American journal of physiology. Cell physiology最新文献

{"title":"Rab7-regulated ferroptosis contributes to tubular epithelial cells injury by degradation of GPX4 via chaperone-mediated autophagy in AKI.","authors":"Lei Liu, Qishuang Wei, Renyu Wang, Hui Sun, Sijing He, Lijuan Tang, Shuang Zhang, Yifei Liu, Shali Yu","doi":"10.1152/ajpcell.00636.2023","DOIUrl":"https://doi.org/10.1152/ajpcell.00636.2023","url":null,"abstract":"<p><p>Evidence suggests that the progression of acute kidney injury (AKI) is driven by tubular epithelial cell (TEC) injury. However, the role of ferroptosis during the regulatory process remains unclear. Fifty-three patients with AKI were included to examine the expressions of Rab7, glutathione peroxidase 4 (GPX4), and Hif-1α by immunohistochemistry. The relationship between these expressions and serum creatinine (Scr) and blood urea nitrogen (BUN) levels was analyzed. After inducing AKI and ferroptosis through bilateral renal artery ischemia-reperfusion injury (I/R) in vivo and hypoxia in vitro, we examined the expression of Rab7. The injury and ferroptosis were observed following the administration of erastin or ferrostatin-1 (Fer-1), as well as the downregulation of Rab7. In addition, we investigated the degradation of GPX4 and chaperone-mediated autophagy (CMA). Finally, we assessed the injury and ferroptosis after the combination of RAS-selective lethal 3 (RSL3) and downregulation of Rab7. GPX4 exhibited an inverse correlation with Hif-1α, Scr, BUN, and Rab7. Conversely, Rab7 was positively correlated with Scr and BUN. Both in vivo and in vitro models resulted in elevated levels of ferroptosis and Rab7. Erastin exacerbated ferroptosis and injury, but this effect was mitigated by Fer-1. Downregulation of Rab7 reversed the increased ferroptosis and injury. Hypoxia enhanced lysosomal transport and degradation of GPX4 through activation of CMA. Furthermore, the reversal of these effects was observed upon the downregulation of Rab7. However, the results obtained from Rab7 downregulation were subsequently reversed by RSL3. Ferroptosis is important in TEC injury during AKI and Rab7 promotes tubular ferroptosis by facilitating CMA-mediated degradation of GPX4.<b>NEW & NOTEWORTHY</b> To explore the mechanism underlying ferroptosis in I/R-induced renal injury and to confirm the effect of Rab7, we first evaluated ferroptosis in renal biopsy samples, and then examined Rab7 expression and renal tubular injury during AKI in vivo and in vitro. Finally, we performed in vitro experiments to investigate the specific role of Rab7 in the regulation of ferroptosis and showed that the regulatory mechanism was related to CMA-mediated GPX4 degradation in renal TECs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 2","pages":"C699-C709"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389615","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":"Does force depression resulting from shortening against series elasticity contribute to the activation dependence of optimum length?","authors":"Dean L Mayfield, Natalie C Holt","doi":"10.1152/ajpcell.00638.2024","DOIUrl":"10.1152/ajpcell.00638.2024","url":null,"abstract":"<p><p>The optimum length for force generation (<i>L</i>₀) increases as activation is reduced, challenging classic theories of muscle contraction. Although the activation dependence of <i>L</i>₀ is seemingly consistent with length-dependent Ca²⁺ sensitivity, this mechanism cannot explain the apparent force dependence of <i>L</i>₀ or the effect of series compliance on activation-related shifts in <i>L</i>₀. We have tested a theory proposing that the activation dependence of <i>L</i>₀ relates to force depression resulting from shortening against series elasticity. This theory predicts that significant series compliance would cause tetanic <i>L</i>₀ to be shorter than the length corresponding to optimal filament overlap, thereby increasing the activation dependence of <i>L</i>₀. We tested this prediction by determining <i>L</i>₀ and maximum tetanic force (<i>P</i>₀) with (<i>L</i>_{0_spring}, <i>P</i>_{0_spring}) and without added compliance in bullfrog semitendinosus muscles. The activation dependence of <i>L</i>₀ was characterized with the addition of twitch and doublet contractions. Springs attached to muscles gave added fixed-end compliances of 11%-39% and induced force depression for tetanic fixed-end contractions (<i>P</i>_{0_spring} < <i>P</i>₀). We found strong, negative correlations between spring compliance and both <i>P</i>_{0_spring} (<i>r</i>² = 0.89-0.91) and <i>L</i>_{0_spring} (<i>r</i>² = 0.60-0.63; <i>P</i> < 0.001), whereas the activation dependence of <i>L</i>₀ was positively correlated to added compliance (<i>r</i>² = 0.45, <i>P</i> = 0.011). However, since the compliance-mediated reduction in <i>L</i>₀ was modest relative to the activation-related shift reported for the bullfrog plantaris muscle, additional factors must be considered. Our demonstration of force depression under novel conditions adds support to the involvement of a stress-induced inhibition of cross-bridge binding.<b>NEW & NOTEWORTHY</b> Length-dependent Ca²⁺ sensitivity does not fully explain the activation dependence of optimum length (<i>L</i>₀). We demonstrate using an isolated muscle preparation and added series compliance that substantial force depression can arise during an isometric contraction, causing tetanic <i>L</i>₀ to shift to a shorter length. Our findings illustrate that series compliance, via the work and length dependencies of force depression, partially uncouples force generation from myofilament overlap, which ultimately increases the activation (or force) dependence of <i>L</i>₀.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C528-C540"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891411","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":"Knockdown of KLF6 ameliorates myocardial infarction by regulating autophagy via transcriptional regulation of PTTG1.","authors":"Yixin Chen, Qian Zhao, Tengfei Wu, Feifei Sun, Weineng Fu","doi":"10.1152/ajpcell.00191.2024","DOIUrl":"10.1152/ajpcell.00191.2024","url":null,"abstract":"<p><p>Krüppel-like factor 6 (KLF6) knockdown provides protection against kidney ischemia/reperfusion injury and ischemic stroke. However, it is unclear whether it plays a role in myocardial infarction (MI). Here, the expression of KLF6 was analyzed using the Gene Expression Omnibus (GEO) database and determined in patients with MI. The impact of KLF6 knockdown was further confirmed in in vivo and in vitro models of MI. The interaction between KLF6 and pituitary tumor-transforming gene 1 (PTTG1) was also evaluated. According to the GEO database, KLF6 expression was found to be upregulated in mouse hearts after MI compared to sham-operated mice. The upregulation of KLF6 in hearts from mice post-MI and in patients with MI was confirmed. KLF6 knockdown was found to alleviate myocardial injury, diminish infarct size, and suppress apoptosis and autophagy in mice with MI. In addition, inactivation of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling was observed after KLF6 knockdown in mice with MI. In an in vitro model of MI, the knockdown of KLF6 increased cell survival and inhibited autophagy through the AMPK/mTOR pathway. In addition, KLF6 interacted with the promoter of PTTG1 and negatively regulated its expression. Knockdown of PTTG1 abolished the function of KLF6 knockdown in vitro. This study demonstrates the protective effect of KLF6 knockdown against MI, which is attributed to the elevation of PTTG1 expression and inhibition of the AMPK/mTOR pathway. These findings provide a novel insight into MI treatment.<b>NEW & NOTEWORTHY</b> Our study demonstrates for the first time the role of Krüppel-like factor 6 (KLF6)/PTTG1 axis in myocardial infarction (MI). This study demonstrates the protective effect of KLF6 knockdown against MI, which is attributed to the elevation of PTTG1 expression and inhibition of the AMPK/mTOR pathway. These findings provide a novel insight into MI treatment.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C115-C127"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798685","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":"Role of versican in extracellular matrix formation: analysis in 3D culture.","authors":"Nushrat Jahan, Shamima Islam, Karnan Sivasundaram, Akinobu Ota, Munekazu Naito, Junpei Kuroda, Hideto Watanabe","doi":"10.1152/ajpcell.00495.2024","DOIUrl":"10.1152/ajpcell.00495.2024","url":null,"abstract":"<p><p>Three-dimensional (3-D) cell culture creates an environment that allows cells to grow and interact with the surrounding extracellular framework. Versican plays a pivotal role in forming the provisional matrix, but it is still unclear how this proteoglycan affects the formation of the extracellular matrix. Here, we established a 3-D culture system using fibrin gel, which enables a long-term culture up to a month. With this system, we characterized fibroblasts obtained from the newborn knock-in homozygotes, termed R/R, expressing a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-resistant versican and wild-type mice. R/R fibroblasts showed higher levels of versican deposition than wild-type, demonstrating that the initial ADAMTS-cleavage site is involved in versican turnover. These fibroblasts exhibited faster proliferation and myofibroblastic differentiation, concomitant with higher levels of transforming growth factor β-signaling. R/R fibroblast culture had higher deposition levels of fibronectin, type I and V collagens, and fibrillin-1, especially at the late stages of culture. These results suggest that versican expressed by dermal fibroblasts facilitates the extracellular matrix formation, at least by affecting fibroblast behavior.<b>NEW & NOTEWORTHY</b> We established a 3-D-culture system useful for analyzing fibroblast behavior and matrix formation. The initial cleavage site by ADAMTSs in versican core protein is mainly involved in versican turnover. Accumulating versican facilitates fibroblast proliferation and myofibroblastic differentiation in an autocrine or paracrine manner. Accumulating versican promotes the deposition of fibronectin and collagens.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C245-C257"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798695","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":"The impact of diet-induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity.","authors":"Brandon N VanderVeen, Thomas D Cardaci, Brooke M Bullard, Christian A Unger, Jeffrey C Freeman, Reilly T Enos, Michael Shtutman, Michael D Wyatt, Daping Fan, E Angela Murphy","doi":"10.1152/ajpcell.00687.2024","DOIUrl":"10.1152/ajpcell.00687.2024","url":null,"abstract":"<p><p>Obesity increases the risk for developing several cancers, including colorectal cancer (CRC), and is associated with liver perturbations, which likely impacts treatment tolerance. 5 fluorouracil (5FU) remains a first line treatment for CRC, but efficacy is hampered by interpatient variable responsiveness and off-target toxicities. The current study examined the impact of diet-induced obesity (DIO) on 5FU cytopenia and efficacy using two established CRC models: MC38 (C57BL/6) and C26 (CD2F1). DIO increased tumor size in both MC38 and C26. DIO reduced liver dihydropyrimidine dehydrogenase (<i>dpyd</i>) expression, the enzyme that catalyzes 5FU's catabolism to become inactive, in MC38 mice, but not in C26. 5FU remained efficacious against early MC38 and C26 tumor growth; however, 5FU-induced tumor and liver immune cell death was exacerbated following three cycles of 5FU with MC38. DIO caused dramatic changes to liver Kupffer cells (KCs), wherein there were increased prometastatic, immunosuppressive KCs in Obese Control and MC38. 5FU, however, depleted these KCs and increased inflammatory KCs in both Lean and Obese MC38. DIO yielded a milder obesity phenotype in CD2F1 mice, and 5FU-induced cytopenia was not different between Lean and Obese. DIO increased total liver KCs; however, C26 tumors increased liver KCs, which were normalized with 5FU treatment, irrespective of DIO. Although 5FU remained efficacious in both models of CRC and did not reduce survival, multiple cycles of 5FU monotherapy increased liver and tumor immune cell death in DIO mice. Altogether, obesity was not protective but rather exacerbated chemotherapy-induced cytotoxicity and promoted a prometastatic liver environment.<b>NEW & NOTEWORTHY</b> The current study aimed to examine the impact of obesity on tumorigenesis and 5FU safety and efficacy with two established murine models of colorectal cancer. Diet-induced obesity increased tumor burden in both models, and 5FU's antitumor efficacy remained and extended survival with both tumor models. Obese mice demonstrated increased 5FU-induced immune cell cytotoxicity following multiple cycles of 5FU with distinct changes to liver macrophages, suggesting an increased propensity for liver metastasis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C56-C77"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11901352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685977","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":"Cohesin <i>rad21</i> mutation dysregulates erythropoiesis and granulopoiesis output within the whole kidney marrow of adult zebrafish.","authors":"Gregory Gimenez, Maggie L Kalev-Zylinska, Ian Morison, Stefan K Bohlander, Julia A Horsfield, Jisha Antony","doi":"10.1152/ajpcell.00657.2024","DOIUrl":"10.1152/ajpcell.00657.2024","url":null,"abstract":"<p><p>Cohesin complex is essential for cell division and regulating cell type-specific gene expression programs. Mutations in genes encoding the cohesin subunits are associated with hematological malignancies, preleukemia, and clonal hematopoiesis of indeterminate potential. In this study, we examined how cohesin mutation impacts hematopoiesis using adult zebrafish that carry heterozygous germline nonsense mutation in the cohesin subunit, <i>rad21</i> (<i>rad21^+/-</i>) that is orthologous to human <i>RAD21</i>. Single-cell RNA sequencing analyses showed that adult zebrafish harboring <i>rad21^+/-</i> mutation exhibit significant transcriptional dysregulation within the whole kidney marrow and have altered erythroid and granulocyte output. Erythroid progenitors were expanded in <i>rad21^+/-</i> and erythroid differentiation was altered. The expression profile of several erythroid genes, including <i>gata1a</i>, was dysregulated in <i>rad21^+/-</i> erythroid cells. Mature granulocyte population declined in <i>rad21^+/-</i>, and the transcriptional program of granulocytes was impaired but granulocytic maturation was maintained. Granulocytes from <i>rad21^+/-</i> showed upregulation of stress hematopoiesis factor, <i>cebpb</i>. These findings show that normal <i>rad21</i> is required to maintain steady erythropoiesis and granulopoiesis in the adult zebrafish marrow.<b>NEW & NOTEWORTHY</b> Mutations in cohesin subunit genes are early events in leukemogenesis. This study characterizes the hematopoietic compartment of adult zebrafish that carry germline heterozygous mutation in cohesin subunit, <i>rad21</i>. Our results show that despite normal appearance, <i>rad21</i> mutant adult zebrafish exhibit transcriptional dysregulation and altered erythroid and granulocyte output. No obvious morphological dysplasia was observed in the <i>rad21</i> mutant hematopoietic cells. These results suggest that <i>rad21</i> mutation can cause underlying hematopoietic disturbances.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C9-C19"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643240","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":"No detectable loss of myonuclei from human muscle fibers after 6 wk of immobilization following an Achilles tendon rupture.","authors":"Oscar Horwath, Kristoffer Toldnes Cumming, Einar Eftestøl, Björn Ekblom, Paul Ackermann, Truls Raastad, Kristian Gundersen, Niklas Psilander","doi":"10.1152/ajpcell.00692.2024","DOIUrl":"10.1152/ajpcell.00692.2024","url":null,"abstract":"<p><p>Muscle disuse has rapid and debilitating effects on muscle mass and overall health, making it an important issue from both scientific and clinical perspectives. However, the myocellular adaptations to muscle disuse are not yet fully understood, particularly those related to the myonuclear permanence hypothesis. Therefore, in this study, we assessed fiber size, number of myonuclei, satellite cells, and capillaries in human gastrocnemius muscle after a period of immobilization following an Achilles tendon rupture. Six physically active patients (5 males/1 female, 43 ± 15 yr) were recruited to participate after sustaining an acute unilateral Achilles tendon rupture. Muscle biopsies were obtained from the lateral part of the gastrocnemius before and after 6 wk of immobilization using a plaster cast and orthosis. Muscle fiber characteristics were analyzed in tissue cross-sections and isolated single fibers using immunofluorescence and high-resolution microscopy. Immobilization did not change muscle fiber type composition nor cross-sectional area of type I or type II fibers, but muscle fiber volume tended to decline by 13% (<i>P</i> = 0.077). After immobilization, the volume per myonucleus was significantly reduced by 20% (<i>P</i> = 0.008). Myonuclei were not lost in response to immobilization but tended to increase in single fibers and type II fibers. No significant changes were observed for satellite cells or capillaries. Myonuclei were not lost in the gastrocnemius muscle after a prolonged period of immobilization, which may provide support to the myonuclear permanence hypothesis in human muscle. Capillaries remained stable throughout the immobilization period, whereas the response was variable for satellite cells, particularly in type II fibers.<b>NEW & NOTEWORTHY</b> The impact of prolonged immobilization on muscle fiber characteristics is difficult to study in humans and therefore remains poorly understood. We analyzed cross-sections and single fibers from gastrocnemius before and after 6 wk of immobilization due to an Achilles tendon rupture. Our data suggest that myonuclei are not lost in response to such stimuli, thus lending support to the hypothesis of myonuclear permanency in human muscle.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C20-C26"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638537","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":"Focal adhesions, reticular adhesions, flat clathrin lattices: what divides them, what unites them?","authors":"Fabian Lukas, Marlen Duchmann, Tanja Maritzen","doi":"10.1152/ajpcell.00821.2024","DOIUrl":"10.1152/ajpcell.00821.2024","url":null,"abstract":"<p><p>The majority of cells within multicellular organisms requires anchorage to their surroundings in the form of cell-cell or cell-matrix adhesions. In regards to cell-matrix adhesions, the transmembrane receptors of the integrin family have long been recognized as the central scaffold around which these adhesion complexes are built. Via their extracellular domains integrins bind extracellular matrix ligands while their intracellular tails interact with a plethora of proteins that link integrin-based adhesions to the cytoskeleton and turn them also into important signaling platforms. Depending on the specific intracellular interactome of the integrins, different types of integrin adhesion complexes have been classified. The best-studied ones are the focal adhesions, in which integrins become firmly linked to contractile actomyosin fibers, allowing force transduction. But integrins also form an integral part of adhesion structures that lack the strong actomyosin link and are enriched in endocytic proteins. These have been named reticular adhesions, flat clathrin lattices, or clathrin plaques. Initially, the different types of integrin adhesion complexes have been viewed as discrete entities with their own separate life cycles. However, in the past years it has become more and more apparent how closely intertwined they are. In fact, it was shown that they can trigger each other's biogenesis or can even directly convert into each other. Here, we describe similarities as well as differences between integrin adhesion complexes, focusing on the versatile αvβ5 integrins, and discuss the recently discovered close links and interconversion modes between the different αvβ5 integrin adhesion types.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C288-C302"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799111","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":"Alterations in the transcriptome and microRNAs of adipose-derived mesenchymal stem cells from different sites in rats during aging.","authors":"Zhenyang Su, Tianhua Xu, Jin-Yu Sun, Wei Sun, Xiangqing Kong","doi":"10.1152/ajpcell.00044.2024","DOIUrl":"10.1152/ajpcell.00044.2024","url":null,"abstract":"<p><p>Aging is an intricate and gradual process characterized by tissue and cellular dysfunction. Adipose-derived mesenchymal stem cells (ADMSCs) experience a functional decline as part of systemic aging. However, the alterations in ADMSCs across various anatomical sites throughout an individual's lifespan remain unclear. To shed light on these changes, we collected white adipose tissue and brown adipose tissue samples from the epididymis, perirenal, inguinal, and scapular regions of young, adult, and aged rats and subsequently isolated ADMSCs for RNA sequencing. As aging progressed, we observed a reduction in the number of ADMSCs at all anatomical sites. Marker genes of ADMSCs from different sites were identified. Aging triggered notable activation of inflammatory and immune responses while diminishing the ADMSC differentiation capacity and ability to maintain a normal tissue morphology. Furthermore, miR-195-5p and miR-497-3p, which promoted cell senescence and apoptosis while inhibiting proliferation and differentiation, were positively correlated with aging. These findings increase our understanding of ADMSC senescence and underscore the unique physiological changes and functions of ADMSCs across different anatomical sites during aging.<b>NEW & NOTEWORTHY</b> Dynamic changes in mRNAs and miRNAs of ADMSCs during aging are shown. As aging progressed, we observed a reduction in the number of ADMSCs at all anatomical sites. Aging leads to the activation of inflammatory and cellular dysfunction. miR-195-5p and miR-497-3p are positively correlated with aging, which promoted cell senescence and apoptosis while inhibiting proliferation and differentiation. ADMSCs associated with different anatomical sites have site-specific markers.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C78-C94"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567348","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":"Altered sphingolipid profile in response to skeletal muscle injury in a mouse model of type 1 diabetes mellitus.","authors":"Jacob M Ouellette, Michael D Mallender, Dylan J Hian-Cheong, Daniel L Scurto, James E Nicholas, Stephen J Trumble, Thomas J Hawke, Matthew P Krause","doi":"10.1152/ajpcell.00158.2024","DOIUrl":"10.1152/ajpcell.00158.2024","url":null,"abstract":"<p><p>A complication of type 1 diabetes mellitus (T1DM) is diabetic myopathy that includes reduced regenerative capacity of skeletal muscle. Sphingolipids are a diverse family of lipids with roles in skeletal muscle regeneration. Some studies have found changes in sphingolipid species levels in T1DM, however, the effect of T1DM on a sphingolipid panel in regenerating skeletal muscle has not been examined. Wild-type (WT) and diabetic <i>Ins2^Akita+/-</i> (Akita) mice received cardiotoxin-induced muscle injury in their left quadriceps, gastrocnemius-plantaris-soleus, and tibialis anterior muscles with the contralateral muscles serving as uninjured controls. Muscles were collected at 1, 3, 5, or 7 days postinjury. In regenerating muscle from Akita mice, lipid staining with BODIPY 493/503 revealed increased intramyocellular and total lipids and perilipin-1-positive cell numbers as compared with WT. Liquid chromatography-mass spectrometry of quadriceps was used to identify sphingolipid levels in skeletal muscle. The C22:0 and C24:0 ceramides were significantly elevated in uninjured Akita, whereas ceramide C24:1 was decreased in injured Akita compared with WT. Ceramide-1-phosphate was increased in Akita compared with WT regardless of injury, whereas sphingosine-1-phosphate (S1P) was elevated with injury in WT but this response was muted in Akita mice. Western blotting of key enzymes involved in sphingolipid metabolism revealed S1P lyase, the enzyme that degrades S1P irreversibly, was significantly elevated in the injured muscle in Akita mice during regeneration, in accordance with lower S1P levels. This mouse model of T1DM demonstrates sphingolipidomic changes that may contribute to delayed muscle regeneration.<b>NEW & NOTEWORTHY</b> Muscle lipids become elevated, and the sphingolipid profile is altered by T1DM in skeletal muscle regeneration. A loss of S1P is accompanied by greater expression of sphingosine-1-phosphate lyase (SPL) in response to injury in Akita mice, suggesting a role for sphingolipids in the attenuated repair of skeletal muscle in T1DM rodent models. Although ceramide-1-phosphate (C1P) is increased with T1DM, there was no increase in ceramide kinase (CerK) suggesting an alternative route of ceramide phosphorylation in skeletal muscle.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C273-C287"},"PeriodicalIF":5.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749759","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}