American Journal Of Physiology. Cell Physiology[JOURNAL]
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200 papers
Systemic metabolite kinetics mirror skeletal muscle energy metabolism during acute aerobic exercise.
Walzik D, Wenzel C, Strotkötter JE … +7 more , Hoenen L, Wences Chirino TY, Trebing S, McCann A, Ueland PM, Zimmer P, Joisten N
Am J Physiol Cell Physiol · 2026 Jan · PMID 41263665 · Publisher ↗
Acute exercise increases energy demand in skeletal muscle and releases metabolic intermediates into circulation, yet the serum kinetics of exercise-mobilized metabolites remain poorly characterized. By applying high-freq...
Acute exercise increases energy demand in skeletal muscle and releases metabolic intermediates into circulation, yet the serum kinetics of exercise-mobilized metabolites remain poorly characterized. By applying high-frequency serial blood sampling and targeted metabolomics in a longitudinal exercise trial with 12 young, healthy adults (6 females, 6 males), we assessed temporal alterations in energy-related metabolites during acute aerobic exercise and after 1 h of recovery. We provide evidence for 42 exercise-responsive metabolites, including end products of glycolysis, tricarboxylic acid cycle intermediates, ketone bodies, and amino acids. Overall, the observed metabolic alterations closely resembled skeletal muscle energy metabolism, thereby refining fundamental principles of exercise biochemistry through detailed serum kinetics, including novel, so far uncharacterized responses in systemic energy homeostasis and interorgan crosstalk. In our study, we provide detailed serum kinetics of energy-related metabolites during acute aerobic exercise and after 1 h of recovery. Semantic interpretation of our results against the backdrop of fundamental principles of exercise biochemistry indicate that serum metabolites mirror skeletal muscle energy metabolism, thus providing new insights into systemic energy homeostasis and interorgan crosstalk.
Adaptation of the endplate in skeletal muscle of Homer 2 mice.
Lorenzon P, Amoretti S, Furlan S … +8 more , Ravara B, Bernareggi A, Sciancalepore M, Sacchetto R, Megighian A, Zampieri S, Nori A, Volpe P
Am J Physiol Cell Physiol · 2025 Dec · PMID 41259107 · Publisher ↗
At the neuromuscular junction, nicotinic acetylcholine receptor (nAChR) dynamics are regulated in a nerve- and activity-dependent manner. Correlated local alterations in myoplasmic [Ca], induced by IP-sensitive subsynapt...
At the neuromuscular junction, nicotinic acetylcholine receptor (nAChR) dynamics are regulated in a nerve- and activity-dependent manner. Correlated local alterations in myoplasmic [Ca], induced by IP-sensitive subsynaptic Ca stores, have been proposed to signal motor endplate adaptation to motor neuron stimulation. Accordingly, there is evidence for a modulatory role of Ca/calmodulin-dependent protein kinase IIβ (CaMKIIβ) in the sorting, targeting, and/or incorporation of nAChRs into the postsynaptic membrane. As the scaffold protein Homer 2 emerges as a key player in integrating downstream postsynaptic signaling pathways, this study investigated the possible involvement of Homer 2 in the molecular mechanism controlling nAChR dynamics. Using Homer 2 transgenic mice, it was found that Homer 2 ablation leads to a chronic adaptation of the endplate characterized by: ) reduction in nAChR activity due to slower insertion of nAChRs into the endplate; ) reduced subsynaptic IPR1 content and IP-releasable Ca; and ) impaired colocalization of CaMKIIβ with nAChRs. Overall, the present results demonstrate that Homer 2 ablation produces a significant alteration in endplate nAChR dynamics, which is associated with impaired organization of the subsynaptic IP-driven Ca signaling mechanism. This research sheds light on the role of Homer 2 in organizing the subsynaptic microdomain, where nAChRs, IPR1s, and CaMKIIβ assemble to regulate nAChR dynamics. The present results point to a novel type of endplate instability, which may have implications for understanding neuromuscular junction function and related disorders.
Mitochondria transplantation mitigates attenuation of muscle fiber regeneration by evoked contractions.
Alway SE, Paez HG, Ferrandi PJ … +6 more , Pitzer CR, Halle JL, Khan MM, Mohamed JS, Deschenes MR, Carson JA
Am J Physiol Cell Physiol · 2026 Jan · PMID 41259105 · Full text
Rest is generally required for full muscle regeneration after an injury; however, rehabilitative activity is often used after injury to attempt a faster recovery. Although rehabilitative activity can enhance muscle regen...
Rest is generally required for full muscle regeneration after an injury; however, rehabilitative activity is often used after injury to attempt a faster recovery. Although rehabilitative activity can enhance muscle regeneration, there is also a risk that returning to vigorous muscle contractions too early after sustaining an injury, could reinjure the muscle and negatively impact full muscle regeneration. It is not known whether mitochondrial transplantation (MT) added to rehabilitative muscle activity would speed the regeneration of muscle morphology more rapidly than resting during the recovery period. Therefore, submaximal electrically evoked isometric contractions (ECs) were given to the injured muscles of MT-treated mice, to test the hypothesis that MT would attenuate the negative regenerative effects of EC and improve the restoration of muscle mass and morphology after muscle injury. Cardiotoxin (CTX) was injected into the tibialis anterior (TA) muscle of one limb of C57BL/6 mice at 8-12 wk of age to induce muscle injury. Systemic delivery of MT or PBS was administered to the mice 48 h after injury. The TA received EC at 40 Hz every other day for up to 14 days after CTX injury. Although EC-induced mechanical injury slowed muscle repair, muscle fiber regeneration and nuclear domain size were improved by MT. The percentage of collagen and other noncontractile tissue was elevated in CTX-injured and EC-treated muscles; however, MT reduced fibrosis/noncontractile tissue deposition in regenerating muscles. Our results provide evidence that systemic mitochondria delivery can improve muscle repair and can attenuate contraction-suppressed muscle fiber regeneration during recovery after injury. Electrically evoked muscle contractions conducted every other day after muscle injury caused additional damage and slowed recovery of muscle regeneration; however, mitochondria transplantation attenuated the negative regenerative effects of rehabilitative contractions on muscle fiber regeneration. This suggests that optimizing mitochondrially regulated repair may improve muscle regeneration. Furthermore, injured muscles treated by mitochondrial transplantation had lower collagen content/fibrosis than those treated with PBS after injury. Mitochondrial transplantation blunts fibrosis and improves muscle fiber repair after injury.
The eIF5A hypusination inhibitor GC7 improves tolerance of pancreatic beta cells to ischemia/reperfusion.
Ouahmi H, Massa F, Cougnon M … +6 more , Rubera I, Jarretou G, Tauc M, Van Obberghen E, Sicard A, Pisani DF
Am J Physiol Cell Physiol · 2026 Jan · PMID 41259093 · Publisher ↗
Transplantation of pancreatic islets, containing insulin-secreting beta cells, provides substantial benefits for individuals with type 1 diabetes. However, the low yield of the procedure limits its therapeutic potential,...
Transplantation of pancreatic islets, containing insulin-secreting beta cells, provides substantial benefits for individuals with type 1 diabetes. However, the low yield of the procedure limits its therapeutic potential, as many islets are lost during preparation and transplantation, primarily due to ischemia/reperfusion injuries and oxidative stress. N1-guanyl-1,7-diaminoheptane (GC7), an inhibitor of eIF5A hypusination, improves the resistance of various cells and organs to ischemia/reperfusion. Our study therefore explored whether GC7 treatment of beta cell models in vitro could serve as a strategy to enhance their resistance to ischemia/reperfusion injuries. We treated rat INS-1 or mouse MIN6 cells with GC7 and analyzed insulin secretion, energetic metabolism, mitochondrial function, and both cell survival and oxidative stress under anoxia/reoxygenation conditions. In beta cells, eIF5A inhibition by GC7 treatment repressed transiently the mitochondrial activity, ATP production, and insulin secretion in response to glucose, which was linked to a metabolic shift from oxidative phosphorylation to anaerobic glycolysis. Following anoxia/reoxygenation to mimic ischemia/reperfusion, GC7 treatment significantly reduced oxidative stress while significantly improving cell survival by >50%. Collectively, these findings are a proof of concept, demonstrating that GC7 treatment of beta cells enhances their resistance to ischemia-reperfusion injury. Hence, the use of GC7 appears as a promising strategy to improve pancreatic islet survival during transplantation. Treatment of rodent beta cell line with GC7, an inhibitor of eIF5A hypusination, reversibly slows down mitochondrial activity and shifts the cells' energy metabolism toward anaerobic glycolysis. As a result, GC7 treatment transiently inhibits ATP production and insulin secretion in response to glucose. These changes enhance the resistance of pancreatic beta cell line to ischemia/reperfusion by reducing oxidative stress and improving cell survival, highlighting the potential anti-ischemic benefits of GC7 for pancreatic islet transplantation.
Zinc deficiency contributes to blunted myogenesis in chronic kidney disease.
Keeble AR, Gonzalez-Velez S, Weiss HC … +9 more , Zuluaga-Osorio KS, Dobis MJ, Paredes W, Duran S, Zhang K, Owen AM, Abramowitz MK, Fry CS, Preserving Physical Function in CKD (PPF-CKD) Investigators
Am J Physiol Cell Physiol · 2026 Jan · PMID 41252408 · Full text
Frailty in patients with chronic kidney disease (CKD) greatly exacerbates disease comorbidities and increases probability of death. Prior research underscores molecular alterations in skeletal muscle physiology that may...
Frailty in patients with chronic kidney disease (CKD) greatly exacerbates disease comorbidities and increases probability of death. Prior research underscores molecular alterations in skeletal muscle physiology that may underly frailty and poor intervention response in this patient population. CKD can negatively affect satellite cell abundance and function, reducing skeletal muscle injury resilience and adaptive capacity. Pathogenic drivers of compromised satellite cell abundance and activity in patients with CKD remain largely unknown. To address this gap in knowledge, we isolated primary myogenic progenitor cells (MPCs) from patients with CKD and control participants. We also sought to define cell-extrinsic and cell-intrinsic processes that may underlie myogenic deficits. We performed RNA sequencing on MPCs from control participants cultured in control serum, MPCs from control participants cultured in CKD serum, and MPCs from participants with CKD cultured in control serum. We identified zinc mishandling as a shared pathway between control cells treated with CKD serum and CKD cells treated with control serum. Consistent with these observations, we found zinc deficiency and attenuated myogenesis in MPCs from patients with CKD. Finally, we showed that zinc supplementation partially restores the myogenic capacity of MPCs from patients with CKD. Together, these data highlight the importance of zinc metabolism in myogenesis and identify a novel mechanism whereby CKD pathogenesis impedes MPC differentiation. Satellite cell abundance and function are negatively affected by chronic kidney disease (CKD). Using primary myogenic progenitor cells (MPCs) cultured from patients with late-stage CKD and matched controls, we expose cells to CKD or control serum and identify metallothionein-induced zinc deficiency as both a cell-autonomous and nonautonomous consequence of CKD on MPCs. We find zinc deficiency likely attenuates myogenesis through an AKT-FOXO1 signaling cascade, which can be partially rescued by supplementation of exogenous zinc.
Celastrol and Cblin peptide activation of IGF-1 signaling prevents microgravity-induced atrophy in rat L6 myotubes.
Park J, Ulla A, Uchida T … +10 more , Lee S, Tsuda H, Ishige Suzuki T, Hashizume T, Higashibata A, Park R, Kobayashi T, Sokabe M, Choi I, Nikawa T
Am J Physiol Cell Physiol · 2026 Jan · PMID 41252406 · Publisher ↗
This study investigated the efficacy of two natural compounds-celastrol, a heat shock protein (HSP) inducer, and Cblin peptide, a ubiquitination inhibitor-in counteracting muscle atrophy under real microgravity condition...
This study investigated the efficacy of two natural compounds-celastrol, a heat shock protein (HSP) inducer, and Cblin peptide, a ubiquitination inhibitor-in counteracting muscle atrophy under real microgravity conditions. Both agents independently attenuated microgravity-induced reductions in myotube thickness, myosin heavy chain protein levels, and atrogene expression. Celastrol primarily enhanced HSP expression, whereas Cblin peptide inhibited insulin receptor substrate-1 degradation, thereby promoting insulin-like growth factor-1 signaling. Despite their distinct molecular actions, no synergistic or additive effects were observed when combined. These findings highlight the potential of celastrol and Cblin peptide as functional ingredients for mitigating muscle atrophy, particularly in the context of space travel. Notably, Cblin peptide is abundant in glycinin-rich soybean protein, and celastrol is derived from the root of (Taiwan vine). Future applications may include incorporating these plant-derived compounds into space foods to improve the quality of life for astronauts in space. This study evaluated the effects of celastrol and the Cblin peptide in mitigating muscle atrophy under microgravity conditions. Both compounds alleviated myotube atrophy through distinct mechanisms, though no synergistic effect was observed. Celastrol upregulated heat shock protein (HSP) expression, whereas Cblin prevented IRS-1 degradation, thereby enhancing IGF-1 signaling. Sourced from and soybean protein, respectively, these agents may serve as functional space foods to help counteract muscle atrophy and support astronauts' health during spaceflight.
Emerging roles of astrocytes in autonomic control of blood pressure and hypertension.
Verma H, Feng Earley Y
Am J Physiol Cell Physiol · 2025 Dec · PMID 41247787 · Full text
Astrocytes, traditionally viewed as passive support cells, have emerged as critical regulators of neuronal signaling, autonomic function, and cardiovascular homeostasis. Accumulating evidence highlights the active partic...
Astrocytes, traditionally viewed as passive support cells, have emerged as critical regulators of neuronal signaling, autonomic function, and cardiovascular homeostasis. Accumulating evidence highlights the active participation of astrocytes in maintaining neurotransmitter balance, ion homeostasis, synaptic plasticity, and cerebral metabolism. In particular, astrocytes form integral components of tripartite synapses, mediating neuronal communication through calcium-dependent release of gliotransmitters, including ATP, glutamate, d-serine, and γ-aminobutyric acid. This astrocyte-mediated signaling is essential in modulating autonomic circuits involved in blood pressure regulation and sympathetic nerve activity. Recent research underscores the role of astrocyte dysfunction-mediated inflammation, termed astrogliosis, in driving pathological states such as hypertension. Astrocyte activation within critical cardiovascular control centers, including the nucleus tractus solitarii, paraventricular nucleus, and rostral ventrolateral medulla, promotes neuroinflammation, disrupts neurotransmitter clearance, and enhances sympathetic nervous system activity. These processes contribute significantly to hypertension development, particularly under conditions of metabolic stress, such as obesity and high-fat diet consumption. Key molecular mechanisms implicated include NF-κB-mediated inflammatory pathways, impaired astrocytic glutamate transporters, overactivation of angiotensin II signaling, and abnormal gliotransmitter release. In this review, we summarize recent advances in our understanding of the physiological roles of astrocytes in autonomic and cardiovascular regulation and discuss the pathological consequences of astrocyte-driven neuroinflammation in hypertension. We further outline promising directions for future research and therapeutic interventions targeting astrocytic pathways, offering potential new strategies for preventing or reversing autonomic dysfunction and hypertension.
Role of Golgi stress-induced ferroptosis on vascular dysfunction after traumatic hemorrhagic shock through connexin43-SLC7A11 pathway.
Zhu Y, Peng X, Lei Y … +5 more , Guo L, Weng C, Li G, Wang J, Yang G
Am J Physiol Cell Physiol · 2026 Jan · PMID 41247785 · Publisher ↗
Vascular dysfunction, particularly vascular hyporeactivity, has been identified as a critical factor for limiting the treatment of patients with traumatic hemorrhagic shock (THS). Nevertheless, the precise mechanisms und...
Vascular dysfunction, particularly vascular hyporeactivity, has been identified as a critical factor for limiting the treatment of patients with traumatic hemorrhagic shock (THS). Nevertheless, the precise mechanisms underlying THS-induced vascular dysfunction remain inadequately understood. Increasing attention has been directed toward the role of Golgi apparatus stress (GAS)-induced cell death in cardiovascular disease, closely linked to redox imbalance. Recent studies indicate that inhibition of connexin43 (Cx43, a key regulator of vascular dysfunction) induces ferroptosis. However, it remains unclear whether THS-induced vascular dysfunction is regulated by GAS through Cx43 and ferroptosis. In this study, we showed that GAS was responsible for inducing vascular hyporeactivity following THS. Using a Cx43-knockout mice model, we subsequently found that GAS reduced the reactivity of superior mesenteric arteries after THS based on the inhibition of Cx43. Furthermore, cell experiments showed that hypocontraction of vascular smooth muscle cells (VSMCs) was induced by GAS; meanwhile, gap junctional intercellular communication (GJIC) disruption and ferroptosis were also triggered. We generated Cx43-knockdown or overexpressed VSMCs and verified that GAS induced hypocontraction of VSMCs through inhibition of Cx43 and SLC7A11. Moreover, increasing the level of SLC7A11 could attenuate GAS-induced ferroptosis and hypocontraction of VSMCs. These results suggest that GAS-induced ferroptosis can cause vascular dysfunction, which is mediated by the inhibition of the Cx43-SLC7A11 pathway in THS. The results highlight the important role of Golgi stress and ferroptosis in traumatic hemorrhagic shock-induced vascular dysfunction and inhibition of Golgi stress and its target pathway (connexin43-SLC7A11 pathway) may be the potential therapeutic target.
Role of Kir7.1 K channel in retinal pigment epithelium probed in a Kir7.1-M125R-expressing mutant mouse.
Vera E, Henao JC, Cid LP … +2 more , Sepúlveda FV, Cornejo I
Am J Physiol Cell Physiol · 2025 Dec · PMID 41247777 · Publisher ↗
Eye disease-associated K channel Kir7.1 is highly expressed together with the Na-K pump at the apical membrane of retinal pigment epithelial cells (RPEs) that line the subretinal space (SRS). SRS K concentration ([K]) de...
Eye disease-associated K channel Kir7.1 is highly expressed together with the Na-K pump at the apical membrane of retinal pigment epithelial cells (RPEs) that line the subretinal space (SRS). SRS K concentration ([K]) decreases from ∼5 to 2 mM upon light stimulation. Kir7.1 is crucial in its buffering, with failure thought to be causal in visual disease mutations of its gene. The unusual inverse relation to [K] of its conductance, deemed essential for [K] buffering, relies on nonconserved outer pore methionine-125. We now probe the role of Kir7.1 in the visual process by generating Kir7.1-M125R mutant mice with the channel predicted to lack [K] buffering ability. RPE cell electrical properties and mouse electroretinograms (ERG) are assessed. Membrane potential of RPE cells was found to be dominated by K, but while conductance decreased with increasing [K] in control cells, the reverse was true for cells of Kir7.1-M125R-expressing mice. ERG of mutant animals revealed a larger c-wave than in controls, consistent with the relative K permeabilities of the RPE. In contrast, there was no difference between the a- and b-waves of Kir7.1-M125R and control mice, suggesting normal functioning of photoreceptors and bipolar cells, and therefore retinal processing of the light signal. If, as predicted, [K] buffering is altered in mutant animals, this does not affect the retinal processing of the light signal. Other consequences of Kir7.1 malfunction, such as proposed function in photoreceptor outer segment recycling, must be involved in originating the disease phenotype associated with mutations in its gene. Retinal pigment epithelium apical membrane K channel Kir7.1 is crucial in the buffering of changes in subretinal K concentration occurring upon light stimulation, this thanks to its unusual inverse conductance relation to extracellular K. We demonstrate that inactivating this property by mutation Kir7.1-M125R in mice did not affect retinal response to light stimulus, suggesting that a different channel function must be affected in eye disease caused by mutations of the Kir7.1 gene.
Pediatric CHOP chemotherapy acutely disrupts satellite-cell dynamics and blunts muscle mass in a sex-specific manner.
Daredia J, Magaña MA, Nascimento CMC … +6 more , Wells JM, Thomas NT, Wen Y, Rauschendorfer SV, Dungan CM, Wiggs MP
Am J Physiol Cell Physiol · 2026 Jan · PMID 41223066 · Publisher ↗
Pediatric cancer survival now exceeds 85% owing, in part, to advances and the use of combination chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Despite its efficacy, CH...
Pediatric cancer survival now exceeds 85% owing, in part, to advances and the use of combination chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Despite its efficacy, CHOP may cause off-target effects during critical pediatric development periods such as impairments of skeletal muscle. We evaluated the acute effects of a CHOP administered to C57Bl/6J mice from postnatal to . CHOP slowed body-weight gain and led to a smaller gastrocnemius fiber cross-sectional area by ∼25% in both sexes ( = 11 or 12 males; = 8 or 9 females). RNA sequencing detected 214 differentially expressed genes in males and 217 in females relative to controls, yet only 29 transcripts overlapped. Males exhibited downregulation of myogenic regulators, indicating impaired progenitor maintenance, whereas females showed an upregulation of extracellular-matrix and translational machinery genes plus cell-cycle regulators. Using immunohistochemistry to assess satellite cell abundance, there were 60% fewer satellite cells in males and 40% fewer in females, which supported our transcriptional findings. These results demonstrate that pediatric CHOP acutely disrupts muscle stem-cell dynamics via sex-specific molecular programs and identify satellite cells as a potential target for preserving muscle health in pediatric cancer survivors. Multiagent CHOP chemotherapy in juvenile mice impairs muscle growth and alters transcriptional programs in a sex-specific manner. CHOP-treated mice showed lower satellite cell abundance and smaller muscle fibers, with RNA-seq revealing distinct gene expression profiles enriched for myogenic regulators, extracellular matrix, and translational machinery. These findings highlight the negative effects of chemotherapy on developing muscle and suggest alterations to satellite cells as a key contributor.
Adipo-epithelial transdifferentiation: old data and new perspectives.
Cinti S
Am J Physiol Cell Physiol · 2025 Dec · PMID 41223062 · Publisher ↗
White and brown adipose tissues are organized to form a true organ. White adipose tissues store energy that is provided to the organism in the intervals between meals and brown adipose tissues burn lipids to produce heat...
White and brown adipose tissues are organized to form a true organ. White adipose tissues store energy that is provided to the organism in the intervals between meals and brown adipose tissues burn lipids to produce heat. When the cold exposure is chronic, white converts into brown (browning) to help thermogenesis and when the energy balance is chronically positive, brown converts into white (whitening) to help store energy. The plastic property of the adipose organ also allows a reversible formation of milk-producing alveolar cells in the mammary fat during pregnancy and lactation (pinking, because the organ is pink during pregnancy). This last striking property of the adipose organ is challenged by other authors, but our data, based on morphology (including electron microscopy), immunohistochemistry, lineage tracing, explants, and in vitro data described here, support this phenomenon. Our experiments, including microarray data comparing cleared fat pad with normal glands in pregnant mice, allowed us to detect four molecular players in the pinking phenomenon: E74-like ETS transcription factor (ELF5), osteopontin, GATA binding protein 3 (GATA3), and Mir200c. Another molecular player could be the parathyroid hormone-related protein (PTHrP). Mice lacking each of these molecules have impaired alveologenesis during pregnancy. Finally, several data seem to suggest a strong functional relationship between the onco-suppressor gene breast cancer gene 1 (BRCA1) and the reversible adipo-epithelial transdifferentiation phenomenon, opening new avenues for future studies in the connection between pinking and breast cancer.
Proteomic and functional analysis on endothelial cell heterogeneity identifies key regulators in hyperglycemia-induced dysfunction.
Minjares M, Jaiswal R, Li H … +4 more , Zhang X, Shvartsman S, Yi Z, Wang JM
Am J Physiol Cell Physiol · 2025 Dec · PMID 41217013 · Full text
Endothelial cells (ECs) play a critical role in managing vascular homeostasis and neovascularization. EC functions vary significantly depending on their anatomic locations, especially for ECs forming macrovascular versus...
Endothelial cells (ECs) play a critical role in managing vascular homeostasis and neovascularization. EC functions vary significantly depending on their anatomic locations, especially for ECs forming macrovascular versus microvascular vessels. ECs possess heterogeneous signaling pathways, energy metabolism, and cellular behaviors that enable them to handle both physiological and hyperglycemic conditions. These variations can impact the efficacy of pharmacotherapy and influence the likelihood of unexpected side effects. In this study, we compared human aortic ECs (HAECs) and human dermal microvascular ECs (HDMVECs) to observe the functional and proteomic differences potentially contributing to EC heterogeneity. Compared with HAECs, HDMVECs exhibited faster proliferation, but lower migration and permeability. Under high glucose (HG), migration was worsened for both cell types, whereas proliferation was unaffected, and permeability increased for HDMVECs. Using proteomic analysis, we identified 126 proteins whose abundance was significantly different between HAECs and HDMVECs. Database for Annotation, Visualization, and Integrated Discovery (DAVID) analysis revealed their biological processes, cellular compartments, molecular functions, and pathways. Under high glucose, WARS1 increased whereas SOD2 decreased. Reversing WARS1 or SOD2 expression levels improved HDMVEC migration and permeability functions. The combined treatment of WARS1 knockdown and SOD2 overexpression fully restored EC migration and reduced permeability to levels comparable with those of their counterparts under normal glucose (NG) conditions. Furthermore, in the cutaneous wound in type 2 diabetic mice, the combination therapy of Wars1 knockdown and SOD2 overexpression accelerated the wound closure and augmented wound angiogenesis. Our studies provide novel molecular insights into EC heterogeneity and identified WARS1 and SOD2 as potential targets for dermal angiogenesis during tissue repair. Our research highlights the functional and proteomic differences between human aortic endothelial cells (HAECs) and human dermal microvascular endothelial cells (HDMVECs). Importantly, we identified WARS1 as a novel target in HDMVECs. Together with SOD2, correcting the abnormalities of these two molecules, HDMVECs' migration and permeability can be fine-tuned under high glucose (HG) conditions. Furthermore, WARS1 knockdown and SOD2 overexpression accelerated wound healing in type 2 diabetic mice, highlighting the therapeutic potential of targeting WARS1 and SOD2 to address delayed wound healing in diabetes.
Endothelial cells retain inflammatory memory through chromatin remodeling in a two-hit model of infection-induced inflammation.
Gonsales Spindola D, Bahr A, Clark S … +13 more , Pin de Jesus G, Martino N, Lowery A, Lyu S, Seeman A, Martino G, Albeche Duarte G, Crosbourne E, Vincent P, Bai G, Adam AP, MacNamara KC, Bossardi Ramos R
Am J Physiol Cell Physiol · 2025 Dec · PMID 41217002 · Full text
Sepsis survivors face a heightened risk of secondary infections following discharge, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein...
Sepsis survivors face a heightened risk of secondary infections following discharge, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein inflammatory exposure induces durable chromatin remodeling in endothelial cells (ECs), priming them for exaggerated responses to a subsequent infection. Utilizing a clinically relevant two-hit mouse model, cecal ligation and puncture (CLP) followed by mild () infection in CLP survivors, we reveal transcriptional activation in endothelial cells (ECs) following secondary infection, marked by significantly elevated expression of proinflammatory cytokines, adhesion molecules, complement factors, and interferon-stimulated genes. Genome-wide ATAC-seq revealed that a subset of inflammatory gene loci retained increased chromatin accessibility even after cytokine withdrawal, demonstrating stable epigenetic remodeling consistent with transcriptional priming and inflammatory memory. In vitro, we uncovered a critical role for the activator protein-1 transcription factor JunB in mediating this epigenetic remodeling. JunB knockdown attenuated chromatin accessibility after an initial IL-6 challenge and subsequent transcriptional amplification upon a secondary LPS challenge, pinpointing JunB-driven chromatin modifications as central to endothelial reprogramming. Our findings offer mechanistic insights into how transient inflammation creates lasting epigenetic states within the endothelium, highlighting JunB as a potential therapeutic target to mitigate chronic endothelial dysfunction and increased susceptibility to secondary infections postsepsis. We uncover that endothelial cells retain a form of inflammatory memory, driven by chromatin remodeling and sustained JunB activity. Using two-hit models in mice and human endothelial cells, we show that an initial inflammatory exposure primes the endothelium for exaggerated responses to future inflammation. This discovery reveals a new mechanism of chronic endothelial dysfunction and identifies JunB as a potential therapeutic target in postsepsis care.
Musculoskeletal responses to spaceflight: mechanisms, countermeasures, and key gaps.
Roberts BM, Deane CS, Szewczyk NJ … +3 more , Fajardo VA, Maden-Wilkinson T, Bagley JR
Am J Physiol Cell Physiol · 2025 Dec · PMID 41217000 · Publisher ↗
Spaceflight and partial-gravity environments impose profound challenges to the human musculoskeletal system, driving rapid muscle atrophy, progressive bone loss, and tendon maladaptation. At the molecular level, unloadin...
Spaceflight and partial-gravity environments impose profound challenges to the human musculoskeletal system, driving rapid muscle atrophy, progressive bone loss, and tendon maladaptation. At the molecular level, unloading suppresses anabolic signaling, enhances proteolysis, and induces mitochondrial stress, whereas bone and tendon exhibit reduced extracellular matrix turnover and impaired mechanotransduction. Recent space-omics and cross-species studies, including rodent and models, reveal that these catabolic responses are evolutionarily conserved and involve systemic pathways mediated by myokines, osteokines, and tendon-derived signals. Current countermeasure strategies primarily consist of structured exercise regimens with limited pharmacologic support. Although these strategies mitigate some loss, they fail to fully preserve musculoskeletal integrity, particularly tendon properties and microarchitectural bone quality. Key gaps remain in the development of tendon-specific interventions, integrated pharmacologic and exercise regimens, nutrition and dietary protocols, and methods for partial-gravity adaptation and safe re-entry. Leveraging real-time monitoring, individualized exercise programs, and systemic biomarker discovery through space omics presents major opportunities for next-generation, personalized countermeasures. This mini-review synthesizes current knowledge of musculoskeletal responses with a particular focus on tendon maladaptation and interorgan cross talk to spaceflight and partial gravity, highlights countermeasure efficacy and limitations, and identifies critical gaps that must be addressed to ensure astronaut health and performance during future missions. Insights from these studies also provide translational relevance for disuse atrophy, osteoporosis, and tendon injuries on Earth.
Hemizygous mutation of in muscle stem cells increases H3K27 methylation on leading to impaired myogenesis.
Tidball JG, Petrossian L, McKee CM … +1 more , Wehling-Henricks M
Am J Physiol Cell Physiol · 2025 Dec · PMID 41212538 · Full text
Development of myogenic cells, called satellite cells, is determined by transcription factors that regulate their quiescence (e.g., Pax7), activation (e.g., MyoD), and terminal differentiation (e.g., myogenin). Demethyla...
Development of myogenic cells, called satellite cells, is determined by transcription factors that regulate their quiescence (e.g., Pax7), activation (e.g., MyoD), and terminal differentiation (e.g., myogenin). Demethylation of lysine 3 on histone 27 (H3K27) activates expression of and In this investigation, we investigated the effects of a satellite cell-targeted, hemizygous mutation of the H3K27 demethylase in healthy muscle. Using sequencing of chromatin fragments precipitated from mutant and control satellite cells using anti-H3K27me3, we found that the promoter was the only chromatin that experienced significantly increased H3K27 methylation in mutant cells. However, RNA sequencing showed that 143 genes were downregulated in mutant cells, including , a direct target of , and at least 72 other genes that contained E-boxes targeted by . Gene ontology analysis showed enrichment of genes involved in myogenesis in the downregulated genes. Reduced expression of , , and was confirmed by quantitative PCR (qPCR), Western blots, and immunohistochemistry. Mutant muscles also had smaller diameter fibers, fewer myonuclei, and diminished myogenic cell fusion, indicating impaired growth and differentiation. These findings show that Jmjd3 affects demethylation of H3K27 at the promoter, and increased H3K27 methylation reduces expression of and its target genes, disrupting muscle growth. This investigation reveals a new mechanism that regulates the development of muscle. Mutating produced epigenetic modifications to the transcription factor , reducing its expression and impairing muscle growth.
Tumor growth and chemotherapy alter skeletal muscle, cardiac, and hepatic amino acid pools in mice.
McCue MV, Rebalka IA, Paquette ML … +2 more , Hawke TJ, MacLean DA
Am J Physiol Cell Physiol · 2025 Dec · PMID 41212532 · Publisher ↗
Amino acids (AAs) play structural and metabolic roles in muscle, heart, and liver-tissues impacted by cancer and chemotherapy. Changes in AA profiles within these tissues have not been evaluated in response to tumor grow...
Amino acids (AAs) play structural and metabolic roles in muscle, heart, and liver-tissues impacted by cancer and chemotherapy. Changes in AA profiles within these tissues have not been evaluated in response to tumor growth and chemotherapy. This study investigated how tumor growth with or without doxorubicin altered tissue-level amino acids. Female C57bl/6 mice ( = 7-10/group) were randomly assigned to groups: control, doxorubicin control at 3 and 7 days, 21-day tumor, 24-day tumor, 28-day tumor, 24-day tumor + doxorubicin, 28-day tumor + doxorubicin. Tumor groups were injected with E0771 cells in the right flank on . Doxorubicin was administered once (intraperitoneally) at 10 mg/kg in doxorubicin control and tumor + doxorubicin groups on , with endpoints at and . Muscle glutamate and aspartate were significantly depleted by in both tumor and tumor + doxorubicin groups ( < 0.05), whereas proline, arginine, leucine, and isoleucine increased ( < 0.05). Hepatic aspartate was elevated by 21 days, and lysine by 24 days ( < 0.05). Cardiac glutamate was depleted at , , and ( < 0.05). Notably, doxorubicin did not add to tumor-induced changes in muscle or heart. Tumor AAs remained largely stable. Tumor growth induced profound changes to skeletal muscle AA pools, reflecting impaired handling of AAs that could serve structural roles, or expand the substrate pool for ATP synthesis. Despite this, most tumor AAs remained stable over tumor growth. These results suggest a link between muscle wasting and skeletal muscle-derived AAs for tumor growth. Further work is needed to characterize the mechanisms mediating the observed changes in AA profiles. This study demonstrates significantly perturbed amino acid pools within muscle as a result of tumor growth, with marginal additive effects of doxorubicin administration. Notably, tumor amino acid pools remain primarily unchanged despite muscle suggesting significant changes, which may be indicative of structural damage or reduced ability to produce energy.
Ca, ROS, IL-6, and p38 MAPK signaling loops underlying alterations in myotube formation induced by a severe MH/CCD mutation in RyR1.
Valle-Clara M, Ávila G
Am J Physiol Cell Physiol · 2025 Dec · PMID 41212187 · Publisher ↗
Mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) can result in muscle diseases, termed RyR1-related myopathies (RyR1-RM). Examples include malignant hyperthermia (MH), central core disease (CC...
Mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) can result in muscle diseases, termed RyR1-related myopathies (RyR1-RM). Examples include malignant hyperthermia (MH), central core disease (CCD), and centronuclear myopathy (CNM). The muscles involved often have more (and mispositioned) nuclei than normal. A subset of the corresponding mutant proteins shows an overactive or leaky sarcoplasmic reticulum (SR) channel behavior that depletes the SR Ca content and increases the level of cytosolic Ca. In addition, two remarkable effects of these RyR1 variants have been reported in cultured myogenic cells: enhanced expression of interleukin-6 (IL-6) and stimulation of myoblast fusion (myonuclei accretion). Here, we have investigated whether the latter effect is due to a possible IL-6-dependent autocrine loop. Toward this goal, we analyzed the impact of the overactive Y523S mutant compared with the wild-type RyR1 after expression in C2C12 cells. The results show that this mutation indeed drastically promotes myoblast fusion up to ∼300%. Moreover, this action depends on the sequential activation of SR Ca release, store-operated Ca channels, reactive oxygen species (ROS, cytosolic and mitochondrial), calpain, and calcineurin. In addition, a neutralizing antibody directed against IL-6 and a p38 inhibitor completely suppressed the stimulation of myoblast fusion. Furthermore, in RyR1-expressing cells, myotube formation was promoted by either exogenous IL-6 or conditioned medium obtained from the Y523S-expressing cells. These findings suggest an autocrine mechanism involving the interplay between Ca, ROS, IL-6, and p38 signaling pathways in controlling myonuclei density, which could be essential to explain the pathogenesis of RyR1-RM. Overactive RyR1 mutant proteins are associated with muscle disease; interestingly, they increase the number of myonuclei when expressed in C2C12 cells. We discovered that this alteration depends on a Ca/ROS loop, which recruits calpain and calcineurin to stimulate the production of IL-6 and the subsequent autocrine activation of p38. Thus, disease-causing RyR1 mutations require an IL-6 autocrine system to alter myonuclear density. This novel mechanism could be critical to understanding the pathogenesis of congenital myopathies.
The release of catecholamines to the cytosol and the exocytosis of secretory vesicles triggered by IP in chromaffin cells.
Sanz-Lázaro S, Jiménez-Pompa A, Hernández-Vivanco A … +6 more , Carmona-Hidalgo B, García-Magro N, Pérez-Alvarez A, Caba-González JC, Rueda-Ruzafa L, Albillos A
Am J Physiol Cell Physiol · 2025 Dec · PMID 41196165 · Publisher ↗
The aim of the present study was to investigate the secretory responses elicited by inositol 1,4,5-trisphosphate (IP) and their regulation by Ca from different sources. Fura-2, carbon fiber amperometry, and plasma membra...
The aim of the present study was to investigate the secretory responses elicited by inositol 1,4,5-trisphosphate (IP) and their regulation by Ca from different sources. Fura-2, carbon fiber amperometry, and plasma membrane capacitance recordings were performed in mouse chromaffin cells to evaluate cytosolic Ca changes, catecholamine release, and exocytosis, respectively. Amperometric recordings revealed that IP triggered the continuous release of catecholamines to the cytosol with a plateau shape, either applied independently or in combination with the V-ATPase blocker bafilomycin A1, without exhibiting additive effects, which suggests that V-ATPase blockade might be a potential mechanism of action. The catecholamine release elicited by IP can take place in the absence of cytosolic Ca; however, it may be also regulated by it through a bell-shaped mechanism, with the contribution of Ca stored in intracellular organelles. Furthermore, plasma membrane capacitance recordings showed that IP could also elicit exocytosis of secretory vesicles with the participation of intracellular organelle Ca stores. This exocytosis could be regulated by vesicular or cytosolic Ca, as shown in experiments with bafilomycin A1 or the Ca chelator BAPTA-AM, respectively, and by kaempferol, an activator of the mitochondrial Ca uniporter, suggesting that mitochondria may exert physiologically this Ca regulatory mechanism. Therefore, in the IP-mediated secretion, Ca from different sources control the different steps of catecholamine release from the secretory vesicle to the cytosol and then finally to the extracellular space. Inositol 1,4,5-trisphosphate (IP) triggers the release of catecholamines from secretory vesicles to the cytosol through a process that may occur in the absence of cytosolic Ca, it is biphasically regulated by it and is dependent on Ca from intracellular organelles. Additionally, IP triggers the exocytosis of secretory vesicles through a cytosolic and vesicular Ca regulatory mechanism that may be physiologically modulated by mitochondria.
Mucin 5ac modulates cancer-associated fibroblast heterogeneity through epigenetic reprogramming of precursor cells.
Kehrberg RJ, Bhyravbhatla N, Alsafwani ZW … +7 more , Li X, Natarajan G, Khan I, Brand RE, Jain M, Batra SK, Kumar S
Am J Physiol Cell Physiol · 2026 Jan · PMID 41196138 · Full text
Pancreatic cancer (PC) is characterized by extensive desmoplasia, with heterogeneous cancer-associated fibroblasts (CAFs) as a major component. However, the contribution of distinct precursor cells to CAF heterogeneity r...
Pancreatic cancer (PC) is characterized by extensive desmoplasia, with heterogeneous cancer-associated fibroblasts (CAFs) as a major component. However, the contribution of distinct precursor cells to CAF heterogeneity remains poorly defined. This study investigated the role of Muc5ac in modulating CAF heterogeneity by maturing precursor cells, including adipose-derived mesenchymal stem cells (AD-MSCs), bone marrow-derived MSCs (BM-MSCs), and pancreatic stellate cells (PSCs), into different CAF subsets. RNA sequencing of precursor cells treated with conditioned media from Muc5ac-proficient or -deficient cancer cells revealed distinct transcriptional profiles. Muc5ac significantly modulated the expression of and in AD-MSCs, promoting the acquisition of extracellular matrix production, cytokine signaling, and antigen presentation programs, characteristic of both inflammatory (iCAF) and myofibroblastic (myCAF) CAF phenotypes. In PSCs, Muc5ac increased H3K27 acetylation independent of its interactome, which was validated in autochthonous murine models. Transcriptome analysis demonstrated that AD-MSCs contributed 44.4% to the CAF population, followed by PSCs (31.5%) and BM-MSCs (21.6%). Gene Ontology (GO) and KEGG analyses revealed distinct functional programs for each precursor population contributing to CAF heterogeneity. An age-dependent signature in AD-MSC maturation was identified, with a significant positive correlation between serum INHBA and MUC5AC from younger (≤55 yr, = 20) compared with older (≥75 yr, = 20) patients. Cancer-associated fibroblast (CAF) heterogeneity limits effective stromal targeting in pancreatic cancer (PC). This study shows that adipose- and bone marrow-derived mesenchymal stem cells and pancreatic stellate cells intrinsically mature into distinct CAF subtypes. Muc5ac modulates the expression of epigenetic regulators and drives adipose-derived cells to dominate the CAF population. Defining precursor cell-specific CAF programs provides a framework to selectively target tumor-promoting CAFs, offering a potential strategy to improve stroma-targeted therapies in PC.
Nherf2 is a major determinant of bile acid pool dynamics and contributes to regulation of Western diet-induced obesity.
Dong D, Shen WJ, Bittner S … +5 more , Chen J, Hao X, Donowitz M, Kraemer FB, Azhar S
Am J Physiol Cell Physiol · 2025 Dec · PMID 41171107 · Full text
Dysregulation of cholesterol metabolism can lead to obesity and increase the risk of developing many diseases, including type 2 diabetes and cardiovascular diseases. Our previous studies have identified postsynaptic dens...
Dysregulation of cholesterol metabolism can lead to obesity and increase the risk of developing many diseases, including type 2 diabetes and cardiovascular diseases. Our previous studies have identified postsynaptic density-95, disc large, and zonula occludens-1 (PDZ) adaptor proteins Na/H exchange regulatory factor Nherf1 (encoded by ) and Nherf2 (encoded by ) to be potential regulators of cholesterol metabolism in vitro. In this study, we explored their physiological regulatory function in vivo by using Nherf1- and Nherf2-deficient ( and ), and wild-type (C57BL/6) mice. All mice were fed either a chow diet or a cholesterol-enriched Western diet (42% fat, 0.2% cholesterol) for 8 wk starting at 8-wk-old. Our results demonstrate that , but not , mice are resistant to diet-induced obesity. In mice, serum high-density lipoprotein and low-density lipoprotein/very low-density lipoprotein decreased substantially without affecting lipolysis or steroid hormone levels. In addition, distended gallbladders were observed in mice, with reduced bile acid output into the intestine and feces, which correlated with decreased cholesterol reabsorption. This led to attenuated Fxr/Shp signaling in the liver and derepressing transcription in the absence of Nherf2. These findings suggest a potential role of in regulating gallbladder emptying and lipid homeostasis, offering new insights into potential therapeutic targets for treating diet-induced obesity. but not mice demonstrate a resistance to diet-induced obesity. Notably, male mice exhibit impaired glucose tolerance and insulin responsiveness, yet neither sex shows further worsening with diet challenge. In addition, elevated hepatic levels were observed in mice, but there was reduced cholesterol absorption in the ileum, along with enlarged gallbladders and diminished ileal bile acid content, highlighting significant metabolic alterations linked to Nherf2 deficiency.
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