American journal of physiology. Cell physiology最新文献

{"title":"Activation of <i>ankrd1a</i> expression marks newly forming myofibers and regulates muscle cell differentiation in adult zebrafish skeletal muscle repair.","authors":"Mina Milovanovic, Mirjana Novkovic, Srdjan Boskovic, Rubén Marí N Juez, Andjela Milicevic, Jovana Jasnic, Emilija Milosevic, Bojan Ilic, Didier Y R Stainier, Snezana Kojic","doi":"10.1152/ajpcell.00807.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00807.2024","url":null,"abstract":"<p><p>Like mammals, zebrafish repair skeletal muscle through a multi-step process that involves satellite cell activation, differentiation of progenitor cells into myocytes, their fusion into myotubes, followed by myotube maturation and myofiber hypertrophy. Coordination and timely regulation of these events are essential for functional muscle recovery. Here we identify <i>ankrd1a</i>, a gene responsive to muscle stress, as a new player in the repair of adult zebrafish skeletal muscle and show its involvement in modulating molecular mechanisms behind myogenic cell differentiation. It is expressed in newly forming muscle fibers from the stage of myoblast-like cells to their differentiation into mature myofibers, as well as in the apparently intact muscle fibers that surround the injury. Loss of <i>ankrd1a</i> function alters regulatory pathways involved in muscle cell differentiation, contraction, and myocyte fusion, leading to the acceleration of myogenic differentiation. Our data point to <i>ankrd1a</i> as a novel marker of newly forming myofibers and a hallmark of the adaptive process occurring in the intact myofibers that are in contact with wounded tissue. Without affecting the main regulatory networks, <i>ankrd1a</i> fine-tunes skeletal muscle repair by preventing premature myogenic differentiation during injury repair, which itself could impair functional recovery.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214652","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":"Caspase-11 deficiency ameliorates elastase-induced abdominal aortic aneurysm in mice by suppressing inflammatory response of macrophages.","authors":"Shekhar Singh, Faxue Zhao, Linlin Fan, Wei Xin, Hao Liu, Guofu Zhu, Chong Xu, Dekui Zhang, Jinlin Tian, Imran Ibrahim Shaikh, Wenliang Che, Yawei Xu, Zuodong Song, Xiankai Li, Dongyang Jiang","doi":"10.1152/ajpcell.00716.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00716.2024","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is a life-threatening inflammation-related vascular disease lacking of specific drugs. Murine caspase-11 (CASP11, its human orthologs CASP4/CASP5) is the major component of the non-canonical inflammasome. However, the role of CASP11 in AAA remains unknown. Using a modified mice model combining oral BAPN administration and periaortic elastase application, we observed the activation of CASP11 during the development of AAA. Genetic deletion of <i>Casp11</i> protected from AAA development with the improved survival rate and ameliorated destruction of vessel walls, compared to wild-type (WT) mice. Correspondingly, <i>Casp11</i> knockout (KO) aortas showed less infiltrated macrophages, lower expression levels of cytokines including IL-1β, IL-6, and MCP-1, and reduced MMP-9 activity. Myeloid CASP11 contributed dominantly to the protective effects analyzed by the bone marrow transplantation experiment. In vitro assay indicated that CASP11 was upregulated in pro-inflammatory M1 macrophages. To explore the mechanism, CD11b⁺F4/80⁺ macrophages were sorted by flow cytometry from the AAA tissues of WT and <i>Casp11</i> KO mice to perform RNA sequencing, and the bioinformatic analysis revealed the downregulation of various inflammatory processes in <i>Casp11</i>-deficient macrophages. Collectively, macrophage CASP11 has a critical role in the development of AAA, providing a potential therapeutic strategy for treating AAA disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214653","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 Biodiversity of KS-Proteoglycans in Cellular Regulation and Tissue Function: Emerging Bioregulatory Roles For Low Sulfation Proteoglycans and Bioconjugates.","authors":"James Melrose","doi":"10.1152/ajpcell.00268.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00268.2025","url":null,"abstract":"<p><p>The aim of this study was to illustrate the biodiverse properties of keratan sulfate (KS) Proteoglycans (PGs), their varied functions in tissues and emerging roles for low sulfation isoforms of KS PGs now detectable due to the development of some novel KS antibodies. KS is a glycosaminoglycan (GAG), of diverse structure and functional properties and decorates a large range of PGs and equips these with cell regulatory properties. KSPGs also have biophysical roles in tissue stabilization and specific roles in electroconductive bioregulation of neural processes controlling tissue functions. Compared to the multitude of studies on other GAGs, KS has been rather neglected. In the past the major focus was on the biology of high charge density isoforms of KS. In the present day the development of antibodies that can now detect low sulfation isoforms of KS have demonstrated their potential roles in novel cell regulatory processes adding to the diverse bioregulatory properties of KSPGs. KS and KSPGs are now entering new areas in bioregulation adding to the functional roles of PGs in the regulation of connective tissue form and function in health and disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214654","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":"Collagen Remodeling Increases After Acute Resistance Exercise in Healthy Skeletal Muscle Irrespective of Age.","authors":"Allyson M Schweitzer, Michael S Koehle, Matthew D Fliss, Cameron J Mitchell","doi":"10.1152/ajpcell.00992.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00992.2024","url":null,"abstract":"<p><p>Alterations to the extracellular matrix of skeletal muscle are implicated in age-related declines in muscle quality. Reduced collagen breakdown and collagen accumulation between muscle fibres are suggested to reduce the force-generating capacity of the muscle and impede adaptation to mechanical loading. The current study investigated total intramuscular collagen content in healthy, physical fitness-matched young and older skeletal muscle and how regulators of collagen breakdown respond to an acute bout of resistance exercise. No differences in intramuscular collagen content between young (5.4% ± 2.1) and older muscle (5.1% ± 3.1, p=0.779) were found. Seventy-two hours after resistance exercise, matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) gene expression (<i>MMP2</i>, p=0.003; <i>MMP9</i>, p=< 0.001; <i>MMP14</i>, p=0.008; <i>TIMP1</i>, p=<0.001), protein content (MMP14 proenzyme, p=0.016) and protein activity (MMP2, p=0.009; MMP9, p=0.014) were elevated in both young and older muscle. An age-by-time interaction was demonstrated 72 hours post-exercise, with older adults demonstrating more MMP14 enzyme content at this time point than young adults (p=0.02). Main effects of age were demonstrated for <i>MMP2</i> (p=<0.001), <i>MMP14</i> (p=0.008) and <i>TIMP2</i> (p=<0.001) gene expression. No significant differences were observed between baseline and 6 hours post-exercise in either age group. Acute resistance exercise potently stimulates upregulation of markers of collagen breakdown in healthy young and older skeletal muscle. Further research is warranted to determine the precise roles of MMPs and TIMPs in skeletal muscle's response to mechanical loading.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198043","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":"Sex-specific dysregulation of cardiac-enriched microRNAs with age in <i>Drosophila melanogaster</i>.","authors":"Lijo N Varghese, Philip W Sheard, Daryl O Schwenke, Rajesh Katare","doi":"10.1152/ajpcell.00134.2025","DOIUrl":"10.1152/ajpcell.00134.2025","url":null,"abstract":"<p><p>Dysregulation of cardiac-enriched microRNA (miRNA) expression is linked to age-associated cardiovascular diseases (CVDs). However, the sex-specificity and age at which dysregulation occurs remain unclear. Given the conserved nature of miRNAs and short lifespan of <i>Drosophila melanogaster</i> (fruit flies), we investigated age-related changes in the expression of cardiac enriched miRNAs (miR-1, -9, -34a, and -133, target miRNAs) and their impact on the cardiac tube in male and female flies. Cardiac tube tissues were collected from male and female flies (<i>n</i> = 5/group) at 7-day intervals from <i>day 7</i> to <i>day 70</i>. miRNAs and predicted target mRNA gene (<i>KCNQ</i>, <i>MRTF</i>, and <i>CCN</i>) expression were quantified by RT-qPCR (<i>n</i> = 4-6/group). Myofibril diameter was assessed by Masson's trichrome staining (<i>n</i> = 4-6) to determine the structural effects of hypertrophic miR-9. In females, miR-1 was downregulated with age (<i>P</i> ≤ 0.0001), whereas in males, miR-9 (<i>P</i> ≤ 0.0001) and miR-34a (<i>P</i> = 0.0017) were downregulated. Interestingly, miR-133 was downregulated in both sexes (<i>P</i> ≤ 0.0001). In males, <i>MRTF</i> (miR-9 target) and <i>CCN</i> (miR-133 target) expression increased with age (<i>P</i> = 0.016 and <i>P</i> = 0.013, respectively), whereas in females, <i>KCNQ</i> (miR-1 target) and <i>CCN</i> expression decreased (<i>P</i> = 0.03 and <i>P</i> = 0.002, respectively). Myofibril thickness significantly increased with age in both sexes (<i>P</i> < 0.0001). miR-9 downregulation may contribute to this effect in males, whereas the mechanism in females remains unclear. This study provides novel insights into sex-specific miRNA dysregulation in cardiac aging, emphasizing the need to consider sex differences in miRNA-mediated cardiovascular aging and the potential of miRNAs as diagnostic tools in age-related CVDs.<b>NEW & NOTEWORTHY</b> Advancements in healthcare and diet have increased life expectancy, doubling the population aged 60 and above by 2050. However, this longevity raises the risk of chronic diseases, especially cardiovascular diseases. We examined age-related changes in cardiovascular-enriched microRNAs in the <i>Drosophila melanogaster</i> heart. This first-of-its-kind observational study tracks microRNA changes across life stages. It highlights sex-specific expression of miRNAs, providing crucial insights into cardiac aging. It lays a strong foundation for future research on microRNA in heart health.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1743-C1751"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958271","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":"ITGA3 participates in the pathogenesis of recurrent spontaneous abortion by downregulating ULK1-mediated autophagy to inhibiting trophoblast function.","authors":"Ruiqi Wang, Fangfang Dai, Zhimin Deng, Lujia Tang, Hua Liu, Liangbin Xia, Yanxiang Cheng","doi":"10.1152/ajpcell.00563.2024","DOIUrl":"10.1152/ajpcell.00563.2024","url":null,"abstract":"<p><p>Recurrent spontaneous abortion (RSA) is a significant challenge encountered by couples of reproductive ages, with inadequate trophoblast invasion identified as a primary factor in RSA pathogenesis. However, the precise molecular mechanisms through which trophoblast cell dysfunction leads to RSA remain incompletely understood. Research has highlighted the critical role of integrins in embryo implantation and development. Although integrin α-3 (ITGA3) is recognized for its promotion of invasion in cancer cells, its involvement in miscarriage remains poorly characterized. This investigation initially assessed ITGA3 expression in villous tissues obtained from patients with RSA and patients with induced abortion. The findings demonstrated a notable reduction in ITGA3 levels in the villous tissues of patients with RSA compared with the control group. Subsequent in vitro analyses indicated that ITGA3 knockdown inhibited the migration, invasion, and proliferation of trophoblast cells. Through RNA sequencing and subsequent experimentation, it was revealed that ITGA3 regulated Unc51-like kinase 1 (ULK1)-mediated autophagy to influence trophoblast cell invasion, migration, and proliferation. Furthermore, utilizing a miscarriage animal model, the diminished expression of ITGA3 and ULK1 in the placentas of RSA mice was confirmed. In conclusion, the study findings suggest that the downregulation of ITGA3 suppresses ULK1 expression, consequently impeding autophagy to initiation and impeding trophoblast cell invasion and migration, thereby contributing to the pathological progression of RSA.<b>NEW & NOTEWORTHY</b> There is a strong correlation between the reduced expression of ITGA3 in villous tissues and RSA. ITGA3 facilitates the expression of ULK1, thereby promoting autophagy formation and elevating autophagy levels in trophoblast cells. Consequently, this enhances the invasion and migration abilities of trophoblast cells.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1941-C1956"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492908","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 theatrics of collagens in the myocardium: the supreme architect of the fibrotic heart.","authors":"Sanchari Chakraborty, Abhi Dutta, Antara Roy, Ashutosh Joshi, Trayambak Basak","doi":"10.1152/ajpcell.01043.2024","DOIUrl":"10.1152/ajpcell.01043.2024","url":null,"abstract":"<p><p>Heart failure (HF) mediated by cardiac fibrosis (CF) is characterized by an excessive accumulation of collagen-based extracellular matrix (ECM) in the myocardium. CF is a common pathophysiological condition in many heart diseases and can be distinctly categorized into two types: replacement and interstitial. In ischemic heart diseases, sudden loss of cardiomyocytes leads to the replacement of CF to prevent ventricular rupture. In contrast, excessive collagen deposition in the interstitial space between cardiomyocytes (often in response to pressure overload, chronic cardiac stress, hypertension, etc.) is termed interstitial CF. The progression of HF due to cardiac fibrosis is mainly driven by compromised diastolic function, resulting from increased stiffness of the heart wall muscle due to collagen-based scar formation. Increased myocardial stiffness is primarily catalyzed by the differential cross linking of deposited collagens forming the scar in the fibrotic heart. Although collagen deposition remained a hallmark of fibrosis, the pathophysiological progression due to biochemical alterations and mechanistic discrepancy of collagens across cardiac fibrosis subtypes remains elusive. With the advent of next-generation RNA sequencing and high-resolution mass spectrometry, mechanistic insights into collagen-mediated scar maturation have gained impetus. A deeper understanding of the spatiocellular transcriptional heterogeneity and site-specific collagen posttranslational modifications (PTMs) in maneuvering ECM remodeling is gaining attention. The unexplored mechanisms of posttranslational modifications and subsequent collagen cross linking in various cardiac fibrosis may provide the prime target for therapeutic interventions. This review comprehensively summarizes the detailed pattern, role, signaling, and mechanical contributions of different collagens and their PTMs, including cross-linking patterns as newer therapeutic regimens during cardiac fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1893-C1920"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957996","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":"GLP-1 and ghrelin inversely regulate insulin secretion and action in pancreatic islets, vagal afferents, and hypothalamus for controlling glycemia and feeding.","authors":"Toshihiko Yada, Katsuya Dezaki, Yusaku Iwasaki","doi":"10.1152/ajpcell.00168.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00168.2025","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) was discovered as an incretin hormone, which is released from the intestine upon nutrient intake and stimulates insulin secretion from the pancreatic islet β-cells. Subsequently, its ability to suppress appetite was recognized. Ghrelin, discovered as the ligand for growth hormone secretagogue-receptor (GHS-R), is released from the stomach and produces appetite. Later, its ability to inhibit insulin secretion and elevate blood glucose was found. Thus, GLP-1 and ghrelin regulate insulin secretion and appetite toward opposite directions. The receptor agonists for GLP-1 and ghrelin have been developed and are now used to treat metabolic diseases, in which insulin plays a key role. However, underlying action mechanism and possible interplay of these hormones have remained elusive. Here, we describe that GLP-1 and ghrelin reciprocally regulate the insulin system. GLP-1 enhances and ghrelin suppresses insulin secretion in pancreatic β-cells. Moreover, GLP-1 cooperates with and ghrelin counteracts insulin action in the vagal afferent and hypothalamic arcuate nucleus (ARC) neurons, the interfaces between the peripheral metabolism and brain. Notably, ghrelin rises and works preprandially and GLP-1 rises and works postprandially. The interplay of ghrelin, GLP-1, and insulin leads to optimal circadian control of feeding, glycemia, and metabolism.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1793-C1807"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964789","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":"Insulin potentiates mechanical responses in small dorsal root ganglion neurons by increasing the sensitization of TRPV4 channels.","authors":"Ayumi Fukazawa, Amane Hori, Juan Estrada, Han-Kyul Kim, Norio Hotta, Gary A Iwamoto, Scott A Smith, Wanpen Vongpatanasin, Masaki Mizuno","doi":"10.1152/ajpcell.00255.2025","DOIUrl":"10.1152/ajpcell.00255.2025","url":null,"abstract":"<p><p>We have previously reported that insulin potentiates the response to mechanical stimuli in small dorsal root ganglion (DRG) neurons. However, the mechanisms underlying the insulin-induced potentiated responsiveness to mechanical stimulation in sensory neurons remain unclear. Transient receptor potential vanilloid 4 (TRPV4) is expressed as a mechanosensitive channel in DRG neurons and is activated by mechanical stimuli. We therefore hypothesized that insulin augments the response to mechanical stimulation in small DRG neurons by enhancing sensitization of TRPV4 channels. Colocalization of TRPV4, insulin receptor (IR), and the C-fiber marker peripherin in small DRG neurons was evaluated by immunofluorescence, demonstrating that 53 ± 10% of TRPV4-positive small DRG neurons were colocalized with IR and peripherin. In in vitro whole cell patch clamp recordings from cultured DRG neurons, mechanically activated currents were significantly increased 5 min after the application of insulin (<i>P</i> = 0.0137) and such augmentation was suppressed by TRPV4 antagonist HC067047. We further examined the impact of insulin on the expression of the IR signaling pathway proteins in cultured DRG neurons using western blotting. Akt was significantly increased in cultured DRG neurons incubated with insulin (phospho-Akt: <i>P</i> = 0.0007, phospho/total Akt ratio: <i>P</i> = 0.0183). Furthermore, blocking IR signaling kinases, phosphoinositide 3-kinase (PI3K), and PKC suppressed the insulin-induced augmentation in TRPV4 agonist-induced currents (PI3K: <i>P</i> = 0.0074, PKC: <i>P</i> = 0.0028). Collectively, our results suggest that insulin-induced potentiation of mechanical response in small DRG neurons occurs through enhanced sensitization of TRPV4 channels.<b>NEW & NOTEWORTHY</b> We investigated whether insulin potentiates the sensitization of TRPV4 channels to mechanical stimulation in DRG neurons. Insulin-induced enhancement of mechanical response was suppressed by blocking TRPV4 channels. Furthermore, blockade of insulin receptor signaling pathways, PI3K and PKC, inhibited insulin-induced sensitization of TRPV4 channels. Our results provide evidence that insulin-induced potentiation of mechanical sensation in small DRG neurons is mediated through enhancing the sensitization of TRPV4 channels via the insulin receptor signaling pathway.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1982-C1994"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959996","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":"Multi-therapeutic strategy targeting Akt-mTOR and FoxO1 pathway to counteract skeletal muscle atrophy consecutive to hypoxia.","authors":"Samir Bensaid, Claudine Fabre, Amir Yahya Rajaei, Charlotte Claeyssen, Frédéric N Daussin, Caroline Cieniewski-Bernard","doi":"10.1152/ajpcell.00851.2024","DOIUrl":"10.1152/ajpcell.00851.2024","url":null,"abstract":"<p><p>Chronic oxygen deprivation, whether due to high altitude or certain diseases such as cardiorespiratory pathologies, leads to muscle atrophy. To limit muscle loss, counteracting programs rely on only one therapeutic approach: return to sea-level altitude, physical activity, or nutritional supplementation. However, little effects are noticed on the muscle mass of subjects presenting severe hypoxemia. We hypothesized that the combination of several treatments (electrical stimulation and/or nutritional supplementation and/or oxygenation) would improve anabolic responses, thus counteracting efficiently hypoxia-induced muscle atrophy. In C2C12 myotubes submitted to hypoxia, we aim at testing several treatments based on the combination of electrical stimulation, amino acid supplementation, and/or an oxygenation period. In comparison with untreated muscle cells under hypoxia, all treatments had an anabolic impact on myotube morphology (myogenic fusion index, diameter, and density of myotubes), on proteosynthesis pathway [protein kinase B (Akt), mammalian target of rapamycin (mTOR), glycogen synthase kinase-3β, 4E-binding protein 1 (4E-BP1), and ribosomal protein S6 kinase (P70S6K)], on proteolysis pathway [Forkhead box protein O1 (FoxO1), myostatin, and ubiquitin-proteasome system], and on hypoxia marker (regulated in development DNA damage responses 1) protein level. Electrical stimulation alone resulted in hyperphosphorylation of Akt and FoxO1, whereas its combination with amino acid supplementation alleviated atrophy, exemplified by fusion index and myotube diameter increase up to 48 h post-application. Electrical stimulation followed by a period of oxygenation of hypoxic muscle cells strongly increased the activation status of 4E-BP1 and P70S6K. Finally, the simultaneous application of all treatments (electrical stimulation, amino acid supplementation, and oxygenation) was the only condition that resulted in activation of mTOR concomitantly with myostatin level decrease. These results support that the activation of the mTOR pathway through the combined application of electrical stimulation and branched-chain amino acids is strongly influenced by oxygen availability and that oxygen plays a critical role in optimizing the protein synthesis pathway in hypoxic skeletal muscle cells.<b>NEW & NOTEWORTHY</b> Our research demonstrates that combining electrical stimulation, BCAA supplementation, and oxygenation effectively counteracts hypoxia-induced muscle atrophy. Unlike isolated treatments, this multi-therapy approach significantly improves myotube morphology and regulates key protein homeostasis pathways, with mTOR activation protein and reduced myostatin expression. These findings highlight the enhanced therapeutic potential of combining physical activity, nutritional support, and oxygen therapy to prevent muscle atrophy in the detrimental reduction of oxygen supply.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C2057-C2069"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964665","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}