JCI insightPub Date : 2026-09-22DOI: 10.1172/jci.insight.207552
Viji Remadevi, Abeda Jamadar, Meekha M Varghese, Haichun Yang, Sumedha Gunewardena, Darren P Wallace, Reena Rao
{"title":"Pirfenidone treatment attenuates fibrosis in autosomal dominant polycystic kidney disease.","authors":"Viji Remadevi, Abeda Jamadar, Meekha M Varghese, Haichun Yang, Sumedha Gunewardena, Darren P Wallace, Reena Rao","doi":"10.1172/jci.insight.207552","DOIUrl":"10.1172/jci.insight.207552","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of kidney failure, characterized by progressive cyst growth, inflammation, and interstitial fibrosis. Renal fibrosis, driven by myofibroblast activation and excessive extracellular matrix (ECM) deposition, is increasingly recognized as a key contributor to disease progression, yet targeted antifibrotic therapies remain limited. Here, we evaluated the therapeutic potential of pirfenidone to suppress fibrosis and disease progression in ADPKD. Single-nucleus RNA sequencing of human ADPKD kidneys identified fibroblasts as the predominant source of fibrous and adhesive ECM, with higher ECM-associated gene expression compared with that in normal kidney fibroblasts. In vitro, primary human ADPKD renal myofibroblasts displayed a similar profibrotic gene expression profile, and pirfenidone treatment suppressed ECM gene expression, cell proliferation, migration, and contractility. In the Pkd1RC/RC mouse model of ADPKD, pirfenidone reduced renal fibrosis, myofibroblast accumulation, ECM deposition, profibrotic gene expression, and associated signaling pathways and improved kidney function. Pirfenidone also reduced kidney enlargement but reduced cyst burden only in female mice. Collectively, these findings demonstrate that pirfenidone attenuates renal fibrosis and improves kidney function in ADPKD by suppressing myofibroblast activation and ECM production, supporting fibrosis as a therapeutic target and highlighting pirfenidone as a potential adjunct to cyst-directed therapies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-22DOI: 10.1172/jci.insight.200149
Peter W Stacpoole, Jose E Abdenur, Jirair K Bedoyan, Lorenzo Botto, Gregory M Enns, Marni J Falk, Rebecca Ganetzky, Cheryl Garganta, Kevin Glinton, Andrea Gropman, Sharon Hamm, Eugenia Henry, Nicola Longo, Richard Neiberger, Russell P Saneto, Fernando Scaglia, Sub H Subramony, Jerry Vockley, Richard E Wagner
{"title":"Phase III trial of sodium dichloroacetate for pyruvate dehydrogenase complex deficiency in children.","authors":"Peter W Stacpoole, Jose E Abdenur, Jirair K Bedoyan, Lorenzo Botto, Gregory M Enns, Marni J Falk, Rebecca Ganetzky, Cheryl Garganta, Kevin Glinton, Andrea Gropman, Sharon Hamm, Eugenia Henry, Nicola Longo, Richard Neiberger, Russell P Saneto, Fernando Scaglia, Sub H Subramony, Jerry Vockley, Richard E Wagner","doi":"10.1172/jci.insight.200149","DOIUrl":"10.1172/jci.insight.200149","url":null,"abstract":"<p><p>BACKGROUNDDichloroacetate (DCA) is an orally administered structural analog of pyruvate, an endogenous pyruvate dehydrogenase kinase inhibitor.METHODSWe conducted a phase III multicenter trial in 34 children with pyruvate dehydrogenase complex deficiency (PDCD). Participants were randomly allocated to 4 months of treatment with DCA or a placebo, followed by a 1-month washout period and crossover to the alternate arm, and could continue into an open-label extension period. DCA dosing was predetermined by pharmacogenomic analysis of GSTZ1, which modulates DCA metabolism. The primary endpoint was the observer-reported outcomes motor domain (ObsROmotor) score. Additional assessments evaluated motor function, plasma lactate levels, and survival.RESULTSChronic DCA was well tolerated and safe. The primary endpoint, ObsROmotor, was not statistically significantly different between the treatment and placebo groups (P = 0.512). However, longer-term treatment, including the open-label extension, showed a statistically significant treatment effect (P = 0.002), especially in participants with higher baseline motor impairment (ObsROmotor ≥ 8; P = 0.001). DCA decreased plasma lactate -0.48 (0.82) mmol/L (-20%; P = 0.006). Survival of participants was significantly greater than that of a natural history cohort (log-rank P = 0.027).CONCLUSIONLonger-term treatment with DCA, dosed based on GSTZ1 haplotype, is safe and was associated with a statistically significant improvement in patient motor function, plasma lactate, and survival.FUNDINGNIH (R01FD005407; R42HD089804), University of Florida Department of Medicine, Saol Therapeutics.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 18","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-17DOI: 10.1172/jci.insight.203039
Yintong Chen, Weiwei Xu, Jieli Yu, Pei Deng, Nianping Liu, Yinyin Li, Hui Zhou, Hong Zhou, Jianchuan Wang, Bo Zhao, Florian Winau, Fan Fan Hou, Yu Hu
{"title":"Kidney fibrosis is mediated by GARP-restricted TGF-β activation in fibroblasts.","authors":"Yintong Chen, Weiwei Xu, Jieli Yu, Pei Deng, Nianping Liu, Yinyin Li, Hui Zhou, Hong Zhou, Jianchuan Wang, Bo Zhao, Florian Winau, Fan Fan Hou, Yu Hu","doi":"10.1172/jci.insight.203039","DOIUrl":"https://doi.org/10.1172/jci.insight.203039","url":null,"abstract":"<p><p>TGF-β is a central driver of kidney fibrosis, a common pathological hallmark of chronic kidney disease (CKD). Initiation of TGF-β signaling requires not only its synthesis but also the conversion of latent TGF-β to its bioactive form. However, the mechanisms governing TGF-β activation in the kidney and their contribution to kidney fibrosis remain poorly understood. Glycoprotein A repetitions predominant (GARP) anchors latent TGF-β on the cell surface and facilitates its bioactive release. Here, we show that GARP-mediated TGF-β activation promotes kidney fibrosis. GARP was upregulated in both human and mouse CKD kidneys, predominantly in fibroblasts, and was induced by TNF in an NF-kB-dependent fashion. In multiple mouse models of kidney fibrosis, either global or fibroblast-specific deletion of GARP significantly reduced fibrosis. Mechanistically, GARP enables sustained production of active TGF-β, thereby amplifying fibroblast stimulation. Deletion of GARP in kidney fibroblasts lowered active TGF-β levels and attenuated fibroblast activation, whereas GARP overexpression enhanced TGF-β signaling. Notably, tamoxifen-induced deletion of GARP after fibrosis onset attenuated kidney fibrosis. Together, our findings identify GARP-mediated release of active TGF-β as a critical step in sustaining fibroblast activation during kidney fibrosis and highlight GARP as a promising therapeutic target for CKD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148989987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-17DOI: 10.1172/jci.insight.193744
Laura A Cooney, Mitch Fahning, Liliane Khoryati, Anna Kus, Sheila Scheiding, Lori Blanchfield, Matthew Lawrance, Basilin Benson, Kristina M Harris, Gretchen A Baltus, Shiuli Agarwal, Richard Wnek, Johannes F Scheid, Kiki Cunningham-Bussel, Nancy D Kim, S Aubrey Stoch, Jyothsna Visweswaraiah, Nathan Higginson-Scott, Katalin Kis-Toth, Joanne L Viney, Kevin L Otipoby, Erik Sampson, Bridget Larkin, Daniel J Campbell, S Alice Long
{"title":"IL-2 mutein selectively expands thymic memory Tregs with increased transendocytosis activity in healthy participants.","authors":"Laura A Cooney, Mitch Fahning, Liliane Khoryati, Anna Kus, Sheila Scheiding, Lori Blanchfield, Matthew Lawrance, Basilin Benson, Kristina M Harris, Gretchen A Baltus, Shiuli Agarwal, Richard Wnek, Johannes F Scheid, Kiki Cunningham-Bussel, Nancy D Kim, S Aubrey Stoch, Jyothsna Visweswaraiah, Nathan Higginson-Scott, Katalin Kis-Toth, Joanne L Viney, Kevin L Otipoby, Erik Sampson, Bridget Larkin, Daniel J Campbell, S Alice Long","doi":"10.1172/jci.insight.193744","DOIUrl":"https://doi.org/10.1172/jci.insight.193744","url":null,"abstract":"<p><p>Tregs play an essential role in immune tolerance, and Treg-promoting therapies are in development for the treatment of many inflammatory disorders. Interleukin-2 (IL-2)-based therapies increase Treg frequency, but little is known about impacts on Treg heterogeneity and function. We extended analyses of an IL-2 mutein (MK-6194) single-ascending-dose trial in healthy human participants by comprehensively defining Treg subsets and gene expression changes in vitro and in vivo. We found highly specific and dose-dependent activation and expansion of Tregs in clinical and pre-clinical studies. Following a single subcutaneous dose in humans, thymic-derived Tregs were selectively activated and expanded, while peripherally induced Tregs were unaffected. Expanded Tregs had increased expression of genes and proteins consistent with activation, suppressor function, and homing to non-lymphoid tissue, as well as increased transendocytosis activity, as measured by CTLA-4-dependent capture of CD80 and CD86 from non-Tregs. These results shed light onto underlying mechanisms by which Treg-targeted therapy may promote immune tolerance.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-17DOI: 10.1172/jci.insight.200429
Bryce C Murillo, Alexander Young, Kaitlyn L Wintruba, Alexander J Eichert, Klara Siejda, Dennon Hoernig, Leigh A Bradley, Bryana N Harris, Catherine Zhao, MIchelle Wu, Emmanuel Deau, Mattias F Lindberg, Laurent Meijer, Jeffrey J Saucerman, Matthew J Wolf
{"title":"Network modeling predicts how DYRK1A inhibition promotes cardiomyocyte cycling after ischemic/reperfusion injury.","authors":"Bryce C Murillo, Alexander Young, Kaitlyn L Wintruba, Alexander J Eichert, Klara Siejda, Dennon Hoernig, Leigh A Bradley, Bryana N Harris, Catherine Zhao, MIchelle Wu, Emmanuel Deau, Mattias F Lindberg, Laurent Meijer, Jeffrey J Saucerman, Matthew J Wolf","doi":"10.1172/jci.insight.200429","DOIUrl":"10.1172/jci.insight.200429","url":null,"abstract":"<p><p>The adult mammalian heart has a limited ability to regenerate lost myocardium following myocardial infarction (MI), largely due to the poor proliferative capacity of cardiomyocytes (CMs). Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a known regulator of cell quiescence, though the mechanisms underlying its function remain unclear. Previous studies have shown that pharmacological inhibition of DYRK1A using harmine induces CM cell cycle re-entry after ischemia/reperfusion (I/R) MI. Here, we developed a computational network model of DYRK1A-mediated regulation of the cell cycle, which predicts how DYRK1A inhibition promotes CM re-entry. To validate these predictions, we tested selective DYRK1A inhibitors and observed robust induction of cell cycle activity in neonatal rat cardiomyocytes (NRCMs). Integrating our network model with bulk RNA-sequencing data from DYRK1A inhibitor-treated NRCMs, we identified E2F1 as a key transcriptional driver of cell cycle gene expression. Finally, we demonstrate that both pharmacological and post-developmental inhibition of DYRK1A enhances heart function and increases CM cycling following I/R MI. Our findings suggest that functional recovery induced by small molecule inhibitor of DYRK1A is mediated by the induction of cycling CMs.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-15DOI: 10.1172/jci.insight.205218
Silvia Romero-Murillo, Irene Peris, Anna Maria Lucianò, Nerea Marcotegui, Carmen Vicente, Brian Tran, Kelsey Barrie, Caitlin M O'Connor, Andrea Torres-López, Maria C Mateos, Maria L Cayuela, Victoriano Mulero, Joaquín Fernández-Irigoyen, Enrique Santamaría, Maria D Odero, Goutham Narla
{"title":"Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML.","authors":"Silvia Romero-Murillo, Irene Peris, Anna Maria Lucianò, Nerea Marcotegui, Carmen Vicente, Brian Tran, Kelsey Barrie, Caitlin M O'Connor, Andrea Torres-López, Maria C Mateos, Maria L Cayuela, Victoriano Mulero, Joaquín Fernández-Irigoyen, Enrique Santamaría, Maria D Odero, Goutham Narla","doi":"10.1172/jci.insight.205218","DOIUrl":"https://doi.org/10.1172/jci.insight.205218","url":null,"abstract":"<p><p>Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the pro-apoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics-based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza-sensitive and -resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-15DOI: 10.1172/jci.insight.201691
Aaditya Khatri, Huimin Wang, Zhicheng Ji, Prekshaben Patel, Smita K Nair, Javid P Mohammed, Beth H Shaz, Andrew B Nixon, Scott M Palmer, Kamran Mahmood
{"title":"Transcriptomic profiling of immune cells in malignant pleural effusions identifies macrophage reprogramming associated with survival.","authors":"Aaditya Khatri, Huimin Wang, Zhicheng Ji, Prekshaben Patel, Smita K Nair, Javid P Mohammed, Beth H Shaz, Andrew B Nixon, Scott M Palmer, Kamran Mahmood","doi":"10.1172/jci.insight.201691","DOIUrl":"https://doi.org/10.1172/jci.insight.201691","url":null,"abstract":"<p><p>Despite advances in treatment approaches for lung cancer, the morbidity and survival of lung cancer patients with malignant pleural effusions (MPE) remain poor. This is in part due to gaps in understanding the role of immune cells in the pleural fluid microenvironment. We performed single cell analysis with flow cytometry validation of CD45+ cells in eight malignant and five benign pleural fluid (BPE) specimens to identify changes in the transcriptomic landscape of immune cells across disease states. We found upregulation of pro-inflammatory signaling pathways, including interferon and TNF signaling, in T cells, B cells, and macrophages in benign compared to malignant pleural effusions. Pro-inflammatory HLA-DR+ macrophages were associated with good survival outcomes while pro-tumorigenic HLA-DR- macrophages with upregulation of angiogenesis, TGFβ, and fibronectin signaling were associated with poor survival outcomes in patients with MPE. We also validated these findings with macrophage cell surface expression markers using flow cytometry in 14 MPE and 7 BPE specimens. Finally, we performed multiplex cytokine analysis which showed enrichment of the type 3 inflammatory cytokine, IL17A, in MPE as a putative mechanism for macrophage reprogramming. These data provide a rich resource for interrogating the immune cell types and states present across the spectrum of pleural disease. They offer not only prognostic value for patient outcomes at the time of pleural fluid collection, but also insights into novel immunotherapy targets.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-10DOI: 10.1172/jci.insight.203732
Shelby R Cain, Gael Genet, Nafiisha Genet, Jordon W Aragon, Madeline G Jackson, Victoria M Milosek, Mark R Schwartz, Umadevi Paila, Aleksandra Cwiek, Zaneta Markowska, Nicholas W Chavkin, Richard J Price, Andrew C Dudley, Karen K Hirschi
{"title":"Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature.","authors":"Shelby R Cain, Gael Genet, Nafiisha Genet, Jordon W Aragon, Madeline G Jackson, Victoria M Milosek, Mark R Schwartz, Umadevi Paila, Aleksandra Cwiek, Zaneta Markowska, Nicholas W Chavkin, Richard J Price, Andrew C Dudley, Karen K Hirschi","doi":"10.1172/jci.insight.203732","DOIUrl":"10.1172/jci.insight.203732","url":null,"abstract":"<p><p>Dysfunctional tumor vessels promote disease progression, whereas improved function enhances therapeutic delivery. However, current approaches to normalize tumor vasculature have limited efficacy. In vascular malformations, vessels are similarly dysfunctional, with endothelial cell (EC) hyperproliferation impairing arterial-venous specification. These defects are corrected with palbociclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that has beneficial effects on tumor and immune cells, but the effects on tumor vasculature are not well characterized. In our studies, murine mammary tumor ECs (TECs) exhibited disrupted cell cycle and specification, and CDK4/6i promoted TEC cycle control, enabling improved tumor vascular function. To investigate transcriptomic changes, we performed single-cell RNA sequencing (scRNAseq) of treated and untreated tumors, and healthy tissues. CDK4/6i-mediated TEC cycle arrest promoted arterial-venous specification, cellular junctions, and pericyte association, and suppressed glycolytic and immunosuppressive gene expression. These effects were associated with increased vessel perfusion, decreased tumor hypoxia, and a more favorable immune landscape with immunotherapy. In scRNAseq datasets from patients treated long-term with CDK4/6i, TECs exhibited similar transcriptomic changes associated with arterial-venous specification, pericyte recruitment, and immune signaling. Thus, in contrast to current strategies, CDK4/6i-mediated vascular changes may be maintained with continued treatment, highlighting the relevance of modulating TEC cycle to improve vessel maturation/function.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-09-10DOI: 10.1172/jci.insight.210523
Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning
{"title":"Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.","authors":"Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning","doi":"10.1172/jci.insight.210523","DOIUrl":"https://doi.org/10.1172/jci.insight.210523","url":null,"abstract":"<p><p>Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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