American journal of physiology. Cell physiology最新文献

{"title":"Mechanistic Modeling of MCUx Gatekeeping, Ca²⁺ Transport, and Coupled Cytosolic-Mitochondrial Ca²⁺ Dynamics.","authors":"Yisak D Asefa, Devanshi D Dave, Said H Audi, Dexuan Xie, Xiaowen Bai, Allen W Cowley, Ranjan K Dash","doi":"10.1152/ajpcell.00204.2026","DOIUrl":"10.1152/ajpcell.00204.2026","url":null,"abstract":"<p><p>Mitochondrial Ca²⁺ uptake is mediated by the mitochondrial calcium uniporter complex (MCUx), in which MICU1/2 serve as cytosolic Ca2+-sensing gatekeepers that set a Ca²⁺-dependent activation threshold. Coordinated control of MCUx activity is critical because mitochondrial Ca²⁺ uptake couples cytosolic Ca²⁺ signals to metabolic activation and must be regulated to prevent mitochondrial Ca²⁺ overload and bioenergetic dysfunction. We developed a mechanistic model that incorporates explicit MICU1/2-dependent MCUx gatekeeping and a thermodynamically constrained Ca²⁺ transport formulation that accounts for Mg²⁺ inhibition and membrane potential dependence. Cytosolic and mitochondrial Ca²⁺ dynamics were simulated by integrating the MCUx model into a mitochondrial cation-handling model under multiple Ca²⁺ stimulation protocols. Because matrix-side Ca²⁺ regulation of MCUx remains controversial, we also evaluated a putative matrix-side regulatory mechanism by comparing simulations with and without an added matrix-side regulatory module, rather than assuming such regulation as a required feature of the MCUx model. The model reproduces key experimental behaviors across genotypes. In wild-type mitochondria, MCUx-mediated Ca²⁺ uptake is negligible below a cytosolic Ca²⁺ threshold (~0.2 µM), whereas MICU1-knockout mitochondria show constitutive uptake and MICU2-knockout mitochondria exhibit an intermediate, lowered threshold. Inclusion of matrix-side MCUx regulation transiently attenuated MCUx-mediated Ca²⁺ uptake over an intermediate mitochondrial Ca²⁺ range, producing higher transient cytosolic Ca²⁺ and lower transient mitochondrial Ca²⁺, while both cases approached similar steady states. In addition, cytosolic Mg²⁺ acts as a graded inhibitor of MCUx-mediated Ca²⁺ uptake, limiting mitochondrial Ca²⁺ loading. These results provide a quantitative framework for coupled cytosolic-mitochondrial Ca²⁺ dynamics across diverse conditions.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of ovarian hormones modulates sex-specific metabolic adaptations to volumetric muscle loss.","authors":"Angela S Bruzina, William T Juckett, Faezeh Mozafari, Carlee G Freeman, Jarrod A Call, Sarah M Greising","doi":"10.1152/ajpcell.00251.2026","DOIUrl":"10.1152/ajpcell.00251.2026","url":null,"abstract":"<p><p>Volumetric muscle loss (VML) results in persistent functional and metabolic deficits, yet the influence of biological sex and ovarian hormones on these outcomes remains poorly understood. Here, we examined male, intact female, and ovariectomized (OVX) female mice at 12 wk following VML to determine how biological sex and the loss of ovarian hormones affect whole body metabolism, functional recovery, and tissue remodeling. Males postinjury relied on greater lipid oxidation postprandially, whereas females maintained robust carbohydrate oxidation and dynamic metabolic flexibility. The loss of ovarian hormones increased adiposity and impaired the sex-specific advantage in glucose responsiveness. Biological sex did not influence maximal isometric torque or contractile properties following VML, which accompanied similarities in mitochondrial content [i.e., citrate synthase, pyruvate dehydrogenase (PDH) activity]. Females exhibited greater complex II activity than males, whereas the loss of ovarian hormones decreased complex I and PDH activity. Despite comparable lipid accumulation in females with and without ovarian hormones, maximal isometric torque and contractile properties were impaired with the loss of ovarian hormones. Proximity to VML defect influenced lipid droplet proteins, specifically perilipin 2, though not affected by biological sex or ovarian hormone loss. Collectively, these findings indicate that sex-specific differences in substrate utilization and mitochondrial function, mediated in part by ovarian hormones, may underlie the divergent metabolic and functional trajectories following VML. These results highlight the importance of considering biological sex and ovarian hormones in preclinical studies and therapeutic strategies for regenerative interventions.<b>NEW & NOTEWORTHY</b> This study combined ovariectomy and volumetric muscle loss injury model to investigate if ovarian hormones play a protective role in females during the sequelae of traumatic skeletal muscle injury. The loss of ovarian hormones induces whole body and cellular metabolic inflexibility and worsened functional recovery, identifying ovarian hormones as key regulators of VML-induced metabolic pathophysiology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C117-C136"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13333190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immediate icing disrupts the very early MCP-1/CCR2 recruitment window and delays muscle regeneration in rats.","authors":"Asano Tamari, Eriko Nitta, Erika Terada, Itsuki Nagata, Masato Kawashima, Tohma Sakuraya, Takahiro Sonomura, Noriaki Maeshige, Ryo Nitta, Takamitsu Arakawa","doi":"10.1152/ajpcell.00190.2026","DOIUrl":"10.1152/ajpcell.00190.2026","url":null,"abstract":"<p><p>Icing is a widely used initial intervention for skeletal muscle injury in sports settings. However, accumulating evidence suggests that icing impairs muscle regeneration, potentially via delayed monocyte/macrophage accumulation. To elucidate the mechanisms underlying this icing-induced delay, we investigated whether icing modulates the monocyte chemoattractant protein 1 (MCP-1)/CC chemokine receptor 2 (CCR2) axis governing monocyte/macrophage recruitment. We comprehensively characterized inflammatory cell dynamics in a rodent crush-injury model using immunostaining and flow cytometry. During the very early phase (up to 5 h postinjury), neutrophils were the dominant inflammatory cell population within the lesion. Subsequently, MCP-1 concentrations and CCR2⁺ monocytes/macrophages increased and became prominent within 24 h, suggesting that MCP-1/CCR2 signaling prominently contributes to monocyte/macrophage recruitment during this early phase. Consistently, CD68^midCD163^lo monocytes/macrophages, which exhibited the highest <i>Ccr2</i> expression, predominated during the first 24 h. Immediate icing transiently suppressed MCP-1 production by neutrophils and monocytes/macrophages during this very early phase and was associated with attenuated subsequent recruitment of circulating monocytes. Consequently, monocyte/macrophage accumulation peaked at 48 h in the nonicing group but was delayed until 72 h in the immediate icing group. Notably, the late-icing model demonstrated that withholding icing during the early phase preserved normal monocyte/macrophage dynamics. Collectively, these results show that immediate icing disrupts the early MCP-1/CCR2-associated recruitment phase, likely by reducing the number of inflammatory cells and their production of MCP-1, thereby contributing to delayed monocyte/macrophage accumulation. These findings provide a crucial mechanistic basis for reconsidering and optimizing the timing of cryotherapy in clinical and sports settings.<b>NEW & NOTEWORTHY</b> Icing after severe muscle injury provides analgesic benefits but delays monocyte/macrophage-mediated regeneration. We demonstrate that immediate icing disrupts early MCP-1 production by neutrophils and infiltrating monocytes/macrophages during the very early postinjury phase, which likely contributes to the subsequent attenuation of circulating monocyte recruitment. These findings provide clinical insight into the importance of optimizing the timing of icing and avoiding its use during the very early phase.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C222-C235"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles in exhaled breath condensate as emerging biomarkers in lung cancer.","authors":"Benjamin Schmidt, Coralie Tambon, Francesca Cortopassi, Carsten Bokemeyer, Meike J Saul","doi":"10.1152/ajpcell.00069.2026","DOIUrl":"10.1152/ajpcell.00069.2026","url":null,"abstract":"<p><p>Exhaled breath condensate (EBC) has emerged as a noninvasive liquid biopsy medium that captures aerosolized material from the respiratory tract and may provide insight into local lung biology. Within this matrix, extracellular vesicles (EVs) can carry DNA, RNA, proteins, and lipids that reflect cellular origin and may report tumor-associated inflammation, airway remodeling, and microenvironmental changes. This review summarizes current evidence on the molecular composition, origin, and biogenesis of EVs detected in EBC, with emphasis on their potential for early lung cancer detection and longitudinal disease monitoring. Proteomic, transcriptomic, and genomic analyses have identified tumor-associated signatures, including cytokines, driver mutations, and epigenetic alterations, whereas lipidomic profiling may capture oxidative, inflammatory, and metabolic stress. Recent methodological advances in EV enrichment, microfluidics, single-vesicle analytics, and digital assays are improving the sensitivity of low-biomass EBC analyses. However, EBC-derived EV research remains technically challenging, and standardization of collection, EV isolation, molecular analysis, and reporting is essential. Artificial intelligence (AI) and machine learning (ML) may support integration of multiomic and clinical data, particularly when validated in prospective cohorts. Together, these developments position EBC-derived EVs as an emerging, patient-friendly, lung-proximal platform for biomarker discovery and future precision oncology applications, while underscoring the need for source-resolved validation and clinical translation studies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C101-C116"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model epithelia from rumen organoids.","authors":"Saeed Khomeijani Farahani, Franziska Liebe, Subhakankha Manna, Franziska Weiß, Friederike Stumpff, Dorothee Günzel","doi":"10.1152/ajpcell.00809.2025","DOIUrl":"10.1152/ajpcell.00809.2025","url":null,"abstract":"<p><p>The ruminal epithelium maintains livestock health by absorbing nutrients while maintaining a tight barrier between the lumen and the plasma space. This study demonstrates that rumen organoid-derived two-dimensional cultures approximate native tissue architecture and reach greater epithelial purity than primary cultures, particularly at later passages. For the initial transcriptomic and structural comparison, cells isolated from stratum basale by fractional trypsinization were used to generate model epithelia on cell culture inserts either from early-passage primary cultures (∼<i>passage 3</i>) or after organoid expansion (∼<i>passage 10</i>). Transcriptomic analysis was used to compare the primary culture inserts, the organoid-derived inserts, and the native tissues from which they had been derived. Although both cell culture models yielded epithelial-like growth with barrier formation (transepithelial electrical resistance > 400 Ω·cm²), transcriptomic analysis revealed higher expression of fibroblast/mesenchymal stromal extracellular matrix (ECM) markers (<i>COL1A1, COL3A1, POSTN</i>, and <i>MFAP5</i>) in the inserts from the primary cultures. In addition, ECM-remodeling genes (<i>TGFB1, TIMP1, TIMP2, TIMP3, MMP2, MMP7, MMP12</i>, and <i>MMP13</i>) were upregulated in primary culture inserts, suggesting increased tissue remodeling activity in conjunction with the expression of inflammatory mediators (<i>ICAM1, IL6</i>, and <i>CXCL12</i>). Organoid-derived inserts showed less affected mitochondrial pathways [Cytochrome c oxidase (<i>COX1</i>, <i>COX2</i>), <i>NDUFA</i>, <i>NDUFB</i>, and <i>ATP</i> synthase genes] and ribosomal machinery (<i>RPL</i> and <i>RPS</i> families), while maintaining epithelial purity with no detectable fibroblast or immune cell contamination. The expression of mRNA for numerous short-chain fatty acid transporters is confirmed, including MCT1, MCT4, DRA, PAT, SMCT1, anion exchanger 2, and <i>SLCO2A1</i>. This study establishes organoids as a physiologically relevant model for studying rumen epithelial physiology.<b>NEW & NOTEWORTHY</b> This study provides a comprehensive comparison between rumen tissue, primary culture, and organoid-derived cell culture inserts through detailed transcriptomic analysis. Cells grown over multiple passages in organoid culture differentiate into model epithelia that better approximate native tissue architecture and reach greater epithelial purity than primary cultures, particularly at later passages. The establishment of a sustainable organoid system with demonstrated molecular fidelity offers a valuable tool for studying rumen epithelial biology while reducing dependence on native tissue.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C137-C156"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"17β-Estradiol mitigates ovariectomy-induced defects in mitochondrial bioenergetics and redox balance after VML injury in female mice.","authors":"Junwon Heo, David L Miller, Jessica R Hoffman, Reese M Groover, Sarah M Greising, Jarrod A Call","doi":"10.1152/ajpcell.00282.2026","DOIUrl":"10.1152/ajpcell.00282.2026","url":null,"abstract":"<p><p>Volumetric muscle loss (VML) is characterized by an irrecoverable loss of skeletal muscle mass, persistent functional deficits, and metabolic dysfunction. A disrupted cellular redox homeostasis is one attribute of this metabolic dysfunction and can lead to excessive reactive oxygen species (ROS) emissions and chronic oxidative stress. The primary objective of this study was to define the role of ovarian hormones, specifically 17β-estradiol (17β-E2), in driving mitochondrial bioenergetic and redox balance after VML injury. Female C57BL/6J mice were randomized into experimental and control groups (VML-sham OVX, VML-OVX, and VML-OVX-E2). A time course of ROS emissions and antioxidant buffering capacity (AoxBC) for VML-injured muscles was established across the first 60 days post injury (dpi) in ovary-intact females. Ovariectomy (OVX) was performed before injury to deplete ovarian hormones, and 17β-E2 was administered via continuous-release pellets to investigate the effects of hormone loss and repletion on ROS emissions and mitochondrial bioenergetics. The long-term effects of 17β-E2 were evaluated to determine whether restoring redox led to sustained redox balance in the long term. Transcriptomic analyses were conducted to explore molecular mechanisms of 17β-E2 benefit after VML. In intact females, ROS emissions were greater during the first 14-dpi, but AoxBC recovered more rapidly than previously observed in males. OVX exacerbated VML-induced metabolic dysfunction, resulting in less AoxBC, greater ROS emissions, and an early suppression of mitochondrial gene networks. 17β-E2 repletion attenuated ROS emissions and improved AoxBC at 7-dpi, and led to greater mitochondrial respiratory capacity, conductance, and bioenergetic efficiency out to 60-dpi. Chronic 17β-E2 depletion resulted in impaired glucose tolerance and greater adiposity, which were mitigated by 17β-E2 treatment. Transcriptomic analyses suggest that 17β-E2 contributes to resolving inflammation and enforcing a temporal decoupling of cellular expansion and mitochondrial maturation after VML injury.<b>NEW & NOTEWORTHY</b> Female mice exhibit accelerated recovery of mitochondrial redox balance after volumetric muscle loss (VML) compared with males. This study demonstrates that 17β-estradiol (17β-E2) drives this resilience. Following VML, ovariectomy induced an early transcriptional arrest and asynchronous repair signaling. 17β-E2 replacement restored regenerative coordination by temporally decoupling early cellular expansion from mitochondrial biogenesis. This precise transcriptional regulation translated to long-term functional resilience, restoring mitochondrial bioenergetic efficiency and resolving oxidative stress.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C205-C221"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13379902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148215993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autonomic nervous system dysregulation as a driver of atrial fibrillation: pathways, modulators, and therapies.","authors":"Sutapa Saha, Jordan Thorpe, Adam P Hill","doi":"10.1152/ajpcell.00871.2025","DOIUrl":"10.1152/ajpcell.00871.2025","url":null,"abstract":"<p><p>Cardiac arrhythmias affect 1%-5% of the global population, with atrial fibrillation (AF) being the most common and clinically relevant. While AF is traditionally linked to electrical and structural remodeling of the atria, growing evidence highlights a critical yet underexplored contributor: dysfunction of the autonomic nervous system (ANS). The ANS regulates heart rate and rhythm through sympathetic and parasympathetic inputs, and its imbalance can initiate and sustain AF by promoting ectopic activity, shortening refractory periods, and enhancing reentry circuits. Autonomic dysregulation is further impacted by lifestyle and environmental influences. Excessive alcohol intake, chronic stress, sleep deprivation, and extreme physical exertion have all been shown to modulate autonomic activity and elevate the risk of AF. Additionally, social determinants such as socioeconomic status and healthcare access indirectly influence AF susceptibility through chronic activation of neurocardiac stress pathways. Mechanistically, emerging research implicates sympathetic hyperinnervation, neuroinflammation, and dysfunction of intrinsic cardiac ganglionated plexi as key contributors to arrhythmogenic remodeling. However, current animal models often fail to capture the complexity of human neuro-cardiac interactions due to species-specific differences in cardiac anatomy, innervation patterns, and immune responses. Human induced pluripotent stem cell (iPSC)-derived models offer an alternative, patient-specific platform to study ANS-driven mechanisms in AF. This review focuses on the role of the ANS in AF pathophysiology, examining the cellular and molecular mechanisms by which autonomic dysregulation promotes arrhythmia. We explore current therapeutic interventions of autonomic-driven AF and discuss the potential of new models to improve mechanistic insight and therapeutic development.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C74-C88"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell analysis of muscle contracture in cerebral palsy reveals profibrotic and antimyogenic stem cell populations with altered cell-cell interactions.","authors":"Madison W Stewart, Lin-Ya Hu, Taryn Loomis, Sarah E Brashear, Lizbeth M De La Torre, Anas Mohamed Sulthan, Marie Villalba, Jon R Davids, Yue Wang, Vedant A Kulkarni, Lucas R Smith","doi":"10.1152/ajpcell.00808.2025","DOIUrl":"10.1152/ajpcell.00808.2025","url":null,"abstract":"<p><p>Development of muscle contractures is common in cerebral palsy (CP) and is characterized by high muscle stiffness that limits function and mobility. However, the state of stem cells within contracture, particularly muscle stem cells and fibroadipogenic progenitors, is largely unknown. This study leverages single cell RNA sequencing technology to determine how specific cell types are altered in the contracture environment. Skeletal muscle biopsies were collected from children with CP or typically developing (TD) children undergoing surgery. The 10X Genomics platform was used on tissue from <i>n</i> = 3 patients per condition. Significant changes in CP compared to TD were investigated within individual cell types for differentially expressed genes, gene ontologies, cell subpopulations, and predicted interactions. CP muscle stem cells demonstrated significant upregulation of fibrotic genes and downregulation of myogenic genes compared to typically developing. Fibroadipogenic progenitors in CP showed the emergence of a significant proportion of a highly profibrotic subpopulation, leading to the most dramatically upregulated genes in CP also being extracellular matrix constituents. Interacting signals between fibroadipogenic progenitors, muscle stem cells, and immune cells were identified that support contracture progression. Contracture is associated with reduced myogenic transcriptional features in muscle stem cells and enhances fibrotic signals in muscle stem cells and fibroadipogenic progenitors that perpetuate contracture. The study reveals specific genes and signaling pathways as therapeutic targets to reduce muscle contracture in children with CP.<b>NEW & NOTEWORTHY</b> The development of skeletal muscle contractures in cerebral palsy is a major component of disability. However, little is known about how contracture influences stem cells. This study is the first to apply single cell RNA sequencing technology to muscle contractures of children with cerebral palsy. The analysis reveals muscle stem cells with reduced myogenic transcription. Critically, a profibrotic subpopulation of fibroadipogenic progenitors is revealed in contracture. Additionally, cell-cell signaling analysis identifies potential therapeutic targets.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C13-C29"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13256198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupting the feed-forward cycle of RyR1 Ca²⁺ leak and oxidative stress mitigates doxorubicin-induced skeletal myopathy.","authors":"Lourdes C Figueroa, Eshwar R Tammineni, Pablo Marco-Moreno, Ainara Vallejo-Illarramendi, Adolfo López de Munain, Maialen Sagartzazu-Aizpurua, Michael Fill, Carlo Manno","doi":"10.1152/ajpcell.00938.2025","DOIUrl":"10.1152/ajpcell.00938.2025","url":null,"abstract":"<p><p>Doxorubicin (DOX) is a highly effective and widely used chemotherapeutic agent used to treat various types of cancer. Unfortunately, DOX also has some undesirable and off-target effects, particularly debilitating muscle weakness and fatigue. The mechanism behind this DOX-induced skeletal myotoxicity (DISM) remains unclear. Here, we show that acute DOX exposure, at clinically relevant concentrations, impairs isometric force production and accelerates fatigue in ex vivo murine flexor digitorum brevis (FDB) muscles. Mechanistically, we found that DOX increases the open probability of single RyR1 and disrupts calcium (Ca²⁺)-dependent inactivation (CDI). This results in a persistent sarcoplasmic reticulum (SR) Ca²⁺ leak, elevated basal cytosolic Ca²⁺, and abnormal Ca²⁺ release during action potentials. This abnormal intracellular Ca²⁺ handling ultimately leads to increased cellular reactive oxygen species (ROS) production, which, in turn, exacerbates the functional instability of RyR1. Interestingly, the cytosolic basal Ca²⁺ elevation precedes ROS generation, suggesting that it initiates a destructive cross talk between Ca²⁺ dysregulation and oxidative stress. Furthermore, our study suggests that DOX disrupts the interaction between RyR1 and FKBP12 and that pharmacological stabilization of this complex with the novel triazole compounds MP-001 and MP-034 normalizes RyR1 function, Ca²⁺ and ROS homeostasis, as well as muscle force and fatigue resistance. Our findings indicate that DISM is initiated by DOX destabilization of the RyR1-FKBP12 complex (abnormal SR Ca²⁺ leak) and then exacerbated by the Ca-ROS vicious cycle. Limiting RyR1-mediated Ca²⁺ leak with MP compounds represents a promising therapeutic strategy for anti-DISM, aiming to normalize muscle function in patients undergoing DOX chemotherapy.<b>NEW & NOTEWORTHY</b> Doxorubicin (DOX), a widely used chemotherapy agent, causes off-target cytotoxicity in healthy cells and often leads to debilitating skeletal muscle fatigue and weakness. In this study, we examined the effects of DOX on excitation-contraction coupling. From single RyR1 channel properties to muscle force production, we identified the underlying mechanisms of muscle dysfunction. We also evaluated novel small molecules that normalize calcium release, highlighting potential therapeutic strategies to prevent DOX-induced skeletal myopathy (DISM).</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C59-C73"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular signatures of lipid peroxidation in cardiomyopathy: unraveling oxidative mechanisms in cardiac cell dysfunction.","authors":"Tahar Hajri, Thomas V Fungwe","doi":"10.1152/ajpcell.00054.2026","DOIUrl":"10.1152/ajpcell.00054.2026","url":null,"abstract":"<p><p>Cardiomyopathy, like other major cardiovascular diseases, is becoming increasingly prevalent and represents a growing public health challenge. Although both genetic and acquired factors contribute to its development, obesity and diabetes remain among the most significant modifiable risks. These conditions share key pathological features, including oxidative stress, inflammation, and elevated lipid peroxidation, all of which can disrupt cellular metabolism and function. Lipid oxidation products, irrespective of their origin, are characterized by increased oxygenation and hydrophilicity compared with their nonoxidized precursors. These properties confer high chemical reactivity toward cellular macromolecules, enabling the formation of covalent protein adducts that alter protein structure and function. Consequently, accumulation of excess lipid oxidation products initiates cytotoxic processes that disrupt mitochondrial homeostasis, potentially impairing cardiomyocyte function and contributing to broader cardiovascular pathology. Although lipid peroxidation frequently accompanies oxidative stress and inflammation, the mechanistic interrelationships among these processes in cardiomyopathy remain poorly defined. This narrative review synthesizes current evidence on the role of lipid peroxidation in cardiomyopathy, with particular emphasis on emerging insights into its interactions with oxidative stress and inflammatory pathways. Furthermore, it examines the impact of lipid oxidation products on mitochondrial dysfunction and cardiomyocyte viability, as well as their role in promoting cardiac fibroblast activation and myocardial fibrosis, all of which are key processes underlying the initiation and progression of cardiomyopathy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C157-C176"},"PeriodicalIF":5.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}