Isaac A Chavez-Guevara, Manuel Fermandez-Escabias, Marco A Hernandez-Lepe, Francisco J Amaro-Gahete
{"title":"Modulation of Fatty Acid Metabolism via Lactate-HCA1 Signaling: Potential Therapeutic Implications.","authors":"Isaac A Chavez-Guevara, Manuel Fermandez-Escabias, Marco A Hernandez-Lepe, Francisco J Amaro-Gahete","doi":"10.1152/ajpcell.00969.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00969.2024","url":null,"abstract":"<p><p>The lactate/HCA1 signaling pathway has emerged as a promising target for the clinical management of metabolic diseases, given its regulatory effects on triglyceride turnover and mobilization. However, the differential roles of this pathway in adipose tissue, skeletal muscle, and the liver raise important questions about whether its activation or inhibition would yield the most favorable outcomes. In adipose tissue, HCA1 activation suppresses lipolysis, while in skeletal muscle, recent evidence suggests that lactate may bypass HCA1 to directly enhance mitochondrial fatty acid oxidation. In the liver, HCA1 activation has been implicated in promoting lipid oxidation, offering potential therapeutic implications. This perspective also explores the potential of the lactate/HCA1 pathway to mediate systemic adaptations induced by exercise training, including enhanced mitochondrial capacity and metabolic flexibility. These insights underscore the pathway's relevance for both metabolic health and exercise physiology. However, the current understanding of the lactate/HCA1 pathway remains incomplete, with critical gaps in knowledge regarding its role in underrepresented populations and the molecular mechanisms underlying its tissue-specific effects. Addressing these limitations will be essential for refining the therapeutic and clinical applications of this pathway.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646947","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}
Rebecca Dörner, Franziska A Hägele, Shauna D O'Donovan, Jennifer L Miles-Chan, Manfred J Müller, Anja Bosy-Westphal
{"title":"Diurnal differences in postprandial glucose and triglyceride metabolism reveal metabolic flexibility and resilience.","authors":"Rebecca Dörner, Franziska A Hägele, Shauna D O'Donovan, Jennifer L Miles-Chan, Manfred J Müller, Anja Bosy-Westphal","doi":"10.1152/ajpcell.00102.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00102.2025","url":null,"abstract":"<p><p>Objective The study investigated the diurnal variance in metabolic resilience (i.e., the robustness, the recovery and re-orientation of metabolism) and metabolic flexibility in glucose and fat oxidation rates to three identical test meals. Methods Eight young, healthy subjects consumed identical liquid mixed meals three times a day (33 % of energy requirement each), followed by a defined bout of physical activity conducted in a whole-room indirect calorimeter to continuously assess energy expenditure and postprandial changes in substrate oxidation rates, as a measure of metabolic flexibility. A mathematical metabolic resilience model was used to analyze the postprandial blood parameters. Results Throughout the day, postprandial glucose area under the curve (AUC) increased (breakfast mean ±SD 17.3 ±2.4 vs. dinner 20.8 ±2.0 g/180min; p<0.001) while triglyceride AUC decreased (breakfast 434 ±158 vs. dinner 365 ±104 mg/180min; p=0.039) at identical insulin AUC and energy balance. Fat oxidation increased from breakfast 24.8 ±8.7 to dinner 28.0 ±8.7 g/180min (p=0.029), while respiratory exchange ratio declined from 0.035 ±0.026 to 0.012 ±0.029 (p=0.005). Metabolic resilience model reveals a diurnal increased rate of lipolysis of circulating triglycerides at a concomitant decrease in the rate of exogenous and endogenous triglyceride appearance. Conclusion Meal-to-meal changes in glucose AUC indicate rising insulin resistance during the day. However, this reflects a resilient metabolism that shifts to triglyceride metabolism in the evening while maintaining insulin AUC and energy balance.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646945","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}
Austin D Thompson, Kai W McAlister, Natalie E Scholpa, Jaroslav Janda, John Hortareas, Rick G Schnellmann
{"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":"https://doi.org/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 RPECs 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 MRPECs 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.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra M Garvin, Dana B Floyd, Alexis C Bailey, Merry L Lindsey, Chad C Carroll, Taben M Hale
{"title":"Transient Angiotensin Converting Enzyme Inhibition Confers Sex-Specific Protection Against Angiotensin II-Induced Cardiac Remodeling.","authors":"Alexandra M Garvin, Dana B Floyd, Alexis C Bailey, Merry L Lindsey, Chad C Carroll, Taben M Hale","doi":"10.1152/ajpcell.00753.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00753.2024","url":null,"abstract":"<p><p>Hypertension increases the prevalence of heart failure to a greater extent in women than in men. The fibrotic remodeling of the left ventricle is a major contributor to increased myocardial stiffness and eventual decrease in cardiac function. Injury-induced cardiac fibrosis can be prevented in the spontaneously hypertensive rat (SHR) by transient angiotensin converting enzyme inhibition (ACEi) in males. Whether transient ACEi also protects against fibrosis in females is not known. In the present study, we evaluated angiotensin II (Ang II)-induced cardiac fibrosis and related signaling in male and female SHR to determine how these responses are altered by prior transient ACEi treatment. Relative changes in blood pressure response to both ACEi and Ang II were similar between sexes, while Ang II-induced cardiac hypertrophy was attenuated by prior ACEi in males only. Ang II-induced changes in gene expression for collagens I, III, and IV were attenuated by prior ACEi in males, but not females. Despite these sex-specific differences, prior ACEi attenuated Ang II-induced increases in fibrogenic proteins (phosphorylated SMAD3/SMAD3, periostin, and lysyl oxidase) and pro-oxidative proteins (NOX2 and NOX4), as well as hydroxyproline content similarly in both sexes. Interestingly, a positive correlation between angiotensin II type 1 receptor gene expression and <i>Col1a1</i> in Ang II treated males is absent in the female SHRs. The observed sex differences in the protection afforded by prior ACEi suggest altered signaling for collagen deposition that may lead to a greater understanding of the sex-dependent efficacy of antihypertensive drugs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584380","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}
Matthew John Read, Andreas Koschinski, Samuel Jitu Bose, Rebecca Ab Burton
{"title":"Physiological Function of Cyclic Nucleotide Phosphodiesterases in Atrial Myocytes and their Potential as Targets in Atrial Fibrillation.","authors":"Matthew John Read, Andreas Koschinski, Samuel Jitu Bose, Rebecca Ab Burton","doi":"10.1152/ajpcell.00782.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00782.2024","url":null,"abstract":"<p><p>Cyclic nucleotide hy drolysing phosphodiesterases (PDEs) are key regulators of cyclic nucleotide (e.g. cAMP and cGMP) signalling. Here we examine the role of PDEs in the physiology of atrial myocytes (AMs), the pathogenesis of atrial fibrillation (AF) and the potential of PDEs as therapeutic targets for AF. PDE1-5 and 8 are present and functional in AMs. PDE2-4 are important regulators of AM contraction but their role beyond atrial contractility is unclear. The role of PDE1,5 and 8 in healthy AMs is unknown but of interest because of their roles in ventricular myocytes. We propose that PDE2-5 and PDE8 are potential targets to prevent the triggering of AF considering their effects on Ca<sup>2+</sup> handling and /or electrical activity. PDE1-5 are possible targets to treat patients with paroxysmal or persistent AF caused by pulmonary vein automaticity. PDE8B2 is a possible target for patients with persistent AF due to its altered expression. Research should aim to identify the presence, localisation, and function of specific PDE isoforms in human atria. Ultimately, the paucity of PDE isoform-specific small molecule modulators and the difficulty of delivering PDE-targeted medications or therapies to particular cell types limit current research and its application.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584307","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}
Nazim Husain, Anoop Kumar, Arivarasu N Anbazhagan, Ravinder K Gill, Pradeep K Dudeja
{"title":"Intestinal Luminal Anion Transporters and their Interplay with Gut Microbiome and Inflammation.","authors":"Nazim Husain, Anoop Kumar, Arivarasu N Anbazhagan, Ravinder K Gill, Pradeep K Dudeja","doi":"10.1152/ajpcell.00026.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00026.2025","url":null,"abstract":"<p><p>The intestine, as a critical interface between the external environment and the internal body, plays a central role in nutrient absorption, immune regulation, and maintaining homeostasis. The intestinal epithelium, composed of specialized epithelial cells, hosts apical anion transporters that primarily mediate the transport of chloride and bicarbonate ions, essential for maintaining electrolyte balance, pH homeostasis, and fluid absorption/secretion. Additionally, the intestine hosts a diverse population of gut microbiota that plays a pivotal role in various physiological processes including nutrient metabolism, immune regulation and maintenance of intestinal barrier integrity, all of which are critical for host gut homeostasis and health. The anion transporters and gut microbiome are intricately interconnected, where alterations in one can trigger changes in the other leading to compromised barrier integrity and increasing susceptibility to pathophysiological states including gut inflammation. This review focuses on the interplay of key apical anion transporters including Down Regulated in Adenoma (DRA, SLC26A3), Putative Anion Transporter-1 (PAT1, SLC26A6) and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR, ABCC7) with the gut microbiome, barrier integrity and their relationship to gut inflammation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565777","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}
Nikos K Karamanos, Zoi Piperigkou, Chrisavgi Gourdoupi, Sylvia Mangani, Maria dM Vivanco
{"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":"https://doi.org/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 3D network, governs cell functionality and play 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 <i>in vitro</i> and <i>in vivo</i> models. Additionally, 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":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-04","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}
Qingrui Duan, Qingxi Zhang, ShuoLin Jiang, Kun Nie, Shujun Feng, Yihui Qiu, Peikun He, Yuxuan Xing, Jiaxuan Liu, Guixian Ma, Yuhu Zhang, Yuyuan Gao, Lijuan Wang
{"title":"Transmission of peripheral blood α-synuclein fibrils exacerbates synucleinopathy and neurodegeneration in Parkinson's disease by endothelial Lag3 endocytosis.","authors":"Qingrui Duan, Qingxi Zhang, ShuoLin Jiang, Kun Nie, Shujun Feng, Yihui Qiu, Peikun He, Yuxuan Xing, Jiaxuan Liu, Guixian Ma, Yuhu Zhang, Yuyuan Gao, Lijuan Wang","doi":"10.1152/ajpcell.00639.2024","DOIUrl":"10.1152/ajpcell.00639.2024","url":null,"abstract":"<p><p>Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal α-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFFs) can be detected in the serum of patients with PD. The peripheral blood α-syn PFF can cross the blood-brain barrier (BBB) and aggravate neuronal damage, but the mechanism remains to be elucidated. We constructed the PD mouse models of different severity: the mild pathology (A53T ONLY) and the severe pathology (A53T + Brain FIB); this was followed by α-syn PFFs intravenous injection. Then, we used endothelium-specific Lag3 knockout mice (Lag3-ECs-CKO) to decrease the blood α-syn PFFs spreading. We observed that intravenous transmission of α-syn PFFs significantly aggravated motor deficits, dopaminergic neuron loss, neuroinflammation, and pathologic α-syn deposition in A53T ONLY, but not in A53T + Brain FIB. Blocking endothelial Lag3 endocytosis by Lag3-ECs-CKO decreased the blood α-syn PFFs spreading and improved the symptoms and pathogenesis of PD mice. Our findings reveal the role of peripheral blood α-syn PFFs transmission in the mild pathology or early-stage PD and the mechanism of endothelial Lag3 endocytosis in the pathology of α-syn transmission. Targeting endothelial Lag3 to prevent α-syn from spreading from the blood to the brain may be a disease-modifying therapy in early-stage PD.<b>NEW & NOTEWORTHY</b> This study highlights the transmission mechanism of peripheral blood α-synuclein preformed fibrils (α-syn PFFs) through endothelial Lag3 endocytosis in the mild pathology or early-stage Parkinson's disease (PD). Targeting endothelial Lag3 as a perspective of decreasing peripheral blood α-syn PFFs transmission may be a disease-modifying therapy in early-stage PD.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C836-C855"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798696","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}
Deena B Snoke, Gary S Atwood, Emma R Bellefleur, Alice M Stokes, Michael J Toth
{"title":"Body composition alterations in patients with lung cancer.","authors":"Deena B Snoke, Gary S Atwood, Emma R Bellefleur, Alice M Stokes, Michael J Toth","doi":"10.1152/ajpcell.01048.2024","DOIUrl":"10.1152/ajpcell.01048.2024","url":null,"abstract":"<p><p>Most patients with lung cancer experience cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting. Knowledge of body composition changes in patients is limited, however, because most studies have been cross-sectional, comparing patients with noncancer controls or patients with and without CC. Few studies, in contrast, have evaluated body composition in patients with lung cancer over time. This review examines our current understanding of longitudinal body composition changes in patients with lung cancer and identifies modifying factors contributing to variation in muscle and adipose tissue wasting, focusing on biological sex. We identified 32 studies conducting longitudinal measurements of body composition by computed tomography, bioelectrical impedance, dual X-ray absorptiometry, or total body nitrogen, with a total of <i>n</i> = 3,951 patients (35% female). All studies evaluated changes following diagnosis while patients were receiving treatment. Most studies reporting muscle-specific outcomes show decreased skeletal muscle mass, with more pronounced muscle wasting in males and male-enriched populations. In a small number of studies reporting muscle density, the majority show increased myosteatosis. Adiposity changes are less frequently reported, although wasting appears more prevalent in late-stage disease. Further studies are needed to define adipose changes along the lung cancer continuum. Our review emphasizes the need for balanced recruitment based on biological sex and sex-based analyses. In addition, consensus reporting of relevant patient data and outcomes in future studies will allow for meta-analysis and assist in the development of effective treatments for lung CC.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C872-C886"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062983","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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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}