American Journal Of Physiology. Cell Physiology[JOURNAL]
Sun
200 papers
A non-hydrolyzable candesartan cilexetil analog reveals synergistic activation as a tractable mechanism for TMEM175 modulation.
Li K, Le SD, Satpute Janve V … +6 more , Lazarenko RM, Romaine IM, Kim K, Sulikowski GA, Waterson AG, Denton JS
Am J Physiol Cell Physiol · 2026 Jul · PMID 42389983 · Publisher ↗
TMEM175 is a lysosomal cation channel essential for maintaining lysosomal pH and function. Dysregulation of TMEM175 has been implicated in Parkinson's disease, highlighting the need for small-molecule modulators to probe...
TMEM175 is a lysosomal cation channel essential for maintaining lysosomal pH and function. Dysregulation of TMEM175 has been implicated in Parkinson's disease, highlighting the need for small-molecule modulators to probe its physiological and therapeutic roles. We previously screened an FDA approved compound library for TMEM175 modulators using a plasma membrane overexpression system that enables functional analysis of channel activity. Here, we report the pharmacological characterization of the most potent hit, candesartan cilexetil. In fluorescence-based thallium flux, automated patch-clamp, and manual patch-clamp assays, candesartan cilexetil robustly activates TMEM175 with efficacy comparable to the reference activator DCPIB, whereas its hydrolyzed metabolite candesartan is inactive. Candesartan cilexetil is active only when applied to the extracellular (lysosome lumen-equivalent) side of the channel and is inactive from the cytosolic-facing side. To determine whether activation requires the intact prodrug, we generated analogs that modify or eliminate the cilexetil and ester functionalities. Structure-activity studies show that selected modifications of the cilexetil moiety reduce potency while preserving maximal efficacy, whereas more extensive modification markedly reduces intrinsic activity. , indicating that it is an essential pharmacophoric element rather than a simple membrane-permeating handle. Manual patch-clamp wash-off experiments further demonstrate direct, reversible activation without requiring membrane permeation or hydrolysis. Unexpectedly, the non-hydrolyzable analog VU0982645 exhibits minimal intrinsic activity yet produces robust synergistic activation with DCPIB. Together, these findings establish the cilexetil handle as a key pharmacophoric element and support synergistic modulation as a tractable mechanism for activating TMEM175.
Mitochondrial Calcium Transport in Amino Acid Metabolism: From nutritional responses to metabolic regulation.
Caetano MV, Ramos VM, Kowaltowski AJ
Am J Physiol Cell Physiol · 2026 Jul · PMID 42389940 · Publisher ↗
Mitochondrial calcium (Ca) transport is a central regulator of cellular metabolism, linking bioenergetics, signaling, and organelle function. While its role in controlling oxidative phosphorylation and cell fate is well...
Mitochondrial calcium (Ca) transport is a central regulator of cellular metabolism, linking bioenergetics, signaling, and organelle function. While its role in controlling oxidative phosphorylation and cell fate is well established, emerging evidence indicates that mitochondrial handling is also tightly connected to amino acid metabolism and nitrogen balance. In this review, we integrate classical and recent findings to examine how mitochondrial transporters, including the mitochondrial calcium uniporter complex (MCUc), Na/ exchangers, and H/Ca exchange systems, respond to nutritional cues and contribute to metabolic adaptation. We discuss how variations in amino acid availability and dietary protein intake may modulate the expression and activity of Ca transport machinery, and explore the emerging role of mitochondrial proteases in regulating transporter turnover and activity, highlighting unexplored questions and future prospects in the field. We discuss how mitochondrial Ca fluxes influence amino acid-sensitive processes including autophagy, mitochondrial morphology, and substrate utilization, while also potentially modulating the urea cycle through effects on key enzymes and metabolite transporters. Overall, we find that mitochondrial Ca transport is a dynamic interface between nutrient availability and metabolic regulation, with implications for physiology and metabolic disease, but significant gaps remain regarding specific mechanisms within the integration of Ca signaling with amino acid-sensing pathways.
N-linked glycosylation regulates SNAT2 trafficking and stability in pancreatic ductal adenocarcinoma cells.
Koe JC, Pashaoskooie K, Johal D … +3 more , Zhong YC, Wu C, Parker SJ
Am J Physiol Cell Physiol · 2026 Jun · PMID 42370970 · Publisher ↗
The sodium-dependent neutral amino acid transporter 2 (SNAT2) is a plasma membrane transporter that facilitates the uptake of small, aliphatic amino acids. Restricting SNAT2-mediated alanine uptake may be a promising the...
The sodium-dependent neutral amino acid transporter 2 (SNAT2) is a plasma membrane transporter that facilitates the uptake of small, aliphatic amino acids. Restricting SNAT2-mediated alanine uptake may be a promising therapeutic strategy for various diseases, including pancreatic ductal adenocarcinoma (PDAC). The post-translational mechanisms regulating the distribution of SNAT2 to intracellular membranes and its turnover remain uncharacterized in the context of PDAC and may be useful to devise future strategies to inhibit SNAT2 function. Human SNAT2 contains three conserved extracellular N-linked glycosylation moieties at N254, N258, and N274. A screen of SNAT2 expression across several human and mouse PDAC cell lines revealed that plasma membrane SNAT2 is exclusively modified by N-linked glycosylation. Preventing SNAT2 N-glycosylation using pharmacological inhibitors or mutagenesis abolished its glycosylation and attenuated its plasma membrane, but not lysosomal, localization. Further, overexpressing glycosylation-deficient SNAT2 in knockout cell lines fails to restore cell proliferative capacity relative to wild-type SNAT2, despite partially rescuing the metabolomic defect associated with SNAT2-deficiency. Using an inducible expression system, we also demonstrate that N-linked glycosylation-deficient SNAT2 mutants exhibit altered degradation kinetics but use similar pathways as wild-type SNAT2 to coordinate its turnover. Our results highlight the importance of N-linked glycosylation for regulating the stability and cell surface expression of nascent SNAT2 in PDAC cells.
Oxaloacetate Inhibition of Succinate Dehydrogenase: Mechanism and Physiological Implications.
Sivitz WI, Yu L
Am J Physiol Cell Physiol · 2026 Jun · PMID 42370956 · Publisher ↗
As has been known for many decades, oxaloacetate (OAA) is a very potent inhibitor of succinate dehydrogenase (SDH). However, the phenomenon has received little attention for several reasons to be discussed. Although the...
As has been known for many decades, oxaloacetate (OAA) is a very potent inhibitor of succinate dehydrogenase (SDH). However, the phenomenon has received little attention for several reasons to be discussed. Although the interaction between OAA and the structure of SDH has been scrutinized, there has been little attention to the mechanism underlying OAA inhibition of SDH in respiring mitochondria or to its functional implications. In recent years, we have used more advanced methodology to examine these issues. OAA is unstable and therefore very difficult to detect by mass spectroscopy. Hence, we used a novel NMR approach to assess OAA in mitochondria of muscle, brown adipose tissue, and liver under active respiratory conditions. We also used a modification of existing technology to assess mitochondrial respiration in states apart from the extremes of state 4 and state 3. We found strong evidence that mitochondrial OAA content and inhibition of SDH is dependent on inner mitochondrial membrane potential (ΔΨ) and the effects of ΔΨ on the NADH/NADM redox state. Further, we examined the effects of perturbed OAA content by deleting glutamic-oxaloacetic transaminase (GOT2) which metabolizes OAA and glutamate to aspartate and α-ketoglutarate. Such deletion enhanced mitochondrial OAA and impaired metabolism through SDH. Here we review historical and recent studies addressing OAA inhibition of SDH. We also discuss the possible physiological role of OAA/SDH interaction and whole-body consequences. Further, we describe novel methodology for detection of OAA and assessment of mitochondrial function under conditions of clamped mitochondrial inner membrane potential.
miR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle.
Yu X, Caria E, Guimarães DSPSF … +7 more , Jollet M, Rizo-Roca D, Marica AA, Mkrtchian S, Gómez-Galán M, Krook A, Pillon NJ
Am J Physiol Cell Physiol · 2026 Jun · PMID 42360291 · Publisher ↗
MicroRNAs (miRNAs) are critical regulators of skeletal muscle development and adaptation, orchestrating the balance between proliferation, differentiation, and tissue repair. Here, we identify miR-339-5p as a previously...
MicroRNAs (miRNAs) are critical regulators of skeletal muscle development and adaptation, orchestrating the balance between proliferation, differentiation, and tissue repair. Here, we identify miR-339-5p as a previously unrecognized, conserved regulator of skeletal muscle remodeling. Transcriptomic analysis from human, mouse, and rat studies revealed that miR-339-5p is consistently upregulated in skeletal muscle under conditions of stress or injury and declines during myogenic differentiation . Gain-of-function experiments demonstrated that miR-339-5p overexpression impairs expression of genes associated with myogenic differentiation and promotes expression of proliferative markers in both primary human myotubes and mouse C2C12 cells. Transcriptomic profiling confirmed widespread repression of pathways involved in cytoskeletal organization, myofibrillar assembly, and mitochondrial function. , electroporation-mediated overexpression of miR-339-5p in mouse altered regeneration-associated gene expression and increased the number of immature fibers, therefore modulating tissue remodeling during post-injury growth. Integrated analyses combining target prediction algorithms, differentiation-associated correlations, and overexpression datasets identified seven conserved high-confidence miR-339-5p targets, among which the autophagy-associated phosphatase emerged as the most consistently regulated candidate. Collectively, our data demonstrate that miR-339-5p functions as a conserved inhibitor of myogenic progression, linking injury-induced stress responses to delayed differentiation and altered muscle remodeling. These findings establish miR-339-5p as a potential therapeutic target in conditions characterized by impaired muscle regeneration or dysregulated tissue remodeling.
Impact of ΔF508 CFTR Mutation on Diaphragm Function During Acute Inflammation.
Ostadan F, Gusev E, Liang F … +3 more , Bautista De Sanctis J, Radzioch D, Petrof BJ
Am J Physiol Cell Physiol · 2026 Jun · PMID 42360227 · Publisher ↗
Cystic fibrosis (CF) is caused by CFTR mutations and associated with skeletal muscle dysfunction. Prior work showed exaggerated inflammatory activation of proteolysis pathways in diaphragms of CFTR-null mice. However, ef...
Cystic fibrosis (CF) is caused by CFTR mutations and associated with skeletal muscle dysfunction. Prior work showed exaggerated inflammatory activation of proteolysis pathways in diaphragms of CFTR-null mice. However, effects of the more clinically relevant ΔF508 (DF-CFTR) mutation on diaphragm function are unknown. Homozygous DF-CFTR mice (Cftr) and wild-type (WT) littermates received intraperitoneal PBS or LPS (5 mg/kg). After 24 h, we evaluated diaphragm mass and fiber types; expression (mRNA) of cytokines (IL1β, IL6), the unfolded protein response (UPR), and proteolysis (ubiquitin-proteasome, autophagy-lysosome); calpain activity; oxidative stress markers (malondialdehyde, 3-nitrotyrosine); and ex vivo muscle contractility. Oxidative stress markers were higher in DF-CFTR diaphragms at baseline and in response to LPS. Atrogin1 and autophagy markers (LC3B, Gabarapl1) were more strongly induced by LPS in DF-CFTR. Expression of cytokines, UPR, and other proteolysis pathways (Murf1, calpain) were equivalent. Diaphragm mass, fiber diameter and fiber type proportions did not differ between groups. Contractile function did not differ at baseline, but only DF-CFTR diaphragms showed reduced force production after LPS. During an acute inflammatory challenge, DF-CFTR diaphragms exhibit exaggerated oxidative stress and proteolysis signalling together with greater force loss. These findings support an increased vulnerability to diaphragm dysfunction linked to the DF-CFTR mutation.
Loss of lncRNA impairs neonatal cardiac regeneration.
Hilbold EA, Costa A, Cushman S … +7 more , Fuchs M, Jansen K, Selich A, Huang CK, Haubner BJ, Thum T, Bär C
Am J Physiol Cell Physiol · 2026 Jun · PMID 42345349 · Publisher ↗
Cardiac regeneration represents a major unmet goal in cardiovascular medicine. While adult mammalian hearts have very limited capacity to regenerate after injury, newborn mouse hearts can fully restore myocardial structu...
Cardiac regeneration represents a major unmet goal in cardiovascular medicine. While adult mammalian hearts have very limited capacity to regenerate after injury, newborn mouse hearts can fully restore myocardial structure and function following ischemic damage. This remarkable regenerative ability is rapidly lost within the first postnatal week, but the molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as important regulators of tissue repair and regeneration. Therefore, we aimed to identify lncRNAs involved in neonatal cardiac regeneration and to investigate the function of a candidate lncRNA in regenerating mouse hearts. RNA-sequencing of postnatal day 1 (P1) and P7 mouse hearts revealed approximately 700 significantly differentially expressed lncRNAs. Mapping three neonatal heart RNA-sequencing datasets identified the conserved lncRNA as a major nodal point. To assess its potential regenerative function, permanent left anterior descending artery (LAD) ligation surgeries were performed in P1 knockout (KO) and wild type (WT) mice. Myocardial infarction (MI) induction and cardiac function were evaluated by echocardiography. Hearts were harvested for molecular biological and histopathological analyses. Unlike H19WT mice, H19KO neonates failed to recover cardiac function after MI. While H19WT hearts showed no fibrotic scarring and complete cardiac regeneration, H19KO hearts exhibited increased collagen and expression one-week post-MI and exhibited fibrotic healing at one and two weeks post-MI. Additionally, H19KO mice displayed increased proliferation of non-cardiomyocytes and altered immune cells when compared to H19WT mice, indicating substantially impaired cardiac regeneration. In conclusion, is essential for complete cardiac regeneration after MI in neonatal mice.
Senescence as a regulatory mechanism in skeletal muscle repair in young mice.
Johnson AL, Bevington RT, Parise G
Am J Physiol Cell Physiol · 2026 Jun · PMID 42314772 · Publisher ↗
Senescence is broadly considered an age-related phenomenon; however, it also been implicated in normal tissue repair and wound healing. Skeletal muscle repair is a complex process that requires the coordination of severa...
Senescence is broadly considered an age-related phenomenon; however, it also been implicated in normal tissue repair and wound healing. Skeletal muscle repair is a complex process that requires the coordination of several different cell populations but the role of senescence in skeletal muscle repair has yet to be fully elucidated. We hypothesize that senescence serves as a control mechanism throughout the regenerative process and the removal of senescent cells through senolytics will negatively impact the repair process in young mice. Briefly, young mice were exposed to either (a) vehicle (VEH), receiving only a cardiotoxin (CTx) injection in one hindlimb or (b) 7 days of senolytic treatment (SEN) pre-CTx and 3x/week for 4 weeks post-CTx. Dasatinib + Quercetin (D+Q) was used to selectively eliminate senescent cells. There were no significant differences between groups in functional measures such as hindlimb grip strength and cross-sectional area. eMHC+ fibers remained elevated at D28 in the SEN group. Macrophage infiltration was twice as high in the SEN group compared to VEH at D7. Satellite cell quantity and fibrotic area were significantly increased at D14 in the SEN group compared to VEH. We conclude that reducing senescent cells during muscle repair in young mice significantly altered the kinetics of muscle repair. Therefore, senescent cells may act as a regulatory mechanism in skeletal muscle to orchestrate the activity of the different cell populations involved in repair and regeneration such as immune cells, satellite cells, and fibrotic cells.
Redox-sensitive GPCR signaling drives Gq-dependent Ca²⁺ mobilization and cytokine production in human bronchial epithelial cells.
Lapiro J, Srisomboon Y, Law K … +1 more , O'Grady SM
Am J Physiol Cell Physiol · 2026 Jun · PMID 42314770 · Publisher ↗
Organic dust (OD) from animal production facilities contains a complex mixture of microbial products, metabolites, and particulates that engage airway epithelial signaling pathways. Here we investigated the mechanisms by...
Organic dust (OD) from animal production facilities contains a complex mixture of microbial products, metabolites, and particulates that engage airway epithelial signaling pathways. Here we investigated the mechanisms by which OD extract (ODE) activates immune signaling pathways in human bronchial epithelial (hBE) cells. ODE rapidly stimulated reactive oxygen species (ROS) generation and a biphasic increase in intracellular Ca²⁺ concentration ([Ca²⁺]i), consisting of an early transient peak followed by a smaller sustained phase. Antioxidant scavenger pretreatment (glutathione, N-acetylcysteine) markedly attenuated both ROS production and Ca²⁺ mobilization, whereas induction of endogenous antioxidant defenses with bardoxolone abolished the response, indicating redox sensitivity. Pharmacologic inhibition of Gqα with YM-254890 suppressed both phases of the Ca²⁺ response, implicating Gq-coupled receptor activation. Consistent with an autocrine amplification mechanism, selective antagonists of histamine (H1), cysteinyl leukotriene (CysLT1 and CysLT2), leukotriene B4 (BLT1), and prostaglandin receptors (EP1) each reduced ODE-evoked Ca²⁺ mobilization. In parallel, inhibitors of histidine decarboxylase, 5-lipoxygenase, and cyclooxygenases (COX-1/COX-2) attenuated Ca2+ signaling, supporting rapid endogenous ligand production and secretion. Downstream of Ca²⁺ mobilization, ODE activated PKCα/β and PKCδ and induced robust transcription of proinflammatory cytokine and chemokine mRNAs (IL1β, IL6, IL8, IL33, TNFα) within 2 hours of exposure. ELISA confirmed increased secretion of IL-1β, IL-6, IL-8, and IL-33, with differential sensitivity to PKC isoforms and NF-κB inhibition. These findings identify a redox-sensitive GPCR network that amplifies Gq-dependent Ca²⁺ signaling in airway epithelial cells and provides a mechanistic framework for epithelial inflammatory activation following ROS-inducing environmental exposures.
High-fat, low-carb diet reduces tumor growth and induces liver metabolism remodeling in a breast cancer mouse model.
Charlot A, Bringolf A, Mallard J … +7 more , Jaulin A, Crouchet E, Duteil D, Alpy F, Tomasetto CL, Baumert T, Zoll J
Am J Physiol Cell Physiol · 2026 Jun · PMID 42302718 · Publisher ↗
Cancer cells require large quantities of glucose to ensure sufficient ATP production through glycolysis, and the liver may facilitate this glucose supply. A high-fat low-carbohydrate ketogenic diet (KD) could represent a...
Cancer cells require large quantities of glucose to ensure sufficient ATP production through glycolysis, and the liver may facilitate this glucose supply. A high-fat low-carbohydrate ketogenic diet (KD) could represent a strategy to reduce tumor growth. However, the molecular effects of carbohydrate restriction mediated by the KD and its hepatic impact remain poorly understood. To address this question, 6-week-old FVB/N-Tg(MMTV-PyVT)634Mul/J mice, which develop spontaneous mammary tumors, were fed a standard chow diet (SD group) or a KD diet (KD group) until reaching the age of 12 weeks. The effects of carbohydrate restriction were assessed by plasma analyses, as well as histological staining, RT-qPCR and Western Blotting in tumors and liver. We found that carbohydrate restriction reduced tumor growth by 46% and was associated with decreased expression of pro-tumorigenic factors (). Moreover, a decrease of metabolic enzymes () highlighted the lack of metabolic flexibility of the tumor cells and underscored their strong dependency on glucose. Conversely, the liver exhibited a strong adaptive response with enhanced ketogenesis and gluconeogenesis, evidenced by elevated blood glucose and upregulation of , and CREB. A high-fat, low-carbohydrate diet exerts a dual metabolic effect: it suppresses tumor progression through local metabolic reprogramming but simultaneously enhances hepatic glucose production. This highlights the pivotal role of systemic glucose availability in tumorigenesis and underscores the need to consider liver metabolism when designing dietary interventions for cancer therapy.
The spatiotemporal distribution of Foxi1-expressing pulmonary ionocytes in the mouse airways.
Villanueva S, Hernà Ndez-Rivas SN, Ermund A … +4 more , Dolan B, Hansson GC, Catalán MA, Flores CA
Am J Physiol Cell Physiol · 2026 Jun · PMID 42302716 · Publisher ↗
Pulmonary ionocytes are rare epithelial cell that bear the highest amount of mRNA for CFTR and whose function is necessary to regulate airway surface liquid homeostasis. Lineage induction is regulated by the transcriptio...
Pulmonary ionocytes are rare epithelial cell that bear the highest amount of mRNA for CFTR and whose function is necessary to regulate airway surface liquid homeostasis. Lineage induction is regulated by the transcription factor Foxi1, but the temporal and spatial localization of Foxi1 cells during airway development and the impact of CFTR mutations remain poorly understood. Here, we used immunofluorescence and RNAscope to detect Foxi1 cells throughout postnatal airway development in male and female mice, from neonatal stages to one year of age, including CftrΔF508 mutant animals in adult stage. Foxi1 cells were observed in higher density in the laryngeal subglottis region, decreasing towards the distal trachea, and principally located in the surface epithelium covering intercartilage zones. The Foxi1 cells were observed at postnatal day 7.5 and their appearance correlated to the development of submucosal glands. The distribution of these cells was not altered in the mutant mouse. These findings demonstrate that pulmonary ionocytes display a highly regionalized distribution pattern in the mouse airway and emerge during a defined postnatal developmental window associated with submucosal gland maturation. Their localization near submucosal gland openings in the mouse trachea and co-appearance during development suggests a potential role in regulating submucosal gland secretion and airway epithelial fluid homeostasis.
β₂‑Adrenergic Receptor Disruption Exacerbates Cardiac Injury and Fibroblast Activation in a Female Mouse Model of Takotsubo Cardiomyopathy.
Sanches B, Tupini F, Espanhol F … +9 more , Costa PAC, Nogueira GM, Pinheiro I, Souza-Neto F, Birbrair A, Guimarães PPG, Castor MGM, van Berlo JH, Guatimosim S
Am J Physiol Cell Physiol · 2026 Jun · PMID 42302406 · Publisher ↗
Takotsubo cardiomyopathy (TTC) is an acute stress‑induced cardiac syndrome that predominantly affects women and is driven by surges in catecholamines that excessively activate β‑adrenergic receptors (βARs). Although β₁AR...
Takotsubo cardiomyopathy (TTC) is an acute stress‑induced cardiac syndrome that predominantly affects women and is driven by surges in catecholamines that excessively activate β‑adrenergic receptors (βARs). Although β₁AR signaling mediates much of the injury, β₂ARs have recognized cytoprotective roles in other cardiac settings, yet their contribution to TTC‑associated remodeling remains unclear. To address this gap, we induced a TTC‑like phenotype in female wild‑type (WT) and β₂AR‑deficient (β2AR-/-) mice using a single high dose of isoproterenol (ISO). Following ISO injection, β2AR-/- mice treated with ISO exhibited exacerbated myocardial injury, characterized by greater hypertrophy, higher levels of apoptosis and necrosis compared with WT/ISO mice. This heightened injury was accompanied by a more robust inflammatory response, including increased inflammatory score, enhanced CD68⁺ macrophage infiltration, and marked recruitment of CCR2+MHC-IIlow monocytes. β₂AR-/-/ISO hearts also displayed more extensive interstitial fibrosis. Because fibrosis is a key driver of long-term functional decline, we isolated cardiac fibroblasts (CFs) and characterized their activation state. CFs from β2AR-/-/ISO hearts displayed a significantly higher percentage of α-SMA+ cells, increased collagen 3 and MMP-2 staining, along with upregulation of pro‑fibrotic genes (Col1a1, Col3a1 and Fap). Functionally, β₂AR-/-/ISO CFs exhibited an activated molecular signature enriched in cytokines and growth factors, and their conditioned media induced greater hypertrophy in neonatal cardiomyocytes, revealing a potent paracrine contribution to the remodeling process. These findings demonstrate that the female heart relies on β₂AR signaling to limit acute catecholamine‑induced injury, underscoring the potential of β₂AR-targeted interventions as therapeutic strategies in a Takotsubo‑like setting.
Elevated circulating bile acids alleviate acute pancreatitis by restoring mitochondrial function via acinar cell uptake.
Chen H, Fan Y, Huang N … +5 more , Wang Q, Wang B, Sun J, Zhang S, Li J
Am J Physiol Cell Physiol · 2026 Jun · PMID 42297571 · Publisher ↗
Acute pancreatitis (AP) is commonly linked to bile acid (BA) dyshomeostasis, yet the causal role of elevated circulating BAs and the functional significance of their uptake by pancreatic acinar cells in AP progression re...
Acute pancreatitis (AP) is commonly linked to bile acid (BA) dyshomeostasis, yet the causal role of elevated circulating BAs and the functional significance of their uptake by pancreatic acinar cells in AP progression remain unclear and controversial. A cerulein (CER)-induced rat model of AP was established, and pathological elevation of circulating BAs was achieved via intraperitoneal injection of sodium taurocholate (Na-TC, 50 mg/kg). Targeted metabolomics was used to quantify BA profiles in serum and pancreatic tissue. In vitro experiments on pancreatic acinar cells were conducted to assess BA uptake and its effects on cell survival. Mitochondrial function was evaluated via confocal microscopy, RNA-sequencing, and biochemical assays for membrane potential, adenosine triphosphate (ATP), and reactive oxygen species. Systemic Na‑TC administration increased serum and pancreatic total BA levels to concentrations comparable to biliary pancreatitis. Under these clinically relevant BA elevations, Na‑TC treatment significantly attenuated CER-induced pancreatic histopathological damage, inflammation, and oxidative stress. In vitro, Na‑TC (10-200 μM) reduced CER-induced acinar cell apoptosis/necrosis, but this protection was abrogated by the BA transporter inhibitor rifamycin sodium salt. RNA-sequencing and functional analyses revealed that BA uptake upregulated mitochondrial electron transport chain subunits, enhanced oxidative phosphorylation, restored mitochondrial membrane potential, and increased ATP production. These findings challenge the traditional view of circulating BA toxicity in AP and indicate that, at levels comparable to those observed in biliary pancreatitis, uptake of a certain amount of BAs by pancreatic acinar cells is beneficial rather than harmful.
Sexual dimorphic pattern of renal transporters and channels in spontaneously hypertensive rats.
Xiong LI, Finch AM, Ralph DL … +3 more , Anidu BS, Evans LC, McDonough AA
Am J Physiol Cell Physiol · 2026 Jun · PMID 42290570 · Publisher ↗
Male-female differences in the pattern of renal transporters have been reported for normotensive Sprague Dawley (SD) rats at baseline, when fed with high-salt diet, and when infused with angiotensin II which raises blood...
Male-female differences in the pattern of renal transporters have been reported for normotensive Sprague Dawley (SD) rats at baseline, when fed with high-salt diet, and when infused with angiotensin II which raises blood pressure (AngII-HTN). Whether these sexual dimorphic patterns are evident in spontaneously hypertensive rats (SHR), which exhibit elevated blood pressure from an early age, is unclear. In this study, we profile renal transporters and channels in 14-week-old male and female SHR using semi-quantitative immunoblots, then performed an integrative analysis comparing sexual dimorphisms in renal transporter abundance across conditions. We found that renal transporter profiles exhibit similar patterns of sex differences in hypertensive SHR as reported for normotensive SD, albeit responses are moderated in hypertensive SHR verses SD. Additionally, sex differences in transporter abundance are smaller in hypertensive SHR compared to sex differences in hypertensive AngII-HTN SD rats. In particular, along the distal nephron, male and female SHR exhibit greater abundance and activation of transporters and channels while proximal sodium transporter patterns are comparable to those in normotensive SD. These findings are consistent with previous physiological studies reporting that male SHR have blunted acute pressure-natriuresis responses and higher renin-angiotensin-aldosterone system activity. Moreover, comparison with normotensive SD rats fed high-salt diet suggests that renal transporter profiles in male and female SHR may be more a function of the pressure natriuresis response than salt overload.
Immediate icing disrupts the very early MCP-1/CCR2 recruitment window and delays muscle regeneration in rats.
Tamari A, Nitta E, Terada E … +7 more , Nagata I, Kawashima M, Sakuraya T, Sonomura T, Maeshige N, Nitta R, Arakawa T
Am J Physiol Cell Physiol · 2026 Jul · PMID 42284081 · Publisher ↗
Icing is a widely used initial intervention for skeletal muscle injury in sports settings. However, accumulating evidence suggests that icing impairs muscle regeneration, potentially via delayed monocyte/macrophage accum...
Icing is a widely used initial intervention for skeletal muscle injury in sports settings. However, accumulating evidence suggests that icing impairs muscle regeneration, potentially via delayed monocyte/macrophage accumulation. To elucidate the mechanisms underlying this icing-induced delay, we investigated whether icing modulates the monocyte chemoattractant protein 1 (MCP-1)/CC chemokine receptor 2 (CCR2) axis governing monocyte/macrophage recruitment. We comprehensively characterized inflammatory cell dynamics in a rodent crush-injury model using immunostaining and flow cytometry. During the very early phase (up to 5 h postinjury), neutrophils were the dominant inflammatory cell population within the lesion. Subsequently, MCP-1 concentrations and CCR2 monocytes/macrophages increased and became prominent within 24 h, suggesting that MCP-1/CCR2 signaling prominently contributes to monocyte/macrophage recruitment during this early phase. Consistently, CD68CD163 monocytes/macrophages, which exhibited the highest expression, predominated during the first 24 h. Immediate icing transiently suppressed MCP-1 production by neutrophils and monocytes/macrophages during this very early phase and was associated with attenuated subsequent recruitment of circulating monocytes. Consequently, monocyte/macrophage accumulation peaked at 48 h in the nonicing group but was delayed until 72 h in the immediate icing group. Notably, the late-icing model demonstrated that withholding icing during the early phase preserved normal monocyte/macrophage dynamics. Collectively, these results show that immediate icing disrupts the early MCP-1/CCR2-associated recruitment phase, likely by reducing the number of inflammatory cells and their production of MCP-1, thereby contributing to delayed monocyte/macrophage accumulation. These findings provide a crucial mechanistic basis for reconsidering and optimizing the timing of cryotherapy in clinical and sports settings. Icing after severe muscle injury provides analgesic benefits but delays monocyte/macrophage-mediated regeneration. We demonstrate that immediate icing disrupts early MCP-1 production by neutrophils and infiltrating monocytes/macrophages during the very early postinjury phase, which likely contributes to the subsequent attenuation of circulating monocyte recruitment. These findings provide clinical insight into the importance of optimizing the timing of icing and avoiding its use during the very early phase.
17β-Estradiol mitigates ovariectomy-induced defects in mitochondrial bioenergetics and redox balance after VML injury in female mice.
Heo J, Miller DL, Hoffman JR … +3 more , Groover RM, Greising SM, Call JA
Am J Physiol Cell Physiol · 2026 Jul · PMID 42275103 · Publisher ↗
Volumetric muscle loss (VML) is characterized by an irrecoverable loss of skeletal muscle mass, persistent functional deficits, and metabolic dysfunction. A disrupted cellular redox homeostasis is one attribute of this m...
Volumetric muscle loss (VML) is characterized by an irrecoverable loss of skeletal muscle mass, persistent functional deficits, and metabolic dysfunction. A disrupted cellular redox homeostasis is one attribute of this metabolic dysfunction and can lead to excessive reactive oxygen species (ROS) emissions and chronic oxidative stress. The primary objective of this study was to define the role of ovarian hormones, specifically 17β-estradiol (17β-E2), in driving mitochondrial bioenergetic and redox balance after VML injury. Female C57BL/6J mice were randomized into experimental and control groups (VML-sham OVX, VML-OVX, and VML-OVX-E2). A time course of ROS emissions and antioxidant buffering capacity (AoxBC) for VML-injured muscles was established across the first 60 days post injury (dpi) in ovary-intact females. Ovariectomy (OVX) was performed before injury to deplete ovarian hormones, and 17β-E2 was administered via continuous-release pellets to investigate the effects of hormone loss and repletion on ROS emissions and mitochondrial bioenergetics. The long-term effects of 17β-E2 were evaluated to determine whether restoring redox led to sustained redox balance in the long term. Transcriptomic analyses were conducted to explore molecular mechanisms of 17β-E2 benefit after VML. In intact females, ROS emissions were greater during the first 14-dpi, but AoxBC recovered more rapidly than previously observed in males. OVX exacerbated VML-induced metabolic dysfunction, resulting in less AoxBC, greater ROS emissions, and an early suppression of mitochondrial gene networks. 17β-E2 repletion attenuated ROS emissions and improved AoxBC at 7-dpi, and led to greater mitochondrial respiratory capacity, conductance, and bioenergetic efficiency out to 60-dpi. Chronic 17β-E2 depletion resulted in impaired glucose tolerance and greater adiposity, which were mitigated by 17β-E2 treatment. Transcriptomic analyses suggest that 17β-E2 contributes to resolving inflammation and enforcing a temporal decoupling of cellular expansion and mitochondrial maturation after VML injury. Female mice exhibit accelerated recovery of mitochondrial redox balance after volumetric muscle loss (VML) compared with males. This study demonstrates that 17β-estradiol (17β-E2) drives this resilience. Following VML, ovariectomy induced an early transcriptional arrest and asynchronous repair signaling. 17β-E2 replacement restored regenerative coordination by temporally decoupling early cellular expansion from mitochondrial biogenesis. This precise transcriptional regulation translated to long-term functional resilience, restoring mitochondrial bioenergetic efficiency and resolving oxidative stress.
Spatial expression of Myocardin protein in normal and disease states.
Doja J, Ishimwe N, Salem AR … +5 more , Slivano OJ, Zhang W, Kumar A, Long X, Miano JM
Am J Physiol Cell Physiol · 2026 Jun · PMID 42275094 · Publisher ↗
Vascular smooth muscle cell (VSMC) dedifferentiation, a phenomenon found in virtually all vascular diseases, is characterized by a transcriptional switch from a contractile to a phenotypically modulated state. Myocardin...
Vascular smooth muscle cell (VSMC) dedifferentiation, a phenomenon found in virtually all vascular diseases, is characterized by a transcriptional switch from a contractile to a phenotypically modulated state. Myocardin (MYOCD) is a smooth muscle cell-restricted co-activator that is necessary and sufficient for the differentiation of VSMC through the transcriptional activation of SMC-restricted cytoskeletal and contractile genes. Despite 25 years of research on MYOCD, the reliable expression of this protein continues to be poorly represented and understood. Accordingly, we generated a novel rat model carrying HA-tagged MYOCD to address pervasive disparities in the literature and elucidate MYOCD protein expression in vivo. Western blotting studies documented highest MYOCD protein expression in aorta, bladder and uterus with low or undetectable expression in all other tissues of the rat, including heart. Predictive modeling supports the C-terminus of MYOCD to be most immunoreactive where the HA tag and one other commercial immunogen reside. Of note, the latter immunogen was used to generate what appears to be the most trustworthy commercial antibody against MYOCD. In vitro transcription/translation and phosphatase treatment of ectopic and endogenous MYOCD protein reveal an intrinsically high molecular weight of MYOCD that has eluded prior reports. Importantly, we present the very first spatial expression profile of MYOCD protein in several mouse and rat tissues under baseline and vascular injury conditions. The results offer the SMC community new resources and insight into the reliable detection of MYOCD protein.
Transcriptomics reveal dysregulated genes during folic acid-induced acute injury and fibrosis in kidney and their attenuation by antioxidant -acetyl cysteine.
Kandel R, Roy P, Warraich I … +1 more , Singh KP
Am J Physiol Cell Physiol · 2026 Jul · PMID 42258342 · Publisher ↗
Renal fibrosis is a common pathogenic stage during the progression of acute injury to chronic kidney disease. Pathophysiological changes such as cellular remodeling, dysregulation of fibrogenic signaling, and extracellul...
Renal fibrosis is a common pathogenic stage during the progression of acute injury to chronic kidney disease. Pathophysiological changes such as cellular remodeling, dysregulation of fibrogenic signaling, and extracellular matrix contribute to kidney fibrosis. Oxidative stress is a common feature of nephrotoxicants. However, the target molecules and mechanistic pathways dysregulated by oxidative stress during acute injury and fibrosis in kidney are not fully understood. Therefore, the objective of this study was to identify the target molecules altered by oxidative stress and determine whether the antioxidant -acetyl cysteine can attenuate acute injury and long-term fibrosis in kidney. Both in vitro cell culture and in vivo mice models were used to address these questions. Multiple approaches, such as serum creatinine-albumin levels, histopathological, immunohistochemical, transcriptome analysis by RNA-sequencing, and target-specific expression of fibrogenic marker genes for cellular remodeling and fibrogenic signaling, were used to evaluate the role of oxidative stress in acute kidney injury (AKI) and kidney fibrosis. Novel findings of this study not only revealed that antioxidants can protect from acute injury and attenuate fibrosis in kidney by abrogating oxidative stress-induced cellular remodeling, activated profibrogenic genes, and signaling pathways, but also identified several target genes and signaling molecules, including those associated with kidney function and extracellular matrix regulation that were previously not known to be associated with AKI and kidney fibrosis. Findings of this study have significance in understanding the pathophysiological effects of nephrotoxicant-induced oxidative stress in kidney fibrosis and the roles of dysregulated genes in the etiology of this disease. Using both in vitro and in vivo models, this study suggests that antioxidants can protect from acute injury and attenuate fibrosis in kidney by abrogating oxidative stress-induced partial-EMT, activated profibrogenic genes, and signaling pathways including TGF-β, Wnt, and Notch signaling. Transcriptome analysis identified several previously unknown fibrosis-associated gene transcripts, and further investigation is needed to understand their precise roles in the etiology of this disease.
The extracellular matrix as a central regulator of aging and tissue adaptation to exercise.
Yeung CC, Nyström A
Am J Physiol Cell Physiol · 2026 Jul · PMID 42242898 · Publisher ↗
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Loss of ovarian hormones modulates sex-specific metabolic adaptations to volumetric muscle loss.
Bruzina AS, Juckett WT, Mozafari F … +3 more , Freeman CG, Call JA, Greising SM
Am J Physiol Cell Physiol · 2026 Jul · PMID 42242894 · Full text
Volumetric muscle loss (VML) results in persistent functional and metabolic deficits, yet the influence of biological sex and ovarian hormones on these outcomes remains poorly understood. Here, we examined male, intact f...
Volumetric muscle loss (VML) results in persistent functional and metabolic deficits, yet the influence of biological sex and ovarian hormones on these outcomes remains poorly understood. Here, we examined male, intact female, and ovariectomized (OVX) female mice at 12 wk following VML to determine how biological sex and the loss of ovarian hormones affect whole body metabolism, functional recovery, and tissue remodeling. Males postinjury relied on greater lipid oxidation postprandially, whereas females maintained robust carbohydrate oxidation and dynamic metabolic flexibility. The loss of ovarian hormones increased adiposity and impaired the sex-specific advantage in glucose responsiveness. Biological sex did not influence maximal isometric torque or contractile properties following VML, which accompanied similarities in mitochondrial content [i.e., citrate synthase, pyruvate dehydrogenase (PDH) activity]. Females exhibited greater complex II activity than males, whereas the loss of ovarian hormones decreased complex I and PDH activity. Despite comparable lipid accumulation in females with and without ovarian hormones, maximal isometric torque and contractile properties were impaired with the loss of ovarian hormones. Proximity to VML defect influenced lipid droplet proteins, specifically perilipin 2, though not affected by biological sex or ovarian hormone loss. Collectively, these findings indicate that sex-specific differences in substrate utilization and mitochondrial function, mediated in part by ovarian hormones, may underlie the divergent metabolic and functional trajectories following VML. These results highlight the importance of considering biological sex and ovarian hormones in preclinical studies and therapeutic strategies for regenerative interventions. This study combined ovariectomy and volumetric muscle loss injury model to investigate if ovarian hormones play a protective role in females during the sequelae of traumatic skeletal muscle injury. The loss of ovarian hormones induces whole body and cellular metabolic inflexibility and worsened functional recovery, identifying ovarian hormones as key regulators of VML-induced metabolic pathophysiology.
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