American Journal Of Physiology. Cell Physiology[JOURNAL]
Sun
200 papers
Role of persistent necroinflammation in chronic tissue remodeling and organ fibrosis.
More SA, Ghosh A, Kulkarni OP … +1 more , Mulay SR
Am J Physiol Cell Physiol · 2026 Jan · PMID 41171080 · Publisher ↗
Persistent necroinflammation is a continuous feedback loop between the regulated necrotic cell death and the sustained immune system activation. It has been increasingly recognized as a key driver of chronic tissue remod...
Persistent necroinflammation is a continuous feedback loop between the regulated necrotic cell death and the sustained immune system activation. It has been increasingly recognized as a key driver of chronic tissue remodeling and fibrosis. Necrosis, unlike apoptosis, is a lytic and immunogenic form of cell death that releases danger-associated molecular patterns (DAMPs) and alarmins, which activate inflammatory pathways including the NOD-like receptor protein 3 (NLRP3) inflammasome. This sustained inflammatory environment promotes pathological remodeling and impairs tissue regeneration. This review elucidates the mechanistic framework of necroinflammation involving key molecular players such as receptor-interacting protein kinases (RIPK) 1, RIPK3, mixed lineage kinase domain-like protein (MLKL), NLRP3, calcium/calmodulin-dependent protein kinase II (CaMKII), gasdermin (GSDM), glutathione peroxidase-4 (GPX-4), acyl-CoA synthetase long-chain family member 4 (ACSL4), ferroptosis suppressor protein 1 (FSP1), and their role in fibrotic pathologies across kidneys, heart, liver, lungs, and brain. We emphasize how these signaling pathways further augment transforming growth factor-beta (TGF-β) signaling, thereby contributing to tissue fibrosis in chronic disease conditions. We also highlight recent advances in targeting these necroinflammatory mediators, especially inhibitors of these pathways, as promising antifibrotic therapeutic strategies. We emphasize the urgent need for further research to deepen our understanding of the temporal and spatial dynamics of necroinflammatory signaling and to develop organ-specific, targeted interventions against fibrosis. This will provide a robust foundation for translational research to exploit these pathways in clinical settings to mitigate chronic inflammatory diseases and their fibrotic consequences across multiple organ systems.
Endothelial protective effects of ferulic acid in preeclampsia treatment.
Zhang X, Zhao X, Wu L … +6 more , Li F, Xu M, Pan Y, Lv T, Yang K, Li R
Am J Physiol Cell Physiol · 2025 Dec · PMID 41165539 · Publisher ↗
Preeclampsia (PE) is a complex gestational disorder marked by vascular abnormalities and elevated blood pressure yet remains without widely effective treatments. This study investigates the efficacy of ferulic acid (FA)...
Preeclampsia (PE) is a complex gestational disorder marked by vascular abnormalities and elevated blood pressure yet remains without widely effective treatments. This study investigates the efficacy of ferulic acid (FA) in alleviating PE symptoms by targeting the signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor (VEGF) signaling axis to enhance endothelial integrity and reduce inflammation. An N-nitro-l-arginine methyl ester hydrochloride (l-NAME)-induced PE mouse model was used, with FA administration to pregnant mice to assess therapeutic effects on key outcomes such as blood pressure, proteinuria, and placental function. Single-cell RNA sequencing (scRNA-seq) and molecular assays were conducted to examine FA's impact on endothelial cell balance, inflammation, and pathway-specific activity. The results showed that FA treatment significantly reduced hypertension, proteinuria, and inflammation, while improving endothelial cell balance in PE mice. In addition, inhibition of STAT3 phosphorylation by FA enhanced endothelial barrier function, stabilized vascular integrity, and supported improved fetal development outcomes. Overall, these findings demonstrate the protective effects of FA in PE by alleviating endothelial impairment and dampening inflammatory activity, offering a promising strategy to improve maternal and fetal health in PE, with implications for managing pregnancy-related vascular dysfunctions. Our study investigates ferulic acid (FA) as a potential therapeutic intervention for preeclampsia (PE), a severe pregnancy complication with limited treatment options. By targeting the STAT3/VEGF signaling pathway, FA demonstrated significant reductions in hypertension, inflammation, and improved endothelial cell balance in PE mice. These results highlight FA's promise in enhancing maternal and fetal health by addressing endothelial dysfunction, suggesting its potential for broader applications in managing pregnancy-related vascular dysfunctions.
From gut to blood: barrier dysfunction as a driver of systemic low-grade inflammation in cardiometabolic disease.
Yang-Jensen SK, Nägele NS, Jensen BAH
Am J Physiol Cell Physiol · 2025 Dec · PMID 41138203 · Publisher ↗
Chronic, low-grade inflammation is increasingly recognized as a fundamental driver of noncommunicable diseases-including obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and neurodegeneration-ye...
Chronic, low-grade inflammation is increasingly recognized as a fundamental driver of noncommunicable diseases-including obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and neurodegeneration-yet the initiating events remain incompletely understood. Accumulating evidence implicates gut barrier dysfunction and bacterial translocation as pivotal mechanisms linking environmental and metabolic stressors to systemic inflammation. Mechanistically, obesity-associated depletion of typically beneficial taxa (e.g., , , ) and enrichment of proinflammatory reduce expression of tight junction proteins-including, occludin, claudins, and zonula occludens-1 (ZO-1)-and increase the vascular permeability marker, plasmalemma vesicle-associated protein (PV-1). Combined with diminished secretion of host defense peptides (e.g., Reg3γ, lysozyme) and mucus thinning, these changes facilitate LPS-driven activation of Toll-like receptor (TLR)4 and downstream cytokines. We integrate preclinical and clinical data demonstrating how these processes propagate systemic inflammation via the gut-liver and gut-vascular axes, contributing to MASLD, insulin resistance, and vascular dysfunction. Finally, we highlight emerging interventions aimed at restoring barrier integrity-ranging from short-chain fatty acid (SCFA) supplementation and Glucagon-like peptide-2 (GLP-2) receptor agonists to host defense peptide-based therapies-and discuss methodological advances for assessing gut permeability in vivo. Understanding the gut as a dynamic interface between host and environment, and its crucial role in mediating inflammation, will be pivotal for the development of effective interventions targeting the global epidemic of obesity-related disease.
Incorporation of gas/liquid equilibration control into a perifusion system to measure tissue-specific O concentration dependency of O consumption rate.
Kamat V, Bao K, Grumbine MK … +9 more , Tsumura L, Hermanson JC, Kramlich J, Pyle L, Lim R, Chao JR, Hass D, Hurley JB, Sweet IR
Am J Physiol Cell Physiol · 2025 Dec · PMID 41138202 · Publisher ↗
Oxygen (O) regulates a multitude of cell functions, and many pathological states are linked to its delivery. We present an automated system for implementing rapid changes in dissolved gas composition in the inflow of a p...
Oxygen (O) regulates a multitude of cell functions, and many pathological states are linked to its delivery. We present an automated system for implementing rapid changes in dissolved gas composition in the inflow of a perifusion system that facilitates multiple assessments of tissue function. Features of the system include the ability to assess the effects of changes in both aqueous and dissolved components of the inflow media, and to collect fractions while measuring O consumption rate (OCR) (in the face of changing dissolved O), facilitating the subsequent measurement of multiple classes of secreted compounds including metabolites, hormones, neurotransmitters, cell signals, and cytokines. We quantified OCR and lactate secretion rate (LSR) from retinal pigment epithelial (RPE) and INS-1 cells, and from primary tissues (retina, liver, and islets). Higher concentrations of extracellular O were required for tissues than cells monolayers. Consistent with this observation, we found that OCR was not maximal at 21% O for any tissue type we tested. That suggests 21% is too low to adequately provide O for tissues in vitro. However, we found that at high levels of O, OCR in some tissues/cells rapidly decrease. LSR was reciprocally regulated relative to the O dependency of OCR, except in tissue where high O inhibits OCR. In summary, we describe a system that can control the concentration of extracellular O and other gases. This instrument will allow researchers to investigate rapid effects of dissolved O on metabolic activities of tissues and cells at O concentrations optimal for the biological specimen. Oxygen regulates a multitude of cell functions, and many diseases are linked to its delivery. In vitro experiments are critical for elucidating intracellular mechanisms. Whereas standard cell culture incubators allow exposure to varying oxygen concentrations over hours and days, systems enabling rapid and precise control of dissolved oxygen are not available. We present a system for implementing rapid changes in dissolved gas composition with a perifusion system that facilitates multiple assessments of tissue function.
Decoding fibrosis in nonresolvable COVID-19: a role for myeloid-specific HIF1A deletion.
Philip K, Thompson HP, Collum SD … +8 more , Lefebvre I, Akkanti B, Zhao B, Hussain R, Patel M, Blackburn MR, Mills TW, Karmouty-Quintana H
Am J Physiol Cell Physiol · 2025 Dec · PMID 41138198 · Publisher ↗
A complication of viral lung infections is the development of pulmonary fibrosis. This phenomenon is most evident in patients with COVID-19, where in its most aggressive form patients developed nonresolvable (NR) COVID-1...
A complication of viral lung infections is the development of pulmonary fibrosis. This phenomenon is most evident in patients with COVID-19, where in its most aggressive form patients developed nonresolvable (NR) COVID-19 requiring lung transplantation. NR-COVID-19 was characterized by the presentation of a fulminant fibrotic lung injury that progressed rapidly, even in patients with limited comorbidities. However, the mechanisms that led to this rapidly progressing form of fibrosis are not fully understood. A common clinical manifestation in the most severe cases of COVID-19 was the presence of "silent" hypoxemia. Thus, we hypothesized that a dysfunctional hypoxic response may result in exacerbated lung injury seen in patients with severe forms of COVID-19. Our results demonstrate that despite increased expression of hypoxia-inducible factor 1A (HIF1A) and its downstream mediator adenosine A receptor (ADORA2B), reduced macrophage HIF1A was observed in patients with severe COVID-19, including NR-COVID-19. Utilizing mice lacking HIF1A in myeloid cells using the lysozyme M Cre promoter, we demonstrate that these mice present with increased lung inflammation and pulmonary fibrosis following chronic low-dose bleomycin treatment. The augmented lung injury was associated with reduced markers for alternatively activated macrophages also observed in NR-COVID-19 lungs. These results point to reduced myeloid HIF1A as a mechanism that can lead to exacerbated lung injury in mice, which parallels the rapid fibrotic response observed in NR-COVID-19. Collectively, our results point to using HIF1A stabilizers as a potential avenue to prevent the development of rapidly progressing postviral lung fibrosis. However, special care is necessary since chronic HIF1A activation is also linked to fibrotic outcomes. Postviral-induced lung fibrosis represents a severe and potentially fatal outcome. This was most evident during the COVID-19 pandemic, where a subset of individuals presented with fulminant lung fibrosis requiring lung transplantation. The mechanisms that promote this exacerbated lung injury are not fully known. Herein, we demonstrate that mice lacking myeloid hypoxia-inducible factor 1A (HIF1A) develop an exacerbated lung injury response to bleomycin that was consistent with reduced macrophage HIF1A expression in nonresolvable (NR)-COVID-19, characterized by extensive lung fibrosis.
Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy.
Halle JL, Zhang Q, Baumfalk DR … +6 more , Puppa MJ, Mohamed JS, Glazer ES, Smuder AJ, Alway SE, Carson JA
Am J Physiol Cell Physiol · 2026 Jan · PMID 41134647 · Full text
Cancer-induced inflammation has been widely investigated as a driver of cachexia, and sex can affect the inflammatory response to cancer. We have an incomplete understanding of how anticancer treatments and sex impact th...
Cancer-induced inflammation has been widely investigated as a driver of cachexia, and sex can affect the inflammatory response to cancer. We have an incomplete understanding of how anticancer treatments and sex impact the relationship between inflammatory responses and changes to body composition and physical function during cancer treatment. We investigated the effect of FOLFOX chemotherapy (5-fluorouracil, leucovorin, oxaliplatin) on circulating inflammatory cytokines, body composition, and physical function in CT26 tumor-bearing male and female mice. BALB/c mice were injected with CT26 tumor cells, and after the tumor was palpable, underwent three cycles of FOLFOX. FOLFOX reduced tumor mass in both sexes. CT26 induced plasma interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and tumor necrosis factor-alpha (TNF-α) in males and females. FOLFOX attenuated the CT26-induced IL-6 and LIF levels in males, but in females FOLFOX alone induced IL-6 and TNF-α, and did not attenuate their CT26 induction. In CT26 males, but not females, total lean and hindlimb mass were negatively associated with IL-6, and FOLFOX disrupted this association. The CT26-induced muscle p-STAT3 was inversely associated with muscle mass in males only and disrupted by FOLFOX. Circulating inflammatory cytokines were associated with body composition changes and functional deficits in CT26 males, but FOLFOX and female sex altered this relationship. Our results provide evidence that the female response to circulating inflammatory cytokines in the CT26 tumor environment, following FOLFOX chemotherapy, differs from that of males, and the physiological ramifications of this regulation warrant further investigation. The present study demonstrates that in colon tumor-bearing mice, the administration of FOLFOX chemotherapy alters plasma inflammatory cytokines' relationship to tumor mass, body composition, and physical function. Furthermore, sex influences these responses. These findings have implications for mechanistically understanding sex-specific muscle wasting and metabolic complications experienced by patients with colorectal cancer undergoing chemotherapy treatment.
Spatially distinct ECM-producing fibroblasts and myonuclei orchestrate early adaptation to mechanical loading in the human muscle-tendon unit.
Møbjerg A, Steffen D, Schjerling P … +9 more , Jakobsen JR, Jokipii-Utzon A, Batiuk MY, Khodosevich K, Krogsgaard MR, Izzi V, Mackey AL, Kjaer M, Yeung CC
Am J Physiol Cell Physiol · 2025 Dec · PMID 41117483 · Publisher ↗
Mechanical loading drives structural and functional improvements in muscle and tendon, protecting against injury at their interface, at the myotendinous junction (MTJ), and within the tendon matrix. However, the early ce...
Mechanical loading drives structural and functional improvements in muscle and tendon, protecting against injury at their interface, at the myotendinous junction (MTJ), and within the tendon matrix. However, the early cellular and molecular events that initiate these adaptations in humans remain poorly understood. To investigate this, we applied single-nucleus RNA sequencing and in situ hybridization to map the acute transcriptional response of the human muscle-tendon unit to a single bout of eccentric resistance exercise, with a focus on extracellular matrix (ECM) regulation. We identified four transcriptionally distinct fibroblast subtypes expressing key ECM components, including and . Three of these subtypes were localized to the tendon and responded to exercise: two were spatially restricted to the collagen fascicles or the MTJ, while the third, enriched in the interfascicular matrix (IFM), exhibited the strongest response. This IFM population, marked by , upregulated and , ECM genes linked to tissue lubrication and resilience. In parallel, exercise induced dynamic ECM regulation in myonuclei, particularly in a distinct subset of type II myonuclei at the MTJ, that expanded in number and robustly upregulated , a collagen essential for MTJ integrity. Together, these findings uncover a spatially organized, cell type-specific program of ECM remodeling in response to mechanical load, offering new insight into the early molecular events of human muscle-tendon adaptation. We provide the first high-resolution, in vivo single-nucleus map of the acute human muscle-tendon response to mechanical loading. Within 4 hours of resistance exercise, spatially distinct tendon fibroblasts and myonuclei activate coordinated extracellular matrix programs. Interfascicular fibroblasts upregulate and in the tendon, while myonuclei at the myotendinous junction induce and . These findings reveal a new principle of human mechanobiology, where exercise rapidly engages niche-specific programs to initiate extracellular matrix adaptation.
Dynamic time course of muscle proteome adaptation to programmed resistance training in rats.
Stead CA, Hesketh SJ, Thomas ACQ … +4 more , Viggars MR, Sutherland H, Jarvis JC, Burniston JG
Am J Physiol Cell Physiol · 2025 Dec · PMID 41117415 · Publisher ↗
Resistance training promotes muscle protein accretion and myofiber hypertrophy, driven by dynamic processes of protein synthesis and degradation. Muscle adaptations to ongoing resistance training occur over weeks, but mo...
Resistance training promotes muscle protein accretion and myofiber hypertrophy, driven by dynamic processes of protein synthesis and degradation. Muscle adaptations to ongoing resistance training occur over weeks, but most molecular knowledge on the process of adaptation is derived from static measurements at specific time points, which do not capture the dynamics of the adaptation process. To address this, we utilized deuterium oxide labeling and peptide mass spectrometry to quantify absolute protein content (grams) and synthesis rates (grams/day) in skeletal muscle during a time series experimental design. A daily programmed resistance training regimen was applied to male rat tibialis anterior via electrical stimulation of the left hindlimb for 10, 20, and 30 days (5 sets of 10 repetitions daily). Muscle samples from stimulated and contralateral control limbs were analyzed, quantifying 658 protein abundances and 215 protein synthesis rates. Unsupervised temporal clustering of protein responses revealed distinct phases of muscle adaptation. The early (0-10 days) response was driven by greater rates of ribosomal protein accretion and the mid (10-20 days) response by expansion of mitochondrial networks. These findings highlight that subsets of proteins exhibit distinct adaptation timelines due to variations in translation and/or degradation rates. The new understanding of temporal patterns highlighted by our dynamic proteomic data helps interpret static data from studies at isolated time points and could improve the development of strategies for optimizing muscle growth and functional adaptation to resistance training. We used stable isotope labeling and proteomic analyses to quantify absolute changes in the synthesis and abundance of muscle proteins during programmed resistance training in rat in vivo. This novel time-resolved approach revealed distinct phases of adaptation, characterized by early ribosomal and later mitochondrial protein accretion. Strikingly, we observed substantial "oversynthesis" of muscle proteins; that is, the net gain in muscle protein content was much less than the amount of newly synthesized protein.
Metabolic responses to airway infection.
Bünsow D, Winstel V
Am J Physiol Cell Physiol · 2025 Nov · PMID 41117409 · Publisher ↗
Respiratory tract infections caused by antibiotic-resistant are often fatal and largely influenced by the pathogen's ability to overcome host immune defenses. Despite the importance of immune evasion, staphylococci, alo...
Respiratory tract infections caused by antibiotic-resistant are often fatal and largely influenced by the pathogen's ability to overcome host immune defenses. Despite the importance of immune evasion, staphylococci, along with their exoproducts, are also known to modulate specific metabolic pathways within the respiratory epithelium and infection hot spot-infiltrating phagocytic cells, thereby impacting inflammatory and antimicrobial responses. Here, we briefly discuss how induces disease-related metabolic alterations in professional and nonprofessional phagocytes during acute and chronic infections of the lung. Specifically, we focus on metabolic plasticity of airway epithelial cells and predominant phagocytes upon sensing of and further detail metabolic adaptation strategies of staphylococcal small colony variants that often cause persistent and hard-to-treat infections within the airways of individuals suffering from cystic fibrosis. In this context, we highlight how metabolic rerouting and buildup of specific bacterial metabolites, including intermediates of the tricarboxylic acid cycle, can shift the lifestyle of toward sessility and intracellular persistence. Coupled with a section addressing the role of bacterial energy metabolism during respiratory infections, these insights may aid in the design of novel anti-infective and immunometabolism-based therapeutic strategies.
The role of the fibroblast in cardiorenal syndrome.
Åvall K, Williams JM
Am J Physiol Cell Physiol · 2025 Dec · PMID 41115063 · Publisher ↗
The diversity of fibroblasts across different organs, and within the same structures, means that their role in both health and disease is manifold. This review focuses on their job in the heart and kidney, specifically d...
The diversity of fibroblasts across different organs, and within the same structures, means that their role in both health and disease is manifold. This review focuses on their job in the heart and kidney, specifically during the course of cardiorenal syndrome (CRS). During CRS, there is a complex bidirectional interplay between the two body systems whereby the failure of one drives the decline of the other. These effects manifest by a response that leads to the deposition of fibrotic tissue, attributable to fibroblast dysfunction. Fibroblasts in themselves provide essential functions within organs, which are determined by the specific identity of their subtype. During disease, fibroblast function is further constrained and directed by the niches that form at the sites of injury. This review delves into the origins of fibroblasts in the heart and kidney, their functions in each tissue, and the processes and stressors whereby they become activated to form myofibroblasts. We discuss tools that can be used to study the phenomenon of fibroblast activation in vitro and in human studies and, finally, what therapeutic possibilities there may be in the future.
Protease-activated receptor 1-mediated matrix metalloprotease signaling in sensory neurons.
Williams KJ, Galimberti G, Higham JP … +5 more , Overington E, Bhebhe CN, Raine T, Sacerdote P, Bulmer DC
Am J Physiol Cell Physiol · 2025 Nov · PMID 41115057 · Publisher ↗
Visceral pain is a prevalent and debilitating symptom of inflammatory bowel disease (IBD). However, current pain therapies are often ineffective, raising the possibility that novel disease mediators might be contributing...
Visceral pain is a prevalent and debilitating symptom of inflammatory bowel disease (IBD). However, current pain therapies are often ineffective, raising the possibility that novel disease mediators might be contributing to pain during inflammation. Our study provides new insights into how matrix metalloproteases (MMPs), which are elevated in IBD, stimulate sensory neurons. We demonstrate that MMP3, MMP8, and MMP9 induce intracellular Ca release in dorsal root ganglion (DRG) neurons through activation of protease-activated receptor 1 (PAR1) and subsequent activation of phospholipase C (PLC). Characterization of the neuronal populations stimulated by these MMPs suggests that a subset is likely nociceptive. In contrast, MMP2 and MMP13, although capable of cleaving PAR1 in other cell types, do not induce Ca mobilization in DRG neurons. Interestingly, pretreatment with MMP2 or MMP13 reduces the neuronal response to MMP3 or TRAP6, a synthetic PAR1 agonist, suggesting that MMP2 and MMP13 act on PAR1 in a manner that prevents further activation. In addition, MMP10 induces Ca mobilization in DRG neurons but through a PAR1-independent mechanism. These findings uncover a previously unrecognized role for MMP signaling in sensory neurons, highlighting a potential mechanism by which MMPs could contribute to the pronociceptive environment in the inflamed bowel. Matrix metalloproteases-elevated in colonic biopsies from patients with Crohn's disease-stimulate a subset of nociceptive sensory neurons. As such, matrix metalloproteases may contribute to the pronociceptive environment in the inflamed bowel.
Protonic capacitor cell energetics: transmembrane-electrostatically localized protons/cations.
Lee JW
Am J Physiol Cell Physiol · 2025 Dec · PMID 41106836 · Publisher ↗
The transmembrane-electrostatically localized protons/cations charges (TELPs/TELCs) theory can serve as a theoretical framework to better explain cell electrophysiology and elucidate bioenergetic systems, including both...
The transmembrane-electrostatically localized protons/cations charges (TELPs/TELCs) theory can serve as a theoretical framework to better explain cell electrophysiology and elucidate bioenergetic systems, including both delocalized and localized protonic coupling. According to the TELCs model, the excess positive charges of TELCs at one side of the membrane are balanced by the excess negative charges of transmembrane-electrostatically localized hydroxide anions (TELAs) at the other side of the membrane. Through the TELCs-membrane-TELAs capacitor model, the energetics of oxidative phosphorylation have recently been better elucidated in mitochondria and alkalophilic bacteria, leading to the identification of a novel Type-B energetic process. Both the TELCs model studies and experimental demonstration results showed that the putative "potential well/barrier" model is not needed to explain TELPs formation. Application of the TELCs model to neural cells has recently resulted in novel neural transmembrane potential integral equations. In this review article, we will visit the TELCs-membrane-TELAs model and its applications, including its features and predictions that may help better understand cell energetics. Meanwhile, we will also discuss some of the recent critiques and point out the opportunities and directions for future research. The TELCs model can be well predictive and provide new opportunities as a theoretical tool for further research to better understand cell physiology, bioenergetics, and neurosciences. This Landmark Review article timely provides the latest discoveries, breakthrough advances with new developments and knowledge, directions and opportunities for future research in a major emerging and exciting scientific area of protonic capacitor cell energetics: transmembrane-electrostatically localized protons/cations.
Postnatal developmental dynamics of mitochondrial complex I in mouse tissues.
Siragusa M, Yoval-Sánchez B, Guerrero I … +1 more , Galkin A
Am J Physiol Cell Physiol · 2025 Nov · PMID 41101777 · Full text
Although the content of mitochondrial enzymes in different tissues can vary greatly, understanding the regulation behind these differences has been hampered by a lack of quantitative knowledge in relation to postnatal de...
Although the content of mitochondrial enzymes in different tissues can vary greatly, understanding the regulation behind these differences has been hampered by a lack of quantitative knowledge in relation to postnatal development. Here we report a quantitative analysis of developing brain, heart, kidneys, and muscle tissue of C57BL/6J mice, focusing on the content of mitochondrial complex I, a key component of the respiratory chain. We found that in all tissues except kidneys, complex I content gradually increases after birth, reaching a plateau level at around 25 days. Complex I content in muscles does not change significantly until -, and then also increases. The greatest increment was found in kidneys, where a 16-fold increase in complex I level after birth was observed. We also found that content of complex I in all postnatal tissues, but muscle, is higher in males than in females. These baseline dynamics of this key mitochondrial flavoprotein serve as a reference for evaluating genetic influences on development and provide a standard for assessing mitochondrial complex I function during postnatal growth. Mitochondrial complex I is a key enzyme of mammalian oxidative phosphorylation. Here, we provide the first quantitative map of mitochondrial complex I maturation in postnatal mouse tissues. Complex I content rises after birth with striking tissue- and sex-specific patterns, including a dramatic 16-fold increase in kidney. These findings establish a baseline for developmental bioenergetics and a reference for evaluating genetic or disease-related mitochondrial dysfunction.
Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.
Baehr LM, Oliveira de Sousa LG, Goodman CA … +4 more , Sharples AP, Waddell DS, Bodine SC, Hughes DC
Am J Physiol Cell Physiol · 2025 Dec · PMID 41083217 · Full text
The N-degron pathway contributes to proteolysis by targeting N-terminal residues of destabilized proteins via E3 ligases that contain a UBR-box domain. Emerging evidence suggests the UBR-box family of E3 ubiquitin ligase...
The N-degron pathway contributes to proteolysis by targeting N-terminal residues of destabilized proteins via E3 ligases that contain a UBR-box domain. Emerging evidence suggests the UBR-box family of E3 ubiquitin ligases (UBR1-7) is involved in the positive regulation of skeletal muscle mass. The purpose of this study was to explore the role of UBR-box E3 ubiquitin ligases under enhanced protein synthesis and skeletal muscle growth conditions. Cohorts of adult male mice were electroporated with constitutively active Akt (Akt-CA) or UBR5 RNAi constructs with a rapamycin diet intervention for 7 and 30 days, respectively. In addition, the UBR-box family was studied during the regrowth phase after nerve crush-induced inactivity. Skeletal muscle growth with Akt-CA or regrowth following inactivity increased protein abundance of UBR1, UBR2, UBR4, UBR5, and UBR7. This occurred with corresponding increases in Akt-mTORC1/S6K and MAPK/p90RSK signaling and protein synthesis. The increases in UBR-box E3s, ubiquitination, and proteasomal activity occurred independently of mTORC1 activity and were associated with increases in markers related to autophagy, ER-stress, and protein quality control pathways. Finally, while UBR5 knockdown (KD) evokes atrophy, it occurs together with hyperactivation of mTORC1 and protein synthesis. In UBR5 KD muscles, we identified an increase in protein abundance for UBR2, UBR4, and UBR7, which may highlight a compensatory response to maintain proteome integrity. Future studies will seek to understand the role of UBR-box E3s toward protein quality control in skeletal muscle plasticity. Novel UBR-box E3 ubiquitin ligases are responsive to heightened protein synthesis and alterations in skeletal muscle mass and fiber size, to maintain proteome integrity.
Host-microbiota interactions regulate gut serotonergic signaling: implications for hypertension.
Sree Kumar H, Zubcevic J
Am J Physiol Cell Physiol · 2025 Dec · PMID 41083215 · Publisher ↗
Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved signaling molecule present across diverse taxa, including plants, invertebrates, and vertebrates. In mammals, the majority of peripheral serotonin is synthesize...
Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved signaling molecule present across diverse taxa, including plants, invertebrates, and vertebrates. In mammals, the majority of peripheral serotonin is synthesized in the gastrointestinal tract by enteric neurons and enterochromaffin cells via tryptophan hydroxylases. Its biosynthesis and release are influenced by dietary components and microbial metabolites, particularly short-chain fatty acids produced by the gut microbiota. Once released into the periphery, serotonin exerts pleiotropic effects, regulating intestinal motility and secretion, modulating vascular tone, and influencing blood pressure through both direct actions and vagal sensory pathways engaging central and autonomic circuits. Dysregulation of colonic serotonin production or signaling has been implicated in metabolic, neuropsychiatric, and cardiovascular disorders, including postprandial blood pressure abnormalities and hypertension. Emerging evidence highlights a bidirectional relationship between gut microbes and host serotonergic pathways, suggesting that microbiota-targeted interventions may hold therapeutic potential for cardiometabolic regulation. Advancing our understanding of gut serotonergic signaling, particularly the interplay between host and microbial factors, could inform the development of innovative strategies to treat hypertension and related conditions.
Exercise decreases the number and modifies the transcriptome of M1 macrophages and CD8 T cells in nonoccluded epicardial adipose tissue of female pigs.
Ahmad I, Gupta S, Thomas M … +3 more , Cai JJ, Heaps CL, Newell-Fugate AE
Am J Physiol Cell Physiol · 2025 Dec · PMID 41083194 · Full text
Epicardial adipose tissue (EAT) regulates lipid metabolism and immune cell recruitment in coronary arteries. Increased EAT contributes to coronary artery disease (CAD), but exercise prevents CAD. We hypothesized that exe...
Epicardial adipose tissue (EAT) regulates lipid metabolism and immune cell recruitment in coronary arteries. Increased EAT contributes to coronary artery disease (CAD), but exercise prevents CAD. We hypothesized that exercise, irrespective of CAD presence, would produce EAT with increased M2 macrophages and upregulation of anti-inflammatory cytokine transcripts. Female Yucatan pigs ( = 7) were sedentary or exercised, and the left circumflex coronary artery was occluded or remained nonoccluded (2 × 2 design). Bulk and single-nuclei transcriptomic sequencing performed on EAT identified immune, endothelial, smooth muscle, adipocytes, adipocyte progenitor cells (APSCs), and neuronal cells, with adipocytes and APSCs predominant. Nonoccluded (N) sedentary (Sed) EAT had the most M1 macrophages and CD8 T cells. Sed EAT had the most cells expressing tumor necrosis factor (TNF) superfamily genes. Exercise (Ex) upregulated peroxisome proliferator-activated receptor () γ () expression and enriched PPAR signaling, which suppresses activation, in macrophages and T cells, particularly in occluded (O) Ex EAT. By contrast, N_Ex EAT had few CD8 T cells with low expression. Adipocytes and immune cells in O_Sed EAT had the most communication via growth factors and adhesion molecules. Exercise mitigates EAT inflammation via modulation of immune cell subpopulations, decreased TNF superfamily, and increased gene expression, and decreased communication between adipocytes and immune cells. However, the effect of exercise on the EAT immune environment is modulated by coronary artery occlusion status. Future studies of the impact of exercise and coronary artery occlusion on EAT would benefit from using a progressive nutritionally induced model of CAD. A sedentary lifestyle increases the number of inflammatory M1 macrophages and CD8 T cells, their expression of tumor necrosis factor genes, and the number of communications between these immune cells and adipocytes in epicardial adipose tissue (EAT). The expression of peroxisome proliferator receptor and genes in control of cell activation in macrophages and T cells in nonoccluded and occluded EAT increases in response to exercise.
A tough job: ion channels, transporters, and pumps during organ fibrosis.
Wilczak W, Schleinhege R, Loescher CM … +2 more , Schwab A, Pethő Z
Am J Physiol Cell Physiol · 2025 Dec · PMID 41071674 · Publisher ↗
Fibrosis plays a crucial role in a range of chronic diseases, including cancer. Emerging evidence suggests that ion channels, transporters, and pumps-the transportome-have an essential share in fibrogenesis and fibrosis...
Fibrosis plays a crucial role in a range of chronic diseases, including cancer. Emerging evidence suggests that ion channels, transporters, and pumps-the transportome-have an essential share in fibrogenesis and fibrosis by regulating fibroblast and myofibroblast activity. This review bridges current knowledge gaps by integrating insights from multiple diseases affecting the heart, lungs, pancreas, kidney, and liver, as well as cancer. Thereby, we reveal shared molecular mechanisms of how the transportome modulates fibroblast activation, extracellular matrix deposition, tissue stiffness, and remodeling. We focus on the roles of various ion transport proteins, including PIEZO1, transient receptor potential (TRP), K, and cystic fibrosis transmembrane regulator (CFTR) channels; the Na/H exchanger NHE1; and the Na/K-ATPase. By comparing analogous pathways across different fibrotic diseases such as Ca signaling and transforming growth factor β1 (TGF-β1) and Wnt/β-catenin pathways, we highlight the druggable potential of these ion transport proteins and suggest novel concepts for therapeutic intervention.
Preclinical models of cardio-renal syndrome: a systematic review.
Regenburgh De La Motte L, Bassani B, Trepiccione F … +3 more , Capasso G, Bruno A, Ambrosio G
Am J Physiol Cell Physiol · 2025 Dec · PMID 41071650 · Publisher ↗
The prevalence of heart failure (HF) and of chronic kidney disease (CKD) is continuously rising. Both diseases require significant management efforts, and more importantly, HF is often associated with CKD, aggravating th...
The prevalence of heart failure (HF) and of chronic kidney disease (CKD) is continuously rising. Both diseases require significant management efforts, and more importantly, HF is often associated with CKD, aggravating the clinical scenario and leading to "cardiorenal syndrome" (CRS). Although clinical studies suggest a bidirectional interaction between HF and CKD, the pathophysiological understanding of CRS remains incomplete. Several mechanisms are involved in CRS, including changes in systemic and renal hemodynamics, endothelial dysfunction, inflammation, and activation of the renin-angiotensin-aldosterone and sympathetic nervous systems. However, the precise mechanisms are still unclear, partly because of the incomplete characterization of experimental models recapitulating CRS. In this review, we analyze recent studies using different animal models of CRS, such as primary HF, primary CKD, and the "double-hit" models that have been proposed to investigate the pathophysiology of this condition. In HF models, data on renal pathology showed renal fibrosis, inflammation, and decreased glomerular filtration rate (GFR), whereas kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were used as markers of early kidney damage. In CKD models, data on heart pathology indicated changes in hemodynamics, increased systolic blood pressure, and the presence of fibrosis. These models provide new insights into the pathophysiological development of CRS, particularly the "double-hit" models, which may offer more information about the cross talk between the heart and kidneys. This review emphasizes the complexity of CRS and highlights the need for further research to clarify the underlying interactions and mechanisms.
Glycolytic metabolism and biomass production from glucose in human skeletal muscle growth.
Mäntyselkä S, Ahvenlammi M, Vartiainen J … +10 more , Halonen EJ, Kolari K, Wackerhage H, Permi P, Varjosalo M, Kelahaara MM, Ahtiainen JP, Kalenius E, Kivelä R, Hulmi JJ
Am J Physiol Cell Physiol · 2025 Nov · PMID 41071646 · Publisher ↗
Skeletal muscle is the main consumer of glucose after a mixed meal, and resistance exercise further increases muscle glucose uptake. Emerging evidence suggests that glucose uptake in muscles is not only stored as glycoge...
Skeletal muscle is the main consumer of glucose after a mixed meal, and resistance exercise further increases muscle glucose uptake. Emerging evidence suggests that glucose uptake in muscles is not only stored as glycogen or used as a fuel but can also be incorporated into other biomass during growth. We aimed to study the utilization of glucose-derived carbons for protein, RNA, and lipid synthesis during human skeletal muscle (HSkM) cell growth. We also investigated whether muscle growth in vivo by resistance training (RT) affects the abundance of metabolites and enzymes required for these processes in human muscle. We found that differentiated HSkM cells incorporated glucose-derived carbon into proteins, RNA, and lipids, and anabolic stimulation further increased these processes. Liquid chromatography-mass spectrometry metabolomics and proteomics revealed that 10 wk of RT in humans increased essential metabolites and enzymes for nucleotide, serine, and glycine synthesis, including phosphoglycerate dehydrogenase (PHGDH) in muscle. We also examined whether the PHGDH enzyme, starting the serine synthesis pathway branching from glycolysis, is sufficient and essential for human muscle protein, RNA, and lipid anabolism. We found that PHGDH inhibitors decreased protein synthesis and glucose-derived carbon incorporation into macromolecules, whereas manipulation of PHGDH abundance had mixed effects. Moreover, PHGDH was revealed to be important for myogenesis. The data suggest that glucose is not only used for ATP generation but also as a building block in human muscle cell growth. The results open new avenues for studies investigating the mechanisms of RT and muscle growth in improving muscle glucose metabolism. Human skeletal muscle cells increase glucose utilization for protein, lipid, and especially RNA synthesis during their growth. Resistance training-induced muscle growth increases the abundance of enzymes and metabolites needed for nucleotide, serine, and glycine synthesis. The results suggest an underappreciated role of glucose utilization for biomass production during human muscle cell growth.
Activation of the Piezo1 channel stimulates protein kinase D and migration in human aortic endothelial cells.
Lone M, Singh P, Sinnett-Smith J … +3 more , Jin YP, Reed EF, Rozengurt E
Am J Physiol Cell Physiol · 2025 Nov · PMID 41071645 · Full text
Piezo1 is an evolutionally conserved mechanosensitive ion channel implicated in the regulation of development, differentiation, and growth of multiple tissues. Despite its importance, the pathways induced downstream of P...
Piezo1 is an evolutionally conserved mechanosensitive ion channel implicated in the regulation of development, differentiation, and growth of multiple tissues. Despite its importance, the pathways induced downstream of Piezo1 activation remain incompletely defined. Here, we report that the selective Piezo1 agonists, Yoda1, Yaddle1, and Yoda2, stimulate Protein kinase D (PKD) family activation in a concentration-dependent manner, in human aortic endothelial cells (ECs), as shown by an increase in PKD phosphorylation at Ser, an autophosphorylation site in the C-terminus, and Ser located in the activation loop. Depletion of extracellular Ca by EGTA abolished PKD phosphorylation stimulated by Piezo1 agonists, and exposure to the Ca ionophore ionomycin potently stimulated PKD. The PKD activation induced by Yoda1, Yaddle1, or Yoda2 was prevented by inhibitors of PKDs (CRT0066101) and protein kinase C (Go6983) and abrogated by siRNA-mediated knockdown of Piezo1. Treatment of ECs with H-067047 or apyrase did not alter the increase in the phosphorylation of PKD at either Ser or Ser induced by Yoda1, implying that stimulation of Piezo1 induces PKD activation independently from TRPV4 and autocrine ATP signaling. Exposure of ECs to Yoda1 increased the histone deacetylase (HDAC)7 phosphorylation and migration of ECs into the denuded area of the monolayer, as shown using a scratch wound assay. Treatment of ECs with CRT0066101 prevented HDAC7 phosphorylation and migration of these cells induced by Yoda1, suggesting that Yoda1-stimulated Piezo1 promotes EC migration through a PKD. Our results identify PKD as a novel downstream mediator of effects produced by agonist-induced activation of the Piezo1 mechanosensitive channel in ECs. Protein kinase D (PKD) emerged as a key node in cellular signaling, but its role in mechanobiology remains unknown. Here, we show that stimulation of the mechanosensitive Piezo1 ion channel markedly increases PKD multisite phosphorylation, indicative of activation. Opening of Piezo1 also promotes histone deacetylase (HDAC)7 phosphorylation and endothelial cell migration in a PKD-dependent manner. The results implicate PKD signaling in the function of Piezo 1 and identify a Piezo1/Ca/PKC/PKD/HDA7 signaling pathway in endothelial cells.
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