β-catenin exemplifies the double-edged nature of biological innovation, an ancient protein that enabled multicellular organization yet whose dysregulation underlies fundamental mechanisms of human cancer.
Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
Sztolsztener K, Mahendran T, Hood DA
Am J Physiol Cell Physiol · 2026 Jun · PMID 42126081 · Publisher ↗
Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), th...
Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), the integrated stress response (ISR), and antioxidant signaling. However, the mechanisms by which stressors regulate these retrograde responses remains uncharacterized in muscle. Thus, we examined the effect of mitochondrial stressors on the activation of these pathways in myoblasts and differentiated myotubes. Cells were exposed to either ) 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), a LonP1 protease inhibitor, ) gamitrinib-triphenylphosphonium (GTPP), an HSP90 chaperone inhibitor, ) carbonyl cyanide -chlorophenyl hydrazone (CCCP), an energetic uncoupler, or ) MitoBloCK-10 (MB-10), an inhibitor of protein import, and responses were compared with those induced by acute contractile activity (ACA). LonP1 inhibition activated activating transcription factor 4 (ATF4) and Nrf2 signaling, increased mitochondrial chaperones, and resulted in protein aggregation without elevating reactive oxygen species (ROS). In contrast, blocking HSP90 led to increases in mitochondrial ROS and activation of C/EBP homologous protein (CHOP), indicating protein homeostasis-related stress with limited antioxidant signaling. ACA elicited responses similar to the inhibition of LonP1, including the activation of ATF4 and Nrf2, increased UPRmt markers, and a redox balance. Although CCCP and MB-10 both impaired protein import, they activated distinct downstream responses. CCCP resulted in ISR activation, whereas MB-10 induced Nrf2-mediated antioxidant responses. Together, these findings show that the type of mitochondrial stress determines the direction of the retrograde signaling pathways between protein homeostasis and redox signaling in muscle cells, and they provide insights on how muscle coordinates signaling pathways as part of mitochondrial adaptations to contractile activity. This study investigates how different mitochondrial stressors activate distinct cellular signaling pathways in skeletal muscle cells. It examines how cells maintain a balance between protein homeostasis and oxidative stress when mitochondrial proteases, chaperones, and protein import are inhibited, and during acute contractile activity. The findings from this study provide key insights into mitochondrial protein homeostasis, stress signaling, and muscle adaptation mechanisms highlighting that downstream adaptive responses depend on the type of stressors.
Individual and combined effects of wheel running and ischemic preconditioning in protecting the rat heart from reperfusion injury.
Mishra J, Krier C, Cavanaugh M … +5 more , Asija A, Baker JE, Kwok WM, Camara AKS, Fitts RH
Am J Physiol Cell Physiol · 2026 Jun · PMID 42118006 · Publisher ↗
It is well known that exercise training (TRN) and ischemic preconditioning (IPC) reduce cardiomyocyte (CM) death following ischemia and reperfusion (IR), but it is unknown if protection can be elicited by moderate exerci...
It is well known that exercise training (TRN) and ischemic preconditioning (IPC) reduce cardiomyocyte (CM) death following ischemia and reperfusion (IR), but it is unknown if protection can be elicited by moderate exercise TRN or if the effects of TRN and IPC summate to generate greater protection than either protocol alone. To address these questions, we used wheel running, a moderate-intensity paradigm, to TRN male and female rats, and two IPC protocols. Hearts were studied ex vivo with regional ischemia (RI) produced by occluding the left anterior descending coronary artery for 30 min followed by 3 h reperfusion. IPC consisted of a 5-min period of global ischemia and either 5 (PC5) or 10 (PC10) min reperfusion before the initiation of index RI. We found that wheel running and PC10, but not PC5, reduced CM death compared with sedentary, with the TRN effect greater in males. TRN, but not IPC, showed functional protection by reducing the loss of left ventricular developed pressure. Surprisingly, the TRN and PC10 protection from cell death was not additive, suggesting that these modalities converge on the same pathway. We also showed that TRN significantly improved mitochondrial respiration and ΔΨ repolarization during oxidative phosphorylation after IR when compared with SED rats; the improved bioenergetics was associated with the increased prosurvival kinase, hexokinase II (HKII), translocation to mitochondria, which was mediated by increased total Akt and the phosphorylated Akt. We conclude that TRN-induced cardioprotection is mediated, in part, by preservation of mitochondrial bioenergetics likely mediated via the Akt-pAkt-HKII signaling pathway. Our study produced the novel findings that wheel running in rats, a form of moderate-intensity continuous training (MICT), can provide protection against IR injury as evidenced by a reduction in cardiomyocyte death following 3 h reperfusion and that the protection generated by MICT and IPC is not additive. Importantly, we demonstrate for the first time that MICT-induced cardioprotection is associated with preservations of mitochondrial bioenergetics likely by the Akt-pAkt-HKII signaling pathway.
Empagliflozin targets a renal neuro-epithelial-immune axis in heart failure.
Nogueira-Coelho J, Simonete LC, Ribeiro-Silva JC … +10 more , Jesus ÉF, Boaro A, Martins FL, Corrêa JWN, Ferreira-Santos L, Silva Dos Santos D, Antonio EL, Szawka RE, Serra AJ, Girardi ACC
Am J Physiol Cell Physiol · 2026 Jun · PMID 42117592 · Publisher ↗
Persistent neurohormonal activation drives maladaptive remodeling and disease progression in heart failure (HF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors confer robust renoprotective effects in HF, but whether t...
Persistent neurohormonal activation drives maladaptive remodeling and disease progression in heart failure (HF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors confer robust renoprotective effects in HF, but whether these effects involve modulation of renal neurohormonal activity remains unclear. We tested the hypothesis that SGLT2 inhibitor-mediated renoprotection in HF is associated with attenuation of excessive renal neurohormonal activation. Male rats with myocardial infarction-induced HF and sham controls were treated with standard chow or empagliflozin (EMPA, 300 mg/kg) for 4 wk. Parallel in vitro studies using THP-1 macrophages (a human acute monocytic leukemia cell line) and HK-2 proximal tubule cells evaluated the direct effects of EMPA and/or norepinephrine (NE)-dependent tubular inflammatory signaling. HF was associated with higher renal cortical renin expression and angiotensin II levels, which were not modified by EMPA. In contrast, EMPA normalized the elevated urinary norepinephrine (NE) excretion and renal cortical NE content observed in HF. Given the inflammatory role of sympathetic hyperactivity, we assessed renal macrophage activation. EMPA-treated HF rats showed reduced expression of proinflammatory markers [tumor necrosis factor (), C-C motif chemokine receptor 2 (), nitric oxide synthase 2 (), and Interleukin-6 ()] and increased expression of markers associated with a reparative macrophage profile [Arginase 1 (), Mannose receptor C-type 1 (), and ()], supported by higher CD206 macrophages in kidney sections. Although EMPA did not directly alter THP-1 macrophage activation, it significantly reduced NE-induced SGLT2 expression and interleukin-6 (IL-6) release by HK-2 human proximal tubule epithelial cells. These findings support a model in which SGLT2 inhibitors confer renoprotection in HF by suppressing renal sympathetic hyperactivity, independently of the intrarenal renin-angiotensin system, thereby disrupting a maladaptive renal neuro-epithelial-immune axis and promoting a reparative macrophage phenotype. Our findings identify a renal neuro-epithelial-immune axis that may, at least in part, underlie empagliflozin-mediated renoprotection in heart failure. Empagliflozin selectively attenuated surrogate markers of renal sympathetic activity, lowering cortical and urinary norepinephrine without detectable changes in intrarenal renin-angiotensin system components. These changes were accompanied by a shift toward a reparative macrophage phenotype. In vitro, empagliflozin blocked norepinephrine-induced SGLT2 upregulation and IL-6 production, linking sympathetic signaling to tubular inflammation.
Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.
Ducharme JB, Ebert SM, Cameron ME … +7 more , Schonk MM, Callaway CS, D'Lugos AC, Talley JJ, Judge SM, Adams CM, Judge AR
Am J Physiol Cell Physiol · 2026 Jun · PMID 42117587 · Full text
Skeletal muscle atrophy is a devastating and defining feature of cancer cachexia that reduces quality of life, treatment tolerance, and survival, but cannot be prevented or reversed by current management strategies. Urso...
Skeletal muscle atrophy is a devastating and defining feature of cancer cachexia that reduces quality of life, treatment tolerance, and survival, but cannot be prevented or reversed by current management strategies. Ursolic acid is a natural dietary compound that has been shown to inhibit atrophy-associated changes in skeletal muscle mRNA expression in rodents and dogs, leading to beneficial changes in skeletal muscle structure and function. We hypothesized that dietary supplementation with ursolic acid might help support skeletal muscle mass and function during cancer. To test this hypothesis, we investigated ursolic acid's effects in five in vivo mouse models of cancer cachexia that are driven by pancreatic, colon, and lung cancer cells of mouse and human origin. We found that dietary supplementation with ursolic acid has broad-spectrum effects toward cancer-induced skeletal muscle atrophy, significantly preserving muscle mass in all five cancer cachexia models. Ursolic acid's positive effects on muscle mass and muscle fiber size led to significant improvements in grip strength and muscle tetanic force, persisted in the presence of chemotherapy, and were not associated with discernible changes in food intake or tumor growth. Ursolic acid appeared to generate its beneficial effects in skeletal muscle by acting directly on muscle cells, inhibiting catabolic effects of tumor-derived secreted factors, and inhibiting >90% of cancer-induced changes in skeletal muscle mRNA expression. These results strongly nominate ursolic acid as a promising potential nutritional approach for supporting muscle mass and function in individuals with cancer. Cancer-induced muscle wasting affects many people with cancer, reducing treatment tolerance and survival. We identified a natural dietary compound, ursolic acid, that attenuates muscle atrophy across five preclinical cancer models spanning pancreatic, colon, and lung cancer. Ursolic acid inhibits cancer-induced changes in muscle mRNA expression, preserves muscle strength, and remains protective during chemotherapy, without affecting food intake or tumor burden. These results identify ursolic acid as a promising, translatable dietary supplement for supportive cancer care.
Fluid shear regulation of local Ca transients in right and left rat atrial myocytes under normal and increased beating rate.
Kim JC, Luong KP, Woo SH
Am J Physiol Cell Physiol · 2026 Jun · PMID 42102391 · Publisher ↗
During volume increase or hemodynamic disturbances in the atrium, fluid shear and beating rate often increase. Shear stress induces Ca waves in resting atrial myocytes. Here, we examined whether shear stress alters local...
During volume increase or hemodynamic disturbances in the atrium, fluid shear and beating rate often increase. Shear stress induces Ca waves in resting atrial myocytes. Here, we examined whether shear stress alters local Ca signaling and how such shear adaptation changes with increased beating frequency in right atrial (RA) and left atrial (LA) myocytes. Using two-dimensional confocal Ca imaging in combination with micropuffing, we examined the spatiotemporal properties of junctional (peripheral) and nonjunctional (central) Ca signals in field-stimulated rat atrial myocytes. Shear stress (∼16 dyn/cm) immediately enhanced Ca transients, with a larger effect in the center, followed by their inhibition. During the early stimulatory phase only, Ca release and decay were prolonged, with greater lengthening in the periphery. Whereas no difference was observed between RA and LA shear responses at 1 Hz, larger stimulatory effects were observed in RA myocytes than LA myocytes at 3 Hz, with no late inhibition. At 3 Hz, only RA myocytes showed early shear-induced prolongation of Ca release in the periphery. Sarcoplasmic reticulum (SR) Ca contents were similarly reduced by prolonged shear in both sides at 1- and 3-Hz. Increased frequency caused attenuations in Ca transients and peripheral SR Ca content in LA, but not RA, myocytes under control conditions. Our data suggest that shear stress transiently enhances central Ca release during depolarization via prolonged peripheral release but later suppresses it, and that early shear-mediated Ca release stimulation deteriorates more readily in LA myocytes at increased frequencies, partly due to a reduced peripheral store. We demonstrated, for the first time, that shear stress immediately enhances central Ca release by prolonging peripheral release during depolarization but suppresses it when sustained. Under increased beating rates, early shear-Ca adaptation deteriorates more readily in left than right atrial myocytes due to reduced peripheral Ca store. Our data provide a cellular basis for atrial volume- or impinging flow-dependent acute positive inotropy and frequency-dependent differences in its efficiency between right and left atrial myocytes.
The role of glycolysis in inflammation.
Dehantschutter ET, Taylor CT
Am J Physiol Cell Physiol · 2026 Jun · PMID 42102390 · Publisher ↗
A characteristic feature of inflamed tissue is hypoxia, which arises from elevated oxygen consumption and impaired perfusion. Inflammation is accompanied by metabolic reprogramming enabling immune and nonimmune cells to...
A characteristic feature of inflamed tissue is hypoxia, which arises from elevated oxygen consumption and impaired perfusion. Inflammation is accompanied by metabolic reprogramming enabling immune and nonimmune cells to meet increased bioenergetic and biosynthetic demands. Glycolysis is among the most ancient and fundamental metabolic pathways in biology. Hypoxia reduces mitochondrial oxidative phosphorylation, driving cells toward a reliance on glycolysis to sustain ATP production. This requires an increase in flux through the glycolytic pathway, which is mediated through rapid allosteric regulation of glycolytic enzymes, transcriptional upregulation of glucose transporters and glycolytic enzymes, and the formation of glycolytic enzyme complexes. In immune cells such as macrophages, neutrophils, and lymphocytes, enhanced glycolytic flux determines effector functions, including, but not limited to, cytokine production, phagocytosis, migration, and antimicrobial activity, as well as maintaining bioenergetic homeostasis. Similarly, nonimmune cells within inflamed tissues, including epithelial cells and stromal cells, utilize glycolysis to influence barrier function, tissue remodeling, and inflammation. In this review, we summarize our current understanding of how hypoxia drives glycolytic reprogramming during inflammation, examine the cell-type-specific impact of this, and discuss the therapeutic potential of targeting glycolytic pathways for inflammatory diseases.
Rethinking holocrine secretion: functional logic in lipid-producing epithelia.
Schneider MR
Am J Physiol Cell Physiol · 2026 Jun · PMID 42102388 · Publisher ↗
Holocrine secretion is typically described as an exception among glandular strategies, distinguished by cell disintegration and release of cellular fragments rather than vesicular contents. Yet this description treats ho...
Holocrine secretion is typically described as an exception among glandular strategies, distinguished by cell disintegration and release of cellular fragments rather than vesicular contents. Yet this description treats holocrine glands primarily as anatomical curiosities and leaves their underlying biological logic largely unexplored. Here, we propose that holocrine secretion can instead be understood as a differentiation program that couples lipid accumulation, terminal differentiation, and cell elimination. This design supports surface barrier function and points toward differentiation-based approaches for controlled epithelial cell removal.
Publisher's note.
Am J Physiol Cell Physiol · 2026 May · PMID 42090302 · Publisher ↗
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