American journal of physiology. Regulatory, integrative and comparative physiology最新文献

{"title":"Cooling-induced changes in intracellular hydrogen peroxide and gene expression in mouse skeletal muscle in vivo.","authors":"Ryotaro Kano, Reo Takeda, Yuta Sotani, Ryo Takagi, Ayaka Tabuchi, Hideki Shirakawa, David C Poole, Yutaka Kano, Daisuke Hoshino","doi":"10.1152/ajpregu.00014.2025","DOIUrl":"10.1152/ajpregu.00014.2025","url":null,"abstract":"<p><p>Changes in intracellular hydrogen peroxide concentration ([H₂O₂]) constitute an important signal-controlling cellular adaptations. In response to cooling, decreases in [H₂O₂] and changes in antioxidant-related gene expression have been observed in skeletal muscle. However, the specific temperature dependence of cooling-induced [H₂O₂] changes and their quantitative relationship to induced gene expression are unknown. This investigation tested the hypothesis that differences in muscle cytosolic and mitochondrial [H₂O₂] changes during cooling/rewarming determine the pattern of H₂O₂-related gene expression. H₂O₂-sensitive cytosolic (HyPer7) and mitochondrial (MLS-HyPer7) fluorescent proteins were expressed into tibialis anterior (TA) muscle of male C57BL/6J mice. The temperature dependence of [H₂O₂] was determined via in vivo imaging during a 3-min cooling protocol from 35°C to 0°C. Two cooling patterns [6 bouts of intermittent cooling (I-Cool) vs. sustained cooling (S-Cool); both to 13°C] were applied over 60 min. Three hours after cooling, the muscles were removed, and gene expression was evaluated using real-time PCR. The decrease in [H₂O₂] was observed in both cytosolic and mitochondrial compartments from 35°C to 13°C but was of greater magnitude in the cytosol; in contrast, further cooling from 12°C to 0°C induced a rebound increase especially in cytosolic [H₂O₂]. I-Cool increased the mRNA level of Nrf2 (+15%, <i>P</i> < 0.001). S-Cool decreased the mRNA levels of Sod2, Cat, and Ucp3 (i.e., -20, -23, and -30%, respectively, <i>P</i> < 0.05). In conclusion, the greatest decrease in temperature-dependent [H₂O₂] occurred at 13°C in the cytosolic and mitochondrial compartments of muscle fibers, and I-Cool increased Nrf2 mRNA expression, whereas S-Cool decreased several antioxidant-related genes.<b>NEW & NOTEWORTHY</b> This in vivo model successfully characterized the effects of cooling on cytosolic and mitochondrial [H₂O₂] in mouse tibialis anterior skeletal muscle. Cooling decreased [H₂O₂] down to ∼13°C, but the effect was reversed at still lower temperatures. Sustained cooling decreased mRNA levels of antioxidant-related genes (Sod2, Cat, and Ucp3), whereas intermittent cooling increased Nrf mRNA expression. These results help elucidate the mechanistic bases for skeletal muscle adaptation to cooling.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R758-R766"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat exposure, heat strain, and off-work recovery of Guatemalan sugarcane workers.","authors":"Lyndsay Krisher, Karely Villarreal Hernandez, Yaqiang Li, Jaime Butler-Dawson, Diana Jaramillo, Hillary A Yoder, Kevin E Miller, Evan C Johnson, Katherine A James, Miranda Dally, Elizabeth J Carlton, Daniel Pilloni Alessio, Alex Cruz, Joshua Schaeffer, John L Adgate, Lee S Newman","doi":"10.1152/ajpregu.00004.2025","DOIUrl":"10.1152/ajpregu.00004.2025","url":null,"abstract":"<p><p>Agricultural workers are at high risk for heat-related illnesses when performing heavy labor in hot conditions. Occupational heat strain, the physiological response to heat stress, is hypothesized to be common in this worker population but has rarely been measured objectively through core body temperature (T_c). The objective of this study was twofold: <i>1</i>) evaluate workday heat strain and <i>2</i>) examine the trajectory of heat exposure and T_c from the workday through the off-work hours to advance understanding of the recovery process and conditions of heat-exposed agricultural workers. Among 55 male Guatemalan agricultural workers, individual heat exposure (using ambient temperature loggers) and T_c (via an ingestible pill) were measured across a 24-h period, including workday and off-work hours. Urine samples were collected to assess hydration status on and off-work. Workers reported off-work activities, hydration practices, sleep, and nutrition through a survey. Data were summarized using descriptive statistics and visualizations. Workers experienced excessive heat strain (44% with T_c > 38.0°C, 16% with T_c > 38.3°C, and 6% with T_c > 38.5°C) during the workday. Approximately 29% achieved a higher maximal T_c during off-work hours than during the workday. Nearly 15% of workers reported sleeping <7 h. There is a need to understand off-work conditions, practices, and resources available to workers to mitigate heat strain and related illnesses. Heat stress and T_c monitoring should extend to postwork shift for assessment of workers' physiological recovery and to inform more comprehensive interventions to protect worker health.<b>NEW & NOTEWORTHY</b> This study examined the trajectory of heat exposure and core body temperature (T_c) across the workday into off-work hours among agricultural workers at risk of heat-related illness. Workday heat strain was common, and a significant proportion of workers experienced higher off-work T_c compared with their workday T_c. Survey and environmental data collected from workers provide insights into the off-work practices and conditions of the home environment that could influence the recovery of workers.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R703-R717"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of CYP450 pathways reduces functional sympatholysis in healthy young adults.","authors":"Alexander A Buelow, Jacob E Matney, Sarah M Skillett, John D Ashley, Jiwon Song, Chris Mixon, Amir Akbari Fakhrabadi, Matthew Stanford, Debra A Bemben, Daniel J Larson, J Mikhail Kellawan","doi":"10.1152/ajpregu.00173.2024","DOIUrl":"10.1152/ajpregu.00173.2024","url":null,"abstract":"<p><p>Functional sympatholysis, the blunting of sympathetic vasoconstriction during exercise, is critical for regulating exercise hyperemia. The role of cytochrome P450-2C9 (CYP450) pathways in functional sympatholysis remains unclear. A total of 21 participants (11 females) completed three study visits (2 experimental). Participants ingested a placebo (PLA) or CYP450 inhibitor fluconazole (FLZ) 120 min before testing in a double-blind, randomized, crossover design. Forearm blood flow (FBF) and mean arterial pressure (MAP) were continuously measured to calculate forearm vascular conductance (FVC) during baseline, -20 mmHg lower body negative pressure (LBNPrest), rhythmic handgrip exercise (Ex) at 20% maximum voluntary contraction, and exercise with LBNP (LBNPex). FLZ did not change FVC at baseline or during Ex (<i>P</i> > 0.05). However, adding LBNPex to Ex reduced FVC in the FLZ condition compared with PLA (PLA: 2 ± 12 Δ% vs. FLZ: -12 ± 13 Δ%, <i>P</i> < 0.001, <i>d</i>: 0.9). A significant change in FVC across time (baseline + LBNPrest vs. Ex + LBNPex) was observed (<i>P</i> < 0.001, [Formula: see text]: 0.8), along with significant effects of condition (PLA vs. FLZ) (<i>P</i>: 0.003, [Formula: see text]: 0.4) and their interaction (<i>P</i>: 0.05, [Formula: see text]: 0.2). Functional sympatholysis magnitude differed between conditions (PLA: 107 ± 41% vs. FLZ: 67 ± 50%, <i>P</i>: 0.001, <i>r</i>: 0.7). Therefore, CYP450 pathways are mechanistically involved in functional sympatholysis. However, CYP450 inhibition does not augment resting or exercising vascular responses without constrictor stimuli.<b>NEW & NOTEWORTHY</b> Evidence suggests that functional sympatholysis is an endothelial-dependent, nitric oxide and prostaglandin-independent process. We found that cytochrome P450-2C9 (CYP450-2C9) inhibition attenuated sympatholytic responses during dynamic handgrip exercise with superimposed lower body negative pressure. These data indicate that CYP450 pathways contribute to functional sympatholysis in young healthy humans.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":"328 6","pages":"R642-R650"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticosterone induces fatty liver syndrome in chickens via glucocorticoid receptor and inhibition of mitochondrial supercomplex formation.","authors":"Huimin Chen, Ke Zhang, Hui Yu, Ziting Guan, Ruqian Zhao, Lei Wu","doi":"10.1152/ajpregu.00313.2024","DOIUrl":"10.1152/ajpregu.00313.2024","url":null,"abstract":"<p><p>Stress is a primary contributor to fatty liver syndrome (FLS) in chickens. Mitochondrial functionality is pivotal in FLS progression, with diminished supercomplex (SC) formation disrupting electron transport and escalating reactive oxygen species (ROS) production. However, the impact of stress on mitochondrial SC in chicken FLS remains elusive. This study used corticosterone (CORT) to model chronic stress and examined its consequences on mitochondrial performance and SC configuration in both in vivo and in vitro FLS models. Notably, the CORT-treated hepatocytes exhibited elevated triglyceride content (<i>P</i> < 0.05), accompanied by increased mitochondrial ROS (<i>P</i> < 0.01). Moreover, CORT-exposed broilers displayed reduced body weight (<i>P</i> < 0.05) alongside heightened liver-to-body weight ratio (<i>P</i> < 0.01), indicative of liver steatosis with increased triglyceride levels in both liver and plasma (<i>P</i> < 0.01). Mitochondrial alterations in reduced ATP content (<i>P</i> < 0.05). Gene expression analysis revealed enrichment in the mitochondrial respiratory chain pathway, with downregulated mRNA expression of complex I-associated SC assembly factors NADH: ubiquinone oxidoreductase complex assembly factor 5 (<i>NDUFAF5</i>), NADH: ubiquinone oxidoreductase complex assembly factor, and translocase of inner mitochondrial membrane domain containing 1 (<i>P</i> < 0.05). Meanwhile, the glucocorticoid receptor (GR) protein level and its specific binding to the <i>NDUFAF5</i> gene promoter were reduced in the CORT group (<i>P</i> < 0.01 and <i>P</i> < 0.05, respectively), accompanied by a decrease in NDUFAF5 protein expression in liver, primary hepatocytes, and AML12 cells (<i>P</i> < 0.05). GR knockdown in AML12 cells reduced NDUFAF5 protein expression (<i>P</i> < 0.05). Thus, these findings imply that GR-mediated transcriptional regulation of complex I assembly factor NDUFAF5 may influence SC assembly, shedding light on stress-induced FLS mechanisms in broilers.<b>NEW & NOTEWORTHY</b> This study reveals the pivotal role of GR-mediated transcriptional regulation in stress-induced FLS in chickens. Chronic stress modeled with CORT disrupted mitochondrial SC assembly, impairing electron transport, elevated ROS production, and liver steatosis. Notably, the downregulation of complex I assembly factors (<i>NDUFAF5</i>, <i>NDUFAF7</i>, and <i>TIMMDC1</i>) and reduced GR binding to <i>NDUFAF5</i> were key mechanisms. These findings provide new insights into stress-driven mitochondrial dysfunction in broiler FLS.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R770-R782"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for HCO₃^- and NH₃/NH₄⁺-dependent pH regulatory mechanisms in the alkaline midgut of the sea urchin larva.","authors":"Inga Petersen, Sima Jonusaite, Femke Thoben, Marian Y Hu","doi":"10.1152/ajpregu.00222.2024","DOIUrl":"https://doi.org/10.1152/ajpregu.00222.2024","url":null,"abstract":"<p><p>Alkaline digestive systems are well described for some insect species and their larval stages. More recently, larvae of the members of ambulacraria superphylum consisting of echinoderms and hemichordates were also discovered to have highly alkaline midguts (pH 9.5-10.5) with the underlying acid-base regulatory mechanisms largely unknown. Using pharmacological inhibition of acid-base transporters in conjunction with ion-selective microelectrode measurements and pH-sensitive dyes, we investigated intracellular and extracellular pH regulatory mechanisms of midgut epithelial cells of a sea urchin (<i>Strongylocentrotus purpuratus</i>) larva. Our findings suggest that vacuolar-type H⁺-ATPase (inhibited by bafilomycin a1), carbonic anhydrase (inhibited by acetazolamide), anion-exchangers (inhibited by 4,4'-diisothiocyano-2,2'-disulfonic acid or DIDS), and soluble adenylyl cyclase (inhibited by KH7) play crucial roles in cellular acid-base regulation as well as midgut alkalization. Ammonia excretion rates were decreased in the presence of bafilomycin and colchicine, pointing toward vesicular [Formula: see text] trapping and exocytosis mechanism in eliminating nitrogenous proton equivalents from midgut cells. Finally, midgut perfusion studies revealed ouabain-sensitive luminal [Formula: see text] uptake, suggesting a role for Na⁺/K⁺-ATPase-mediated ammonia transport in midgut alkalization. This comprehensive pharmacological analysis provides a new working model relying on the CO₂/[Formula: see text] and NH₃/[Formula: see text] buffer systems for midgut alkalization in the sea urchin larva. These findings are discussed in the context of other alkalizing systems with strong implications for the conserved role of [Formula: see text] and NH₃-driven mechanism of midgut alkalization across the animal kingdom.<b>NEW & NOTEWORTHY</b> Sea urchin larvae evolved highly alkaline conditions in their digestive tracts, and the underlying acid-base regulatory mechanisms are little understood. Here we present evidence that the process of luminal alkalization is cAMP-dependent. Furthermore, our data point toward the involvement of bicarbonate and ammonia in regulating midgut fluid pH. These results identified a novel mechanism for luminal alkalization in the digestive tract of a marine animal with strong implications for other alkalizing systems in animals.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":"328 6","pages":"R685-R699"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is cardiac baroreflex function associated with cardiovascular disease?","authors":"Ryota Asahara, Shigehiko Ogoh","doi":"10.1152/ajpregu.00083.2025","DOIUrl":"10.1152/ajpregu.00083.2025","url":null,"abstract":"","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R727-R729"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irregular sleep patterns and emerging cardiovascular risks: insights from anxiety research.","authors":"Ruwaida Ben Musa","doi":"10.1152/ajpregu.00085.2025","DOIUrl":"10.1152/ajpregu.00085.2025","url":null,"abstract":"","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R767-R769"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Augmented analgesic effect of tyramine or octopamine in combination with lidocaine is mediated with α-adrenergic receptors.","authors":"An-Kuo Chou, Chong-Chi Chiu, Yu-Wen Chen, Ching-Hsia Hung, Jhi-Joung Wang","doi":"10.1152/ajpregu.00225.2024","DOIUrl":"10.1152/ajpregu.00225.2024","url":null,"abstract":"<p><p>Although norepinephrine is known to enhance the antinociceptive effect of the local anesthetic lidocaine, the effects of two precursors of norepinephrine, tyramine and octopamine, on the antinociceptive potency of lidocaine are not known. We aimed to investigate cutaneous antinociceptive interactions and mechanism of action of tyramine and octopamine, and their respective coinjections with lidocaine, in comparison with norepinephrine. Cutaneous nociceptive blockade in rats was quantified by the blockage of cutaneous trunci muscle reflexes induced by needle pinpricks. Isobolographic analysis was used to estimate the interactions between lidocaine and drugs (tyramine, octopamine, or norepinephrine). Phentolamine was added to a two-drug combination. At ED₇₅ (75% effective dose), subcutaneous injection of tyramine and lidocaine provoked 73% and 77% nociceptive blockade. After isobolographic analysis, the theoretical 50% effective dose (ED₅₀) was significantly greater than the experimental ED₅₀ in both octopamine-lidocaine combination and norepinephrine-lidocaine combination (<i>P</i> < 0.01), but not in tyramine-lidocaine combination. Lidocaine (ED₉₅) in combination with tyramine (30 µmole), octopamine (12 µmole), or norepinephrine (0.007 µmole) prolonged the duration of nociceptive blockade (<i>P</i> < 0.05). The addition of phentolamine (0.06 µmole) to a combination of tyramine (30 µmole) and lidocaine (ED₉₅), a combination of octopamine (12 µmole) and lidocaine (ED₉₅), or a combination of norepinephrine (0.007 µmole) and lidocaine (ED₉₅) showed a nociceptive blocking effect similar to that of lidocaine (ED₉₅) alone. Tyramine and octopamine presented dose-dependent cutaneous nociceptive blockades. Tyramine-lidocaine combination produced an additive effect. The combination of octopamine-lidocaine and norepinephrine-lidocaine showed synergistic effects that were inhibited by phentolamine, suggesting that this synergistic effect is mediated with α-adrenergic receptors.<b>NEW & NOTEWORTHY</b> Tyramine and octopamine prolonged the duration of cutaneous nociceptive blockades by lidocaine. We have identified a new mechanism that augmented analgesic effect of tyramine or octopamine in combination with lidocaine is mediated with α-adrenergic receptors.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R783-R790"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutritional modulation of the mTORC1 pathway in muscle: differential effect according to muscle and sex.","authors":"C Breuillard, S Le Plénier, C Guihenneuc, C Choisy, C Hourdé, C Moinard","doi":"10.1152/ajpregu.00156.2024","DOIUrl":"10.1152/ajpregu.00156.2024","url":null,"abstract":"<p><p>Numerous studies have focused on nutrient-driven regulation of muscle metabolism/homeostasis through the mammalian target of rapamycin complex 1 (mTORC1) pathway, but their results fail to converge, perhaps due to differences in mTORC1 pathway protein studied, muscle type, and/or sex. The aim of this work was to study the influence of these factors on mTORC1 pathway activation in response to food intake. Rats (16 male and 16 female) were fasted for 20 h and then were randomized into two groups: a postabsorptive group in which the animals were euthanized in the fasted state and a postprandial group in which the animals were euthanized 30 min after food intake (10 g). Plasma glucose, insulin, and amino acids were assayed. Muscles (extensor digitorum longus, tibialis, soleus, gastrocnemius and plantaris) were removed and Western blotted to analyze the activation of the mTORC1 pathway [phosphorylation of Akt, 4E-binding protein 1 (4E-BP1), and S6K1]. Levels of Akt, 4E-BP1, and S6K1 activation were compared between muscles and by sex in different nutritional states, and a Kruskal-Wallis test was performed to find statistically significant differences.Food intake led to an increase in plasma concentrations of glucose, insulin, and total amino acids (<i>P</i> < 0.0001). Levels of Akt, 4E-BP1, and S6K1 activation differed significantly between muscles and by sex and nutritional state. Different phosphorylation sites in the same muscle were not correlated with each other. These results suggest that mTORC1 activation level is sensitive to muscle type, sex, and nutritional state. Studies on this signal transduction pathway therefore require an individualized approach, considering all the factors that may affect it.<b>NEW & NOTEWORTHY</b> This work demonstrates the complexity of the regulation of the mTOR pathway depending on the protein, muscle, sex, and nutritional status studied. This systemic approach is very little/not considered in the articles.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":" ","pages":"R730-R740"},"PeriodicalIF":2.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice.","authors":"Joshua R Huot, Nicholas A Jamnick, Fabrizio Pin, Patrick D Livingston, Chandler S Callaway, Sarah Morrow, Andrea Bonetto","doi":"10.1152/ajpregu.00035.2025","DOIUrl":"10.1152/ajpregu.00035.2025","url":null,"abstract":"<p><p>The survival rate for children and adolescents has increased to over 85%. However, there is limited understanding of the impact of pediatric cancers on muscle development and physiology. Given that brain tumors alone account for 26% of all pediatric cancers, this study aimed to investigate the skeletal muscle consequences of tumor growth in young mice. C2C12 myotubes were cocultured with GL261 murine glioblastoma cells to assess myotube size. GL261 cells were then injected subcutaneously into 4-wk-old male C57BL/6J mice. Animals were euthanized 28 days post-GL261 implantation. Muscle function was tested in vivo and ex vivo. Muscle protein synthesis was estimated via the SUnSET method, and gene/protein expression levels were assessed via Western blotting and qPCR. In vitro, the C2C12 cultures exposed to GL261 exhibited myotube atrophy, consistent with a disrupted anabolic/catabolic balance. In vivo, carcass, heart, and fat mass were significantly reduced in the tumor-bearing mice. Skeletal muscle growth was impeded in the GL261 hosts, along with a smaller muscle cross-sectional area (CSA). Both in vivo muscle torque and the ex vivo Extensor Digitorum Longus (EDL) muscle force were unchanged. At molecular level, the tumor hosts displayed reduced estimations of muscle protein synthesis and increased muscle protein ubiquitination, in disagreement with decreased muscle ubiquitin ligase mRNA expression. Overall, we showed that GL261 tumors impact the growth of pediatric mice by stunting skeletal muscle development, decreasing muscle mass, reducing muscle fiber size, diminishing muscle protein synthesis, and altering protein catabolism signaling.<b>NEW & NOTEWORTHY</b> This study shows that pediatric brain tumors stunt muscle development in young mice. GL261 glioblastoma cells caused myotube atrophy, reduced carcass, heart, and fat mass, and impeded skeletal muscle growth. Tumor-bearing mice had decreased muscle protein synthesis and increased protein ubiquitination. This is the first demonstration that GL261 tumors reduce muscle mass and fiber size, impair muscle function and innervation, and alter muscle protein turnover.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. Regulatory, integrative and comparative physiology","volume":"328 6","pages":"R628-R641"},"PeriodicalIF":2.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}