American journal of physiology. Cell physiology最新文献

{"title":"Lasmiditan induces mitochondrial biogenesis in primary mouse renal peritubular endothelial cells and augments wound healing and tubular network formation.","authors":"Austin D Thompson, Kai W McAlister, Natalie E Scholpa, Jaroslav Janda, John Hortareas, Rick G Schnellmann","doi":"10.1152/ajpcell.00116.2025","DOIUrl":"10.1152/ajpcell.00116.2025","url":null,"abstract":"<p><p>Kidney disease (KD) is a progressive and life-threatening illness that has manifested into a global health crisis, impacting >10% of the general population. Hallmarks of KD include tubular interstitial fibrosis, renal tubular cell atrophy/necrosis, glomerulosclerosis, persistent inflammation, microvascular endothelial cell (MV-EC) dysfunction/rarefaction, and mitochondrial dysfunction. Following acute kidney injury (AKI), and/or during KD onset/progression, MV-ECs of the renal peritubular endothelial capillaries (RPECs) are highly susceptible to injury, dysfunction, and rarefaction. Pharmacological induction of mitochondrial biogenesis (MB) via 5-hydroxytryptamine receptor 1F (HTR1F) agonism has been shown to enhance mitochondrial function and renal vascular recovery post-AKI in mice; however, little is known about MB in relation to renal MV-ECs and RPEC repair mechanisms. To address this gap in knowledge, the in vitro effects of the potent and selective FDA-approved HTR1F agonist lasmiditan were tested on primary mouse renal peritubular endothelial cells (MRPECs). Lasmiditan increased mitochondrial maximal respiration rates, mRNA and protein expression of MB-related genes, and mitochondrial number in MRPECs. MRPECs were then exposed to pro-inflammatory agents associated with renal MV-EC dysfunction, AKI, and KD (i.e., lipopolysaccharides, transforming growth factor-β1, and tumor necrosis factor-α), in the presence/absence of lasmiditan. Lasmiditan treatment augmented MRPEC wound healing, endothelial tubular network formation (ETNF), enhanced barrier integrity, and blunted inflammatory-induced MV-EC dysfunctions. Together, these data suggest that lasmiditan induces MB and improves wound healing and ETNF of primary MRPECs in the presence/absence of pro-inflammatory agents, highlighting a potential therapeutic role for lasmiditan treatment in renal MV-EC dysfunction, AKI, and/or KD.<b>NEW & NOTEWORTHY</b> Lasmiditan, an FDA-approved HTR1F agonist, induces mitochondrial biogenesis (MB) and enhances recovery following acute kidney injury in mice. Renal microvascular endothelial cells (MV-ECs) are highly susceptible to dysfunction/rarefaction postinjury. The effect of MB on MV-EC repair/recovery is unknown. We show that lasmiditan induces MB in primary mouse renal peritubular endothelial cells and improves wound healing, endothelial tubular network formation, and barrier integrity after inflammatory-induced dysfunction, indicative of its potential for the treatment of kidney diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1318-C1332"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623183","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":"Optimizing electrical field stimulation parameters reveals the maximum contractile function of human skeletal muscle microtissues.","authors":"Yekaterina Tiper, Zhuoye Xie, Arne Hofemeier, Heta Lad, Mattias Luber, Roman Krawetz, Timo Betz, Wolfram-Hubertus Zimmermann, Aaron B Morton, Steven S Segal, Penney M Gilbert","doi":"10.1152/ajpcell.00308.2024","DOIUrl":"10.1152/ajpcell.00308.2024","url":null,"abstract":"<p><p>Skeletal muscle microtissues are engineered to develop therapies for restoring muscle function in patients. However, optimal electrical field stimulation (EFS) parameters to evaluate the function of muscle microtissues remain unestablished. This study reports a protocol to optimize EFS parameters for eliciting contractile force of muscle microtissues cultured in micropost platforms. Muscle microtissues were produced across an opposing pair of microposts in polydimethylsiloxane and polymethyl methacrylate culture platforms using primary, immortalized, and induced pluripotent stem cell-derived myoblasts. In response to EFS between needle electrodes, contraction deflects microposts proportional to developed force. At 5 V, pulse durations used for native muscle (0.1-1 ms) failed to elicit contraction of microtissues; durations reported for engineered muscle (5-10 ms) failed to elicit peak force. Instead, pulse durations of 20-80 ms were required to elicit peak twitch force across microtissues derived from five myoblast lines. Similarly, although peak tetanic force occurs at 20-50 Hz for native human muscles, it varied across microtissues depending on the cell line type, ranging from 7 to 60 Hz. A new parameter, the dynamic oscillation of force, captured trends during rhythmic contractions, whereas quantifying the duration-at-peak force provides an extended kinetics parameter. Our findings indicate that muscle microtissues have cell line type-specific contractile properties, yet all contract and relax more slowly than native muscle, implicating underdeveloped excitation-contraction coupling. Failure to optimize EFS parameters can mask the functional potential of muscle microtissues by underestimating force production. Optimizing and reporting EFS parameters and metrics is necessary to leverage muscle microtissues for advancing skeletal muscle therapies.<b>NEW & NOTEWORTHY</b> Electrical field stimulation (EFS) parameters remain to be standardized for engineered skeletal muscle. Herein, we report a protocol for defining EFS parameters that elicit the maximal contractile force of muscle microtissues cultivated in micropost devices and highlight the value of developing appropriate metrics. The dynamic oscillation of force and duration-at-peak force are introduced as novel metrics of contraction kinetics.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1160-C1176"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522426","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":"Abnormal purine metabolism in nasal epithelial cells affects allergic rhinitis by regulating Th17/Treg cells.","authors":"Ting Xu, Shitong Xia, Xingjie Zhang, Yixiao Yuan","doi":"10.1152/ajpcell.00873.2024","DOIUrl":"10.1152/ajpcell.00873.2024","url":null,"abstract":"<p><p>We aimed to explore novel pathogenesis in young children with allergic rhinitis (AR), and thus finding novel nasal spray reagents for them, especially under 4 yr old. In this study, nontargeted metabolomics analyses were used to explore the differential metabolites in nasal lavage fluid (NALF) of children with AR. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to assess cell proliferation and apoptosis in human nasal mucosal epithelial cells (HNEpCs). HNEpCs were cocultured with CD4⁺ T cells, and flow cytometry was used to detect Th17/regulatory T (Treg) cells. RNA sequencing was used to assess the key pathways in xanthine-treated Jurkat T cells. Finally, both the in vitro and in vivo experiments were used to assess the effect of 1, 3-dipropyl-8 cyclopentylxanthine (DPCPX, Adora1 inhibitor) on activating transcription factor 4 (ATF4) expression and Th17/Treg cells. Xanthine and uric acid levels were increased in the NALF of children with AR. Xanthine dehydrogenase (XDH), purine nucleoside phosphatase (PNP), xanthine/hypoxanthine, and uric acid levels were elevated in Derp1-treated HNEpCs, and si-XDH reversed the reduced cell viability and increased cell apoptosis in Derp1-treated HNEpCs. Both xanthine and Derp1-treated HNEpCs increased the Th17/Treg ratio. The endoplasmic reticulum stress (ERS) pathway was affected in xanthine-treated Jurkat T cells, and ATF4 was markedly reduced in xanthine-treated Jurkat T cells. Xanthine exhibited no effect on Adora1 expression, whereas DPCPX elevated ATF4 expression and reduced the Th17/Treg ratio in xanthine-treated Jurkat T cells. The in vitro experiments revealed that DPCPX reduced inflammatory infiltration, Th17/Treg ratio, interleukin (IL)-17, tumor necrosis factor (TNF)-α, and IL-6 in AR mice. These results demonstrated that xanthine inhibited ATF4 expression via Adora1 to elevate the Th17/Treg ratio in the nasal cavity, thus participating in AR progression. These findings may provide novel therapeutic interventions for young children with AR.<b>NEW & NOTEWORTHY</b> Current nasal spray hormones exhibited some adverse reactions for young children with allergic rhinitis (AR), and there were no suitable nasal spray hormones for children with AR under 4 yr old. This study emphasized the important role of purine metabolism in the nasal cavity in children with AR and provided novel therapeutic interventions for children with AR.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1193-C1205"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456818","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":"ChREBP mediates metabolic remodeling in FBP1-deficient liver.","authors":"Chen-Ma Wang, Qiu-Fang Bai, Ya-Jin Liu, Jie Lin, Chun-Chun Wei, Xian-Hua Ma, Jia-Mu Zhao, Meng Zhu, Yu-Xia Chen, Ya-Nan Shi, Jian-Hui Shi, Weiping J Zhang","doi":"10.1152/ajpcell.00875.2024","DOIUrl":"10.1152/ajpcell.00875.2024","url":null,"abstract":"<p><p>The deficiency of fructose-1,6-bisphosphatase 1 (FBP1), a key enzyme of gluconeogenesis, causes fatty liver. However, its underlying mechanism and physiological significance are not fully understood. Here we demonstrate that carbohydrate response element-binding protein (ChREBP) mediates lipid metabolic remodeling and promotes progressive triglyceride accumulation against metabolic injury in adult FBP1-deficient liver. Inducible liver-specific deletion of Fbp1 gene caused progressive hepatomegaly and hepatic steatosis, with a marked increase in hepatic de novo lipogenesis (DNL) as well as a decrease in plasma β-hydroxybutyrate levels. Notably, FBP1 deficiency resulted in a persistent activation of ChREBP and its target genes involved in glycolysis, lipogenesis, and fatty acid oxidation, even under fasting conditions. Furthermore, liver-specific ChREBP disruption could markedly restore the phenotypes of enhanced DNL and triglyceride accumulation in FBP1-deficient liver but exacerbated its hepatomegaly and liver injury, which was associated with remarkable energy deficit, impaired mammalian target of rapamycin (mTOR) activation, and increased oxidative stress. Furthermore, metabolomics analysis revealed a robust elevation of phosphoenolpyruvate, phosphoglycerates, phospholipids, and ceramides caused by ChREBP deletion in FBP1-deficient liver. Put together, these results suggest that overactivation of ChREBP pathway mediates liver metabolic remodeling in the absence of FBP1, which contributes to the pathogenesis of progressive hepatic steatosis and provides a protection against liver injury. Thus, our findings point to a beneficial role of ChREBP in metabolic remodeling in the context of excessive gluconeogenic intermediates.<b>NEW & NOTEWORTHY</b> FBP1 deficiency in adulthood causes progressive hepatic steatosis due to the overactivation of ChREBP pathway, which enhances lipid synthesis and inhibits fat oxidation. ChREBP-mediated metabolic remodeling protects against liver injury caused by energy deficit and oxidative stress in FBP1-deficient liver.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1234-C1246"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584285","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":"Modeling statin-induced myopathy with hiPSC-derived myocytes reveals that impaired proteostasis underlies the myotoxicity and is targetable for the prevention.","authors":"Xiaolin Zhao, Liyang Ni, Miharu Kubo, Mariko Matsuto, Hidetoshi Sakurai, Makoto Shimizu, Yu Takahashi, Ryuichiro Sato, Yoshio Yamauchi","doi":"10.1152/ajpcell.00714.2024","DOIUrl":"10.1152/ajpcell.00714.2024","url":null,"abstract":"<p><p>Statins, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, have been widely prescribed to lower circulating low-density lipoprotein cholesterol levels and reduce the risk of cardiovascular disease. Although statins are well tolerated, statin-associated muscle symptoms (SAMS) are the major adverse effect and cause statin intolerance. Therefore, understanding the molecular mechanisms of SAMS and developing effective strategies for its prevention are of significant clinical importance; however, both remain unclear. Here, we establish a model of statin-induced myopathy (SIM) with human induced pluripotent stem cell (hiPSC)-derived myocytes (iPSC-MCs) and investigate the effect of statins on protein homeostasis (proteostasis) that affects skeletal muscle wasting and myotoxicity. We show that treating hiPSC-MCs with statins induces atrophic phenotype and myotoxicity, establishing an hiPSC-based SIM model. We then examine whether statins impair the balance between protein synthesis and degradation. The results show that statins not only suppress protein synthesis but also promote protein degradation by upregulating the expression of the muscle-specific E3 ubiquitin ligase Atrogin-1 in a mevalonate pathway-dependent manner. Mechanistically, blocking the mevalonate pathway inactivates the protein kinase Akt, leading to the inhibition of mTOR complex 1 (mTORC1) but the activation of GSK3β and FOXO1. These changes explain the statin-induced impairment in proteostasis. Finally, we show that pharmacological blockage of FOXO1 prevents SIM in hiPSC-MCs, implicating FOXO1 as a key mediator of SIM. Taken together, this study suggests that the mevalonate pathway is critical for maintaining skeletal muscle proteostasis and identifies FOXO1 as a potential target for preventing SIM.<b>NEW & NOTEWORTHY</b> This work established a human induced pluripotent stem (iPS) cell-based model for statin-induced myopathy (SIM) and demonstrated that blocking the mevalonate pathway disrupts the balance between protein synthesis and degradation, leading to myopathy. Furthermore, the present study showed that pharmacological inhibition of the transcription factor FOXO1 prevents SIM in human iPS cell-derived myocytes, suggesting that FOXO1 is a key mediator of SIM and a potential target for its prevention.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1247-C1259"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584303","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":"Utilizing ¹³C-Labeled internal standards to advance the analysis of heparan sulfate.","authors":"Zhangjie Wang, Jian Liu","doi":"10.1152/ajpcell.00944.2024","DOIUrl":"10.1152/ajpcell.00944.2024","url":null,"abstract":"<p><p>Heparan sulfate (HS) is a highly sulfated and structurally heterogeneous polysaccharide that plays key roles in numerous biological processes. Due to its complex structure and variable sulfation patterns, accurately characterizing and quantifying HS in biological samples poses significant analytical challenges. This review presents an advanced high-performance liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methodology that utilizes isotope-labeled internal standards for the precise quantification of HS disaccharides and rare 3-<i>O</i>-sulfated tetrasaccharides, alongside monitoring 6-<i>O</i>-endosulfatase enzyme activity and the metabolism of synthetic HS oligosaccharides in biological systems. The combination of isotope-labeled standards with LC-MS/MS technology provides a powerful and sensitive approach for comprehensive analysis of HS modifications, offering valuable insights into HS metabolism and its alterations across various biological contexts.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1091-C1100"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456820","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":"Mechanistic insights into SENP1 and OCT4 interaction in promoting drug resistance and stem cell features in colon cancer.","authors":"Jun Zou, Jing Chen, Lei Deng, Bangran Xu, Tenghua Yu, Jun Wang, Chongwu He","doi":"10.1152/ajpcell.00817.2024","DOIUrl":"10.1152/ajpcell.00817.2024","url":null,"abstract":"<p><p>This study explores the molecular mechanism by which sentrin/SUMO-specific protease 1 (SENP1) promotes cisplatin (Cis) resistance and tumor stem cell characteristics in colon adenocarcinoma (COAD) through deSUMOylation-mediated modification of octamer-binding transcription factor 4 (OCT4). By analyzing single-cell and transcriptome sequencing datasets, we identified key genes and regulatory pathways in both resistant and sensitive COAD cells. Malignant cells were isolated and evaluated for stemness using the infercnv package, and differential genes between Cis-resistant and -sensitive groups were identified. Machine learning algorithms highlighted essential genes, and databases predicted interaction sites between OCT4 and SENP1. In vitro experiments using enriched HCT116 stem cells revealed that SENP1 and OCT4 expression significantly elevated CD44 and CD133 levels, enhancing stemness. Functional assays showed that SENP1's deSUMOylation of OCT4 intensified Cis resistance, migration, and invasion in cisplatin-resistant cell line 116 (Cis-116) cells. In vivo, SENP1 knockdown reduced tumor growth and stem cell markers, whereas OCT4 overexpression escalated tumor metastasis and structural damage. These findings demonstrate that SENP1's modulation of OCT4 is central to COAD's resistance and stem cell properties, offering a novel target for COAD therapy.<b>NEW & NOTEWORTHY</b> This study uncovers the critical role of SENP1 in regulating OCT4 through deSUMOylation, driving Cis resistance and tumor stemness in COAD. Targeting this pathway may provide novel therapeutic strategies for COAD management.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1260-C1278"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595818","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":"GSK3 inhibition ameliorates the abnormal contractility of Newfoundland ACM patient iPSC-cardiomyocytes.","authors":"Rebecca J Noort, Wesam Salman, Camila Fuchs, Ursula Braun, David Pace, Kathleen A Hodgkinson, Jessica L Esseltine","doi":"10.1152/ajpcell.01025.2024","DOIUrl":"10.1152/ajpcell.01025.2024","url":null,"abstract":"<p><p>Arrhythmogenic cardiomyopathy (ACM) is clinically characterized by ventricular arrhythmias causing sudden cardiac death and fibrofatty replacement of the myocardium, leading to heart failure. One form of ACM is highly prevalent in the Canadian Province of Newfoundland and Labrador (NL) and has earned the moniker, \"The Newfoundland Curse\". ACM in NL is often caused by a fully penetrant heterozygous missense pathogenic variant in the <i>TMEM43</i> gene (<i>TMEM43</i> c.1073C>T; TMEM43 p.S358L). Although the causative variant has been identified, little is known about the function of the TMEM43 protein in cardiomyocytes, how the TMEM43 p.S358L mutation contributes to the development of arrhythmias, or why the disease is more severe in males than in females. To explore the role of TMEM43 in cardiomyocyte function, we generated induced pluripotent stem cells (iPSCs) from two severely affected male Newfoundland patients with ACM (TMEM43 p.S358L). CRISPR-Cas9 was used to genetically \"repair\" the heterozygous TMEM43 variant in ACM patient iPSCs. ACM patient iPSC-cardiomyocytes (iPSC-CMs) with the TMEM43 p.S358L variant display pro-arrhythmogenic phenotypes in vitro with significantly elevated contraction rates and altered calcium handling, although no obvious gross abnormalities were observed across several major intracellular organelles. GSK3 inhibition significantly increased the protein expression of β-catenin as well as Lamin A/C and ameliorated the proarrhythmic tendencies of ACM patient iPSC-CMs.<b>NEW & NOTEWORTHY</b> This is the first characterization of induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) from Newfoundland patients with ACM. We find that ACM iPSC-CMs exhibit extreme proarrhythmic tendencies that can be normalized with GSK3 inhibition. Importantly, GSK3 inhibition is accompanied by a significant increase in key proteins, such as β-catenin and Lamin A/C, pointing toward a possible mechanism both for disease pathogenesis and therapy via GSK3 inhibitors.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1206-C1219"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584300","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":"Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes.","authors":"Joachim Nielsen, Kristine Grøsfjeld Petersen, Martin Eisemann de Almeida, Sam O Shepherd, Britt Christensen, Maria Houborg Petersen, Kurt Højlund, Niels Ørtenblad, Kasper Degn Gejl","doi":"10.1152/ajpcell.00123.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00123.2025","url":null,"abstract":"<p><p>Endurance athletes exhibit higher skeletal muscle mitochondrial and lipid droplet (LD) content compared to recreationally active individuals, along with greater whole-body oxygen uptake and maximal fat oxidation rates. In this study, we investigated if these differences manifest in a greater LD-mitochondria contact and how this may relate to the organelles' size, shape, and numerical densities. We obtained skeletal muscle biopsies from 17 male elite triathletes and road cyclists and 7 recreationally active men. Using quantitative transmission electron microscopy, we found that the endurance athletes had 2-3-fold greater LD-mitochondria total contact length than the recreationally active individuals. This was related to higher numerical densities of both mitochondria (+30%) and LDs (+100%) in the intermyofibrillar space. Adding data from untrained individuals with equally high intermyofibrillar LD density as the endurance athletes revealed a 24% greater total LD-mitochondria contact length in the endurance athletes. We observed small trivial differences in shape of both organelles between populations. However, large mitochondrial profiles were more elongated and irregular in shape than small mitochondrial profiles, while large LD profiles were more circular and less irregular than small LD profiles. Within athletes, large intermyofibrillar LD profiles correlated (r=0.72) with a high fraction of PLIN5-positive LDs and their maximal fat oxidation rate was positively associated with an interaction between the profile size of both intermyofibrillar LDs and mitochondria. In conclusion, male endurance athletes have a greater LD-mitochondria contact than recreationally active and untrained individuals. This muscular phenotype is restricted to the intermyofibrillar space and to fibers rich in mitochondria.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656109","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":"Cellular mechanisms underlying overreaching in skeletal muscle following excessive high-intensity interval training.","authors":"Daiki Watanabe, Masanobu Wada","doi":"10.1152/ajpcell.00623.2024","DOIUrl":"10.1152/ajpcell.00623.2024","url":null,"abstract":"<p><p>Overreaching (OR) can be defined as a decline in physical performance resulting from excessive exercise training, necessitating days to weeks recovery. Impairments in the contractile function of skeletal muscle are believed to be a primary factor contributing to OR. However, the cellular mechanism triggering OR remains unclear. The purpose of this study was to elucidate the mechanisms underlying OR. Rats' plantar flexor muscles were subjected to repeated electrical stimulations mimicking excessive high-intensity interval training (HIIT) daily for 13 consecutive days, and isometric torques were monitored. The torque was measured one day after HIIT, and subsequently, the physiological function of type II fibers was analyzed by using mechanically skinned-fiber technique. Eleven of 17 rats exhibited torque decline, whereas others did not. Thus, the rats were divided into OR and nonoverreaching (NOR) groups. Skinned fibers from the gastrocnemius (GAS) muscles of both groups showed decreased depolarization-induced force and increased myofibrillar Ca²⁺ sensitivity. However, the fibers from the OR group, but not the NOR group, exhibited a decrease in myofibrillar maximal force. Biochemical analyses of a superficial region of GAS muscle revealed that α-actinin 2 content was increased in the NOR group, but not in the OR group, whereas calpain-3 autolysis was increased in the OR group, but not in the NOR group. These findings shed light on the cellular mechanism underlying OR: OR following excessive HIIT was induced by a decreased myofibrillar maximal force, whereas Ca²⁺ sensitivity was increased.<b>NEW & NOTEWORTHY</b> An early sign of overtraining is a performance impairment known as overreaching (OR). This study revealed the cellular mechanism underlying OR by combining in vivo fatiguing contractions with mechanically skinned-fiber technique. Thirteen consecutive days of intense training result in myofibrillar force depression in OR. This study provides valuable insights not only for athletes and coaches but also for nonathletes who incorporate exercise into their daily activity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C921-C938"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187660","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}