American journal of physiology. Cell physiology最新文献

{"title":"Obesity and type 2 diabetes mellitus: insights from skeletal muscle extracellular matrix remodeling.","authors":"Linda Wu, Dawn K Coletta","doi":"10.1152/ajpcell.00154.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00154.2024","url":null,"abstract":"<p><p>Obesity and type 2 diabetes mellitus (T2DM) are metabolic diseases at epidemic proportions. The economic burden for these diseases is at an all-time high, and as such, there is an urgent need for advancements in identifying targets for treating these complex disorders. The extracellular matrix (ECM), comprising collagen, fibronectin, laminin, elastin, and proteoglycan, surrounds skeletal muscles and plays a critical role in maintaining tissue homeostasis by providing structural support and facilitating cell-to-cell communication. Disruption of the ECM signaling results in changes to its micro/macroenvironment, thereby modifying tissue homeostasis. Skeletal muscle ECM remodeling has been shown to be associated with insulin resistance, an underlying feature of obesity and T2DM. This narrative review explores the critical components of skeletal muscle ECM and its accumulation and remodeling in metabolic diseases. In addition, we discuss potential treatments to mitigate the effects of ECM remodeling in skeletal muscle. We conclude that targeting ECM remodeling in skeletal muscle represents a promising yet underexplored therapeutic avenue in the management of metabolic disorders.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1752-C1763"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955952","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":"Inflammation in cancer cachexia: still the central tenet or just another player?","authors":"Noemi Iaia, Chiara Noviello, Maurizio Muscaritoli, Paola Costelli","doi":"10.1152/ajpcell.00808.2024","DOIUrl":"10.1152/ajpcell.00808.2024","url":null,"abstract":"<p><p>Cancer cachexia, a multifactorial syndrome characterized by body weight loss, muscle, and adipose tissue wasting, affects patients with cancer. Over time, the definition of cachexia has been modified, including inflammation as one of the main causal factors. Evidence has suggested that a range of proinflammatory mediators may be involved in the regulation of intracellular signaling, resulting in enhanced resting energy expenditure, metabolic changes, and muscle atrophy, all of which are typical features of cachexia. Physiologically speaking, however, inflammation is a response aimed at facing potentially damaging events. Along this line, its induction in the cancer hosts could be an attempt to restore the physiological homeostasis. Interesting observations have shown that cytokines such as interleukins 4 and 6 could improve muscle wasting, supporting the view that the same mediator may exert pro- or anti-inflammatory activity depending on the immune cells involved as well as on the tissue metabolic demand. In conclusion, whether inflammation is crucial to the occurrence of cachexia or just one contributor among others, is still unclear. Indeed, while inflammation is a trigger of cachexia, the alterations of energy and protein metabolism and of the hormonal homeostasis occurring in cachexia likely act as inflammatory stimuli on their own. Whether the causative role prevails over the compensatory one likely depends on the tumor type and stage, patient lifestyle, the presence of comorbidities, and the response to anticancer treatments paving the way to a holistic, personalized approach to cancer cachexia.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1837-C1852"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968176","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":"Unraveling the functional and molecular interplay between cellular senescence and the unfolded protein response.","authors":"Joëlle Giroud, Emilie Combémorel, Albin Pourtier, Corinne Abbadie, Olivier Pluquet","doi":"10.1152/ajpcell.00091.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00091.2025","url":null,"abstract":"<p><p>Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1764-C1782"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961003","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":"Mechanometabolism: recent findings on the intersection of cell adhesion, cell migration, and metabolism.","authors":"Emily D Fabiano, Jenna M Poole, Cynthia A Reinhart-King","doi":"10.1152/ajpcell.00892.2024","DOIUrl":"10.1152/ajpcell.00892.2024","url":null,"abstract":"<p><p>Chemical and mechanical cues within the extracellular matrix (ECM) can initiate intracellular signaling that changes an array of fundamental cell functions. In recent work, studies of cell-ECM adhesion have deepened to include the influence of the physical ECM on cell metabolism. Since many biological processes involve metabolic programs, changes to cellular metabolism in response to cues in the ECM can have marked effects on cell health. In this review, we describe molecular mechanisms associated with cell-ECM adhesion that are key players in metabolism-induced changes to cell behaviors, including migration. We first review how changes to metabolite availability in the extracellular environment or manipulation of metabolic machinery in cells impact focal adhesions. We then connect this work to recent findings regarding the reverse relationship, namely, how the manipulation of focal adhesion proteins or integrins feeds back to alter cell metabolism. Finally, we consider the latest findings from studies that describe how the mechanical properties of the ECM, primarily stiffness and confinement, alter cellular metabolism. We identify key areas of future investigation that may elucidate the molecular drivers that permit cells to respond to mechanical and chemical ECM cues by reprogramming their metabolism to better inform future diagnostics and therapeutics for disease states.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1866-C1879"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952249","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":"Sixteen weeks of high-speed treadmill running is insufficient to induce Achilles tendinopathy in a rat model.","authors":"Snehal S Shetye, Margaret K Tamburro, Ashley K Fung, Thomas P Leahy, Madison N Magee, Harina A Raja, Stephanie N Weiss, Courtney A Nuss, Daniel C Farber, Louis J Soslowsky","doi":"10.1152/ajpcell.00186.2025","DOIUrl":"10.1152/ajpcell.00186.2025","url":null,"abstract":"<p><p>Despite the high prevalence of Achilles tendinopathy, clinically relevant animal models of Achilles tendinopathy are lacking. Previous studies have demonstrated possible tendinopathic cell and matrix changes with high-speed treadmill running, but the consistency as well as functional and mechanical consequences of these changes were unclear. We sought to determine the applicability of this protocol as a tendinopathy model by defining changes in Achilles tendon structure, function, and mechanics associated with 16 wk of high-speed treadmill running (26.8 m/min, 60 min/day, and 5 days/wk). We expected that high-speed running would induce detrimental structural, functional, and mechanical changes that worsen over the course of the 16-wk protocol. Treadmill running did influence body weight, hindlimb gait, and tendon cross-sectional area. However, contrary to our hypothesis, treadmill running did not induce tendinopathic changes in matrix organization, cell morphology, or tendon mechanics. As such, alternative strategies for robust and reproducible induction of Achilles tendinopathy in preclinical animal models are needed.<b>NEW & NOTEWORTHY</b> We demonstrated that 16 wk of high-speed treadmill running did not induce structural, functional, or mechanical changes consistent with Achilles tendinopathy in the rat. These findings underscore the importance of exploring alternative approaches to generating reliable and clinically relevant animal models of Achilles tendinopathy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C2013-C2022"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966275","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":"Comprehensive evaluation and application of tissue clearing techniques for 3-D visualization of splenic neural and immune architecture.","authors":"Jianing Li, Letian He, Wenling Wang, Siyu Wang, Dan Zhang, Liyun Liang, Guangping Song, Yijian Zhang, Shaoqing Yu, Lei Wang, Qiuying Han, Shaoyi Huang, Sen Li, Haiqing Tu, Zengqing Song, Huaibin Hu, Huiyan Li, Yang Yang, Min Wu","doi":"10.1152/ajpcell.00084.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00084.2025","url":null,"abstract":"<p><p>As the largest secondary lymphoid organ, the spleen plays a crucial role in initiating and sustaining immune responses against blood-borne pathogens through antigen capture and delivery. It is innervated by both autonomic and sensory nerves, which allows for neural modulation of its immune responses. The intricate spatial structure and precise coordination between immune and neural components are essential for proper splenic function, necessitating three-dimensional (3-D) imaging to reveal its architecture. However, the dense fibrous capsule and exceptionally rich vasculature of the spleen pose significant challenges for achieving comprehensive 3-D visualization of the entire organ. Here, we systematically evaluated and compared five cutting-edge tissue clearing approaches-ImmuView, fast light-microscopic analysis of antibody-stained whole organs, small-micelle-mediated human organ efficient clearing and labeling (SHANEL), advanced clear, unobstructed brain imaging cocktails and computational analysis (advanced CUBIC), and clearing-enhanced 3-D microscopy-for their effectiveness in rendering the spleen transparent for multiplexed antibody staining and high-resolution 3-D imaging. Our results indicated that SHANEL provided the clearest visualization of essential splenic neural and immune components. Meanwhile, advanced CUBIC achieved the greatest labeling efficacy for immune cells, albeit with slightly reduced transparency. Importantly, our study marked the first application of these optimized protocols to human spleen tissue, successfully revealing the highly organized immune cell zones and neural networks with enhanced clarity. Notably, we identified the nociceptive sensory innervation within human spleen tissue for the first time. Collectively, these findings establish optimal imaging strategies for visualizing splenic immune cells and neural structure in both murine and human tissues, providing profound insights into the intricate neuroimmune interactions and their pivotal roles in the immune functions of the spleen.<b>NEW & NOTEWORTHY</b> This study systematically assessed five tissue-clearing techniques and optimized the conditions of each protocol to overcome the challenges of splenic 3-D imaging posed by its dense structure and high pigmentation. The results demonstrated SHANEL and advanced CUBIC as the optimal methods for 3-D visualization of diverse splenic immune and neural architecture, with which we successfully mapped splenic neuroimmune landscape and identified nociceptive nerves within the human spleen for the first time.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1699-C1715"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960887","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 matrix matters: matrix-based bioscaffolds in advancing translational cancer research and targeted therapy.","authors":"Nikos K Karamanos, Zoi Piperigkou, Chrisavgi Gourdoupi, Sylvia Mangani, Maria dM Vivanco","doi":"10.1152/ajpcell.00050.2025","DOIUrl":"10.1152/ajpcell.00050.2025","url":null,"abstract":"<p><p>The onset, development, and progression of cancer are greatly influenced by the microenvironmental cues originating from diverse elements within the tumor niche. Extracellular matrix (ECM), the complex and dynamic macromolecular three-dimensional network (3-D), governs cell functionality and plays key roles in tumor growth and spreading. This article highlights the significance of ECM-based bioscaffolds in providing a relevant microenvironment not only for studying tumor behavior and drug efficacy but also for narrowing the gap between translational cancer research and targeted cancer treatment. The development of novel and user-friendly platforms that resemble the human tumor microenvironment in early and advanced cancer stages, may help to predict treatment response, thus facilitating the development and testing of new drugs, bridging the gap between in vitro and in vivo models. In addition, we present innovative strategies leveraging ECM bioscaffolds for personalized cancer treatment, including drug delivery systems and tissue engineering approaches. Specific case studies as well as ethical concerns related to the use of ECM bioscaffolds in research and therapy are also presented and critically discussed. By elucidating the intricate interplay between ECM and cancer biology, this article underscores the potential of ECM bioscaffolds as novel platforms for shaping future therapeutic interventions and advancing precision oncology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1957-C1963"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539881","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":"Blebs regulate phosphoinositides distribution and promote cell survival through the Septin-SH3KBP1-PI3K axis.","authors":"Zifeng Zhen, Chunlei Zhang, Jiayi Li, Ling Liang, Congying Wu","doi":"10.1152/ajpcell.00096.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00096.2025","url":null,"abstract":"<p><p>Cells rely on substrate adhesion to activate diverse signaling pathways essential for proliferation and survival. In the absence of proper adhesion to extracellular matrix, cells undergo anoikis, a form of programmed cell death. Poorly attached cells often exhibit rounded morphology and form dynamic protrusions called blebs. While the role of blebs in amoeboid migration is well-documented, recent studies have highlighted their role in anoikis resistance. However, little is known about whether the most abundant membrane components-phospholipids- function in blebs-facilitated anoikis resistance. Here, we report an enrichment of PI(3,4,5)P₃ and a depletion of PI(4,5)P₂ at bleb membrane, compared to non-bleb regions of the plasma membrane. Our results have shown that both PI(3,4,5)P₃ and PI(4,5)P₂ have restricted diffusion pattern between the bleb and non-bleb membrane regions. Subsequently, we reveal that PI3K is recruited by SH3KBP1 via liquid-liquid phase separation (LLPS) and interacted with Septin at the bleb necks. This Septin-SH3KBP1-PI3K axis then contributes to differential phosphoinositides (PIs) distribution and anoikis resistance. These novel insights into PIs dynamics and the associated molecular scaffolding not only elucidate the mechanisms of blebs formation and anoikis resistance, but also highlight potential targets for therapeutic interventions in anchorage-independent cancers.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186291","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":"HMGB1-Mediated Pyroptosis Promotes Inflammation and Contributes to Skeletal Muscle Atrophy induced by Cigarette Smoke.","authors":"Guolin Xiong, Yuqing Xie, Yufen Tan, Yuanyuan Ye, Xiaoyu Tan, Limei Jiang, Enyuan Qin, Xinyan Wei, Jie Li, Tong Liang, Xianyan Tang, Yanfei Bin","doi":"10.1152/ajpcell.01014.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.01014.2024","url":null,"abstract":"<p><p>Skeletal muscle atrophy and dysfunction are common comorbidities in chronic obstructive pulmonary disease (COPD), with cigarette smoke (CS) exposure being a significant contributing factor. However, the underlying mechanisms remain unclear. Inflammation driven by damage-associated molecular patterns (DAMPs), such as HMGB1, may play a crucial role. This study investigates the involvement of HMGB1-mediated pyroptosis associated with skeletal muscle atrophy in COPD. Serum HMGB1 levels were measured in healthy non-smokers and patients with COPD. Additionally, mid-thigh circumference and body mass index (BMI) were assessed in patients with COPD, and their correlations with HMGB1 levels were analyzed. Treatment of glycyrrhizin (GL, a direct inhibitor of HMGB1) in CS-exposed mice was further used to demonstrate the effect of HMGB1 on skeletal muscle. A C2C12 cell model exposed to cigarette smoke extract (CSE) was employed to elucidate the role of the HMGB1/TLR4-NLRP3-GSDMD-caspase-1 pathway. In patients with COPD, serum HMGB1 levels were significantly higher than in healthy individuals and negatively correlated with mid-thigh circumference and BMI. Treatment with GL in CS-exposed mice led to the reversal of muscle atrophy and dysfunction, alongside a reduction in the expression of TLR4 and pyroptosis-associated factors within skeletal muscle. In vitro experiments demonstrated that CSE increased HMGB1, which promoted skeletal muscle atrophy by driving inflammation through the HMGB1/TLR4-NLRP3-GSDMD-caspase-1 pathway. HMGB1 induced by CS may trigger skeletal muscle atrophy. It promotes inflammation through HMGB1/TLR4-NLRP3-GSDMD-caspase-1-mediated pyroptosis, thereby exacerbating muscle wasting. Therefore, the pathway represents a potential novel therapeutic target for skeletal muscle atrophy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186292","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 multifaced role of the macrophage-migration-inhibitory-factor (MIF)-family in organ fibrosis.","authors":"Lea Herkens, Patrick Droste, Peter Boor","doi":"10.1152/ajpcell.00198.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00198.2025","url":null,"abstract":"<p><p>The macrophage-migration-inhibitory-factor (MIF)-family consists of the structurally homologous proteins MIF, D-dopachrome tautomerase (D-DT), and D-DT like (D- DTL). While MIF is the most well-described member, much less is known about D- DT, and very little about D-DTL. Here, we provide an overview of the structure, similarities, and biological functions of these proteins. MIF and D-DT can have both protective and aggravating effects on various diseases depending on the disease type, involved organ, cell type, and disease stage. Given that the pathological consequence of many chronic diseases is fibrosis, we here discuss the role of these proteins in organ fibrosis, particularly of the kidney, liver, heart, lung, and skin. We discuss the various roles of these proteins, suggesting that MIF might have pro- and antifibrotic roles in different organs. To date, D-DT has been shown to have only antifibrotic roles. We tackle potential translational considerations and propose future research avenues to better understand the involvement of MIF-family in organ fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186293","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}