American journal of physiology. Cell physiology最新文献

{"title":"Sodium/hydrogen exchanger 8 affects sheet migration of human intestinal epithelial cells (HT29MTX) by influencing the actin cytoskeletal rearrangement.","authors":"Ju Wang, Christian Stock, Azam Salari, Ursula E Seidler, Katerina Nikolovska","doi":"10.1152/ajpcell.00826.2024","DOIUrl":"10.1152/ajpcell.00826.2024","url":null,"abstract":"<p><p>The gastrointestinal Na⁺/H⁺ transporter 8 (NHE8) is downregulated in the mucosa of patients with ulcerative colitis, and its deletion in the murine intestine causes a \"colitis-like\" phenotype. Since ulcerative colitis is characterized by repeated mucosal injury, we investigated the role of NHE8 in intestinal wound repair, by accessing its effect on intracellular pH (pH_i) regulation, cell proliferation, and migration. NHE8 expression was downregulated via shRNA lentiviral transduction in HT29MTX cells. The selected clonal cell line (HT29/shNHE8) with ∼80% reduced NHE8 mRNA expression displayed an increased proliferative but reduced migratory rate compared with the mock-transduced cells (HT29/pLKO1). The wound front of the HT29/shNHE8 cells consisted of both migrating and nonmigrating cells, and pH_i measured in this segment displayed the following values: pH_i(HT29/pLKO.1) = 7.35, pH_i(HT29/shNHE8_migrating) = 7.27, and pH_i(HT29/shNHE8_nonmigrating) = 7.1. The migrating HT29/shNHE8 cells exhibited a significantly increased NHE activity compared with migrating mock-transfected and nonmigrating cells, which was abolished by pharmacological NHE3 inhibition. NHE3 localized to the wound front of HT29/shNHE8, but not to that of HT29/pLKO.1 cells. Cell flattening and lamellipodia development were observed at the wound front in HT29/pLKO.1 cells, whereas the HT29/shNHE8 cells formed tight actin bundles and retained their apical-basal architecture. RAC1 and Cofilin-1, required for the generation of actin-based membrane protrusions, were absent at the wound front of HT29/shNHE8 cells but were expressed in migrating HT29/pLKO.1 cells, where RAC1 partially colocalized with NHE8. The results show that NHE8 downregulation reduces the pH_i and leads to enhanced epithelial cell proliferation, but impairs migration likely due to altered actin polymerization.<b>NEW & NOTEWORTHY</b> The Na⁺/H⁺ exchanger 8 (NHE8) plays an important role in the regulation of intracellular pH_i, cell proliferation, and epithelial sheet migration in HT29MTX intestinal cells. NHE8 knockdown cells lack the ability to dynamically rearrange the actin cytoskeleton at the wound front, resulting in a reduced migration rate. These observations provide insights into the molecular mechanism of the downregulation of this transporter in human ulcerative colitis and its role in epithelial restitution.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C50-C67"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155498","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":"Modulation of pain by ketones: a mini-review.","authors":"Lana L Heslop, Douglas E Wright","doi":"10.1152/ajpcell.00305.2025","DOIUrl":"10.1152/ajpcell.00305.2025","url":null,"abstract":"<p><p>Ketones, or ketone bodies, are organic molecules produced via ketogenesis in the liver in response to changing energy demands. Three ketones are generated that can act as metabolic messengers and a fuel source for the body, typically forming when glucose levels decrease within the bloodstream. A ketogenic diet, a form of low-carbohydrate, high-fat diet, stimulates ketogenesis and forces ketone utilization as an energy source by nonhepatic tissues. Currently, ketones, along with the ketogenic diet, have been of interest to many as a therapeutic mechanism for multiple conditions, including epilepsy, numerous neurodegenerative diseases, and diabetes. Emerging preclinical evidence suggests that ketones may play a powerful role in modulating acute and chronic pain. Here, we summarize the known benefits of ketones on neurological disease and nociceptive systems associated with pain. We discuss possible mechanisms identified from preclinical studies underlying the identified benefits of ketones in reducing pain.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C31-C37"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155497","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":"10.1152/ajpcell.00123.2025","url":null,"abstract":"<p><p>Endurance athletes exhibit higher skeletal muscle mitochondrial and lipid droplet (LD) content compared with recreationally active individuals, along with greater whole body oxygen uptake and maximal fat oxidation rates. In this study, we investigated whether 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 seven recreationally active men. Using quantitative transmission electron microscopy, we found that the endurance athletes had two- to threefold 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 the shape of both organelles between populations. However, large mitochondrial profiles were more elongated and irregular in shape than small mitochondrial profiles, whereas large LD profiles were more circular and less irregular than small LD profiles. Within athletes, large intermyofibrillar LD profiles correlated (<i>r</i> = 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.<b>NEW & NOTEWORTHY</b> Lipid droplets and mitochondria form membrane contacts in skeletal muscle fibers, but the quantitative magnitude of these contacts remains unknown. Our study reveals that endurance athletes exhibit greater contact length between lipid droplets and mitochondria compared with recreationally active and untrained individuals. This difference is influenced by the content and spatial distribution of mitochondria and lipid droplets. The results provide quantitative insights into lipid droplet and mitochondria morphology across various human populations, including endurance athletes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1-C16"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","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":"Prolactin maintains the neonatal phenotype of enterocytes during lactation in newborn mice.","authors":"José Luis Dena-Beltrán, Ana Luisa Ocampo-Ruiz, Dina I Vázquez-Carrillo, Ericka A de Los Ríos, Xarubet Ruiz-Herrera, Magali Valle-Pacheco, Sairi I Robles-Torres, Gonzalo Martínez de la Escalera, Carmen Clapp, Yazmín Macotela","doi":"10.1152/ajpcell.00981.2024","DOIUrl":"10.1152/ajpcell.00981.2024","url":null,"abstract":"<p><p>After birth, the intestine experiences a gradual maturation process that transforms the gut epithelium to adapt to the changing feeding conditions, from maternal milk to solid food. Milk components regulate this transition from neonatal- to adult-type enterocytes. Prolactin (PRL), a hormone present in milk at high concentrations, regulates the metabolism of the nursing pups. However, the target tissues that mediate its actions are unknown. Here, we hypothesized that milk PRL influences the transition from neonatal- to adult-type enterocytes. We found that PRL and PRL receptors are present in the intestinal epithelium (IE) of neonatal mice where PRL exerts direct actions. PRL activated the AKT and ERK1/2 signaling pathways in intestinal epithelial cells in culture from <i>postnatal day</i> (PD) <i>10</i>-<i>12</i> neonatal mice, and spheroids derived from neonatal intestine proliferate in response to PRL. Moreover, at PD14, the intestine villi length, crypt depth, and number are increased in PRL receptor null mice (<i>Prlr^-/-</i>), suggesting an accelerated maturation phenotype in the absence of PRL signaling. Also, <i>Prlr^-/-</i> mice showed decreased expression of neonatal IE markers and increased expression of adult-type IE markers. Consistently, the activity of lactase and the levels of the immunoglobulins type G (IgG) transporter FcRn were reduced in the intestine of <i>Prlr^-/-</i> nursing pups. In summary, the lack of PRL signaling promotes precocious intestinal enterocyte maturation, which may lead to adverse health consequences such as poor digestion of lactose and reduced passive immunity. By restraining intestinal maturation, PRL helps maintain the neonatal enterocyte phenotype needed to promote the optimal use of milk components in the nursing offspring.<b>NEW & NOTEWORTHY</b> Prolactin promotes lactation in the mother and is present in maternal milk; however, its effects on lactating pups have been overlooked. Our study shows that milk-derived prolactin acts on the intestine of mouse pups, maintaining the neonatal phenotype of the intestinal epithelium, preventing an accelerated transition to an adult-type epithelium. This process allows optimal utilization of nutrients and signals from maternal milk. These findings highlight the relevance of milk-borne maternal signals in regulating neonatal physiology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C17-C30"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963788","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 role of KAT6A in regulating primordial follicle activation in mouse ovary.","authors":"Yan Zhang, Xiaoran Nie, Liu Yang, Tuo Zhang, Jixian Zhang, Xiaojing Yang, Yanhua Yang, Chunlin Zhang, Meina He","doi":"10.1152/ajpcell.00055.2025","DOIUrl":"10.1152/ajpcell.00055.2025","url":null,"abstract":"<p><p>Follicle is a primary structural and functional unit within the mammalian ovary, encompassing a centrally positioned oocyte surrounded by pregranulosa cells. Primordial follicles constitute the ovarian reserve, the activated primary follicle represents the inception of follicular development in mammals. The intricate balance between primordial follicle dormancy and activation is pivotal for sustaining ovarian reproductive function; over-activation of the primordial follicle pool can result in premature ovarian failure among women. Although recent studies have revealed that several functional genes and pathways, such as mammalian target of rapamycin signaling, play roles in controlling the activation of primordial follicles, our understanding of the molecular networks regulating the activation progress is still incomplete. Here, using the mouse in vitro ovarian culture model, we identify a new role for K (lysine) acetyltransferase 6 A (KAT6A) in regulating the activation of primordial follicles in mice. Our results show that the expression of KAT6A is increased during primordial follicle activation in the oocytes. Disruption of KAT6A activity with two specific inhibitors significantly suppresses primordial follicle activation in cultured mouse ovaries. Furthermore, we find that KAT6A regulates processing body (P-body) signaling pathway and the expression levels of <i>Ddx6</i> in oocytes. This suggests that KAT6A may promote primordial follicle activation by regulating the P-body signaling pathway. Collectively, our results elucidate that KAT6A plays a crucial role in controlling the activation of primordial follicles in the mammalian ovary.<b>NEW & NOTEWORTHY</b> The dynamic balance between primordial follicle dormancy and activation is important for the maintenance of ovarian reproductive function. Our results show that the expression of KAT6A is increased during primordial follicle activation in the oocytes. Using two inhibitors of KAT6A exhibited decreased speed of primordial follicles activation in cultured mouse ovaries, and <i>Ddx6</i> expression was increased in oocytes. Collectively, our results reveal that KAT6A controls the activation of primordial follicles in the mammalian ovary.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C38-C49"},"PeriodicalIF":5.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155499","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":"Organoid models for chemosensing cell studies.","authors":"Peihua Jiang, Nancy E Rawson","doi":"10.1152/ajpcell.00047.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00047.2025","url":null,"abstract":"<p><p>Over the past decade, tremendous progress has been made in using organoids-three-dimensional, miniature organ-like structures-to model tissues and organs <i>in vitro</i>, including both regenerative tissues (which contain tissue-residing stem/progenitor cells) and largely non-regenerative tissues, such as the brain. Organoids resemble the tissues from which they are derived in many aspects of structure, function, and organization. As a result, organoid models have been utilized in a variety of fields for cell studies. Many well-written reviews have provided in-depth descriptions of organoid models for various systems. In this article, we review the establishment and application of tissue stem/progenitor cell-derived organoid models relevant to chemosensory cell studies (taste and smell), and discuss the limitations and future directions of using these models to study chemosensation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232947","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":"THBS4 downregulation alters trophoblast function in preeclampsia via the TGF-β1/Smad signaling cascade.","authors":"Haoran Shi, Yan Mao, Jianjian Cui, Ruilin Ma, Zejun Yang, Yin Zhao","doi":"10.1152/ajpcell.00387.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00387.2024","url":null,"abstract":"<p><p>Preeclampsia (PE) is a severe complication specific to pregnancy, characterized by the onset of hypertension after 20 weeks of gestation, often accompanied by proteinuria and damage to important maternal organs. The abnormal invasive function of trophoblast cells leads to impaired remodeling of uterine spiral arteries, shallow placental implantation, and inadequate uteroplacental perfusion, which is one of the important factors in the development of PE. This study aimed to explore key molecules that affect the invasive and migratory functions of trophoblast cells. The study found that THBS4 expression in placental tissue of preeclampsia decreased compared to normal pregnancy and was localized in trophoblast cells. Knocking down THBS4 expression inhibited the TGF-β1 signaling pathway in HTR8/Svneo cells and reduced cell proliferation, migration, and invasion abilities. The knockdown effect of THBS4 could be reversed by TGF-β1 agonist, hyclate. In conclusion, the results of our study indicate that THBS4 may regulate the biological functions of trophoblast cells through the TGF-β1 signaling pathway and may play an important role in placental vascular development.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232948","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 Multifaceted Role of MyoD in Adult Skeletal Muscle: Homeostasis, Regeneration, and Diseases.","authors":"Ryosuke Tsuji, Takuto Hayashi, Satoru Takahashi, Atsushi Asakura, Ryo Fujita","doi":"10.1152/ajpcell.00334.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00334.2025","url":null,"abstract":"<p><p>Myogenic regulatory factors, including myoblast determination protein 1 (MyoD1 or MyoD) and myogenic factor 5 (Myf5), crucially regulate skeletal muscle lineage specification and development. Although MyoD and Myf5 exhibit overlapping functions during embryogenesis, their roles significantly diverge in adult muscles. Single <i>MyoD</i> knockout analysis revealed that MyoD uniquely regulates adult muscle regeneration, considerably influencing delayed myogenic differentiation, enhancing self-renewal, and modulating apoptosis resistance. These findings highlight fundamental differences between embryonic and adult myogenesis. Recent advances in single-cell technologies have revealed the heterogeneity of MyoD expression among adult muscle stem cells (MuSCs), thereby elucidating its diverse functional roles during muscle regeneration. Furthermore, MyoD has been implicated in the regulation of myofiber type specification and plasticity in mature skeletal muscles. Overall, these findings suggest that MyoD serves as a key orchestrator in cellular, functional, and pathological processes in adult skeletal muscle across multiple contexts. Although previous reviews have extensively addressed the role of MyoD in embryonic muscle development, the available literature lacks a focused discussion on its multifaceted functions in adult MuSCs, mature myofibers, and the aging process. In this review, we aimed to bridge this gap by integrating recent discoveries and offering novel insights into the dynamic roles of MyoD in adult skeletal muscles; the information discussed in this review has potential therapeutic implications in muscle regeneration, disease management, and combating age-related muscle decline.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232949","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":"Automated patch clamp analysis of heterologously expressed Kir6.2/SUR1 and Kir6.1/SUR2B K_ATP currents.","authors":"Kangjun Li, Vaishali Satpute Janve, Jerod S Denton","doi":"10.1152/ajpcell.00266.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00266.2025","url":null,"abstract":"<p><p>ATP-sensitive potassium (K^ATP) channels are therapeutic targets for numerous metabolic, cardiovascular, and neurological disorders. Drug development for K^ATP channels requires electrophysiology assays for detailed compound characterization. Parallel automated patch clamp (APC) techniques offer considerable advantages over low-throughput manual patch clamp electrophysiology. Here, we characterized the functional properties and pharmacological sensitivity of heterologously expressed Kir6.2/SUR1 and Kir6.1/SUR2B using a SyncroPatch 384PE APC instrument. Ruptured-membrane and perforated-patch whole-cell recordings in potassium fluoride and fluoride-free assay buffers and electrophysiology chips were evaluated for both subtypes. Effects of internal ATP and ADP and magnesium (Mg²⁺) addition were also assessed. Kir6.2/SUR1 currents were constitutively active in all potassium fluoride-based recordings, insensitive to activation by the SUR1 agonist, VU0071063, and variably inhibited by glibenclamide. Success rates, current run-down, and glibenclamide sensitivity were associated with internal buffer composition. Recordings in fluoride-free buffers revealed a minor population of constitutively active Kir6.2/SUR1 currents and a larger population of currents exhibiting low basal activity and activation by VU0071063. Success rate and stability were associated with internal buffer composition. Kir6.1/SUR2B currents, which were most readily assayed in ruptured-membrane and potassium fluoride-based conditions, were stable, activatable with pinacidil, and inhibited by glibenclamide. Our study sheds new light on the behavior of Kir6.2/SUR1 and Kir6.1/SUR2B currents under available APC conditions and represents an important step toward developing truly high-throughput APC techniques for K^ATP.</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":"144224025","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":"Acute mitochondrial reactive oxygen species emissions drive mitochondrial dysfunction after traumatic muscle injury in male mice.","authors":"Junwon Heo, David L Miller, Jessica R Hoffman, Emma Oberholtzer, Katelyn M Castelli, Genevieve C Sparagna, Kelsey H Fisher-Wellman, Sarah M Greising, Jarrod A Call","doi":"10.1152/ajpcell.00407.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00407.2025","url":null,"abstract":"<p><p>Volumetric muscle loss (VML) is characterized by contractile weakness, dysfunctional mitochondrial bioenergetics, and poor rehabilitation plasticity. A hyperpolarized mitochondrial membrane potential is one attribute of the dysfunction bioenergetics and can lead to excessive reactive oxygen species (ROS) emissions. The primary objective of this study was to define the role of acute ROS emissions after VML injury. Male C57BL/6J mice were randomized into experimental and control groups. A time course of ROS emissions and antioxidant buffering capacity (AoxBC) for VML-injured muscles was established across the first 60-days post-injury (dpi). SS-31, a mitochondrial-targeted peptide, was administered s.c. (8mg/kg/d) for up-to 14-dpi and specific electron transport chain complex ROS emissions and mitochondrial bioenergetics were investigated. SS-31 and wheel running were combined in a regenerative rehabilitation model to determine if attenuating acute ROS emissions improved adaptive capability of the remaining muscle. Lipidomic and proteomic analyses were conducted to explore mechanisms of SS-31 benefit after VML. ROS emissions were greater and AoxBC less during the first 14-dpi and this was associated with dysfunctional mitochondrial bioenergetics regardless of carbohydrate or fat fuel substrate. Complexes I, II, and III were identified as the primary sources of ROS emissions. SS-31 attenuated ROS emissions at both 7- and 14-dpi and led to greater mitochondrial respiratory conductance and efficiency out to 30-dpi. Regenerative rehabilitation did not produce greater contractile adaptations, but there was modest evidence of greater metabolic adaptations compared to rehabilitation alone. Lipidomic and proteomic analyses suggest that SS-31 contributes to redox protein abundance alterations after VML injury.</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":"144224024","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}