Disease Models & Mechanisms最新文献_第2页

Development of a pediatric pig model of extracorporeal cardiopulmonary resuscitation-induced acute kidney injury. 体外心肺复苏（ECPR）致急性肾损伤儿童猪模型的建立。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-10-02 DOI: 10.1242/dmm.052726

Lindsay M Thomson, Christopher A Mancuso, Robert Hyslop, Ludmila Khailova, Camille N Chun, Jack Zakrzewski, Sierra S Niemiec, Tanner M Lehmann, Benjamin S Frank, Jesse A Davidson

{"title":"Development of a pediatric pig model of extracorporeal cardiopulmonary resuscitation-induced acute kidney injury.","authors":"Lindsay M Thomson, Christopher A Mancuso, Robert Hyslop, Ludmila Khailova, Camille N Chun, Jack Zakrzewski, Sierra S Niemiec, Tanner M Lehmann, Benjamin S Frank, Jesse A Davidson","doi":"10.1242/dmm.052726","DOIUrl":"10.1242/dmm.052726","url":null,"abstract":"Acute kidney injury (AKI) is a common and severe morbidity following extracorporeal cardiopulmonary resuscitation (ECPR), particularly in children, where AKI is associated with a fourfold increased risk of death. Research into the mechanisms and treatment of ECPR-induced AKI is hampered by the lack of relevant translational models. In this study, we developed a pediatric swine model of ECPR-induced AKI and defined the histological and transcriptomic changes seen in the kidney following ECPR. Four infant swine underwent hyperkalemic cardiac arrest for 5, 10, 15 or 20 min, followed by 4 h of extracorporeal membrane oxygenation. Mechanically ventilated animals (n=9) were used for comparison. ECPR animals demonstrated progressive histologic, biomarker and physiologic kidney injury with increasing cardiac arrest time. All ECPR-exposed animals demonstrated a distinct transcriptomic response compared to controls, with 1433 differentially expressed genes covering a range of biologic systems including oxidative stress, renal angiogenesis and solute channel formation, protein folding/misfolding, and ribosome biogenesis. This study demonstrates the ability to model ECPR-induced kidney injury in a titratable fashion, serving as a platform for mechanistic and therapeutic studies for this important morbidity.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148722036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex-dependent mild cardiac dysfunction and neurometabolic abnormalities in a model of Huntington's disease. 亨廷顿氏病模型的性别依赖性轻度心功能障碍和神经代谢异常

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-30 DOI: 10.1242/dmm.052922

Kenna L R Hynes, Thomas M O'Brien, Jenna Hanrahan, Rachel Neita, T Nadine Burry, Michael R Hayden, Matthew P Parsons, Amber L Southwell, Lindsay S Cahill

{"title":"Sex-dependent mild cardiac dysfunction and neurometabolic abnormalities in a model of Huntington's disease.","authors":"Kenna L R Hynes, Thomas M O'Brien, Jenna Hanrahan, Rachel Neita, T Nadine Burry, Michael R Hayden, Matthew P Parsons, Amber L Southwell, Lindsay S Cahill","doi":"10.1242/dmm.052922","DOIUrl":"10.1242/dmm.052922","url":null,"abstract":"Huntington's disease (HD) is a neurodegenerative disease with progressive decline in psychiatric, motor and cognitive symptoms. Hallmarks of HD include brain volume loss and abnormal metabolism. However, HD is a multi-system disorder, and the impact on other organ systems is poorly understood. Using high-frequency ultrasound and nuclear magnetic resonance, we studied cardiac function (n=9-11 mice/genotype/sex) and brain metabolism (n=10 mice/genotype/sex) in a humanized transgenic mouse model of HD (Hu97/18 mice) at 12 months of age. The assessments were conducted in different cohorts and analyzed separately. Compared to controls (Hu18/18 mice), Hu97/18 mice showed a decrease in the left ventricle ejection fraction in both sexes and an increase in the E/A ratio (E wave/A wave diastolic filling) in females, indicative of mild cardiac dysfunction. The relative concentrations of several metabolites in the brain were altered in Hu97/18 mice, compared to those in Hu18/18 mice, and depended on sex and brain region. These findings are consistent with clinical features observed in human HD, supporting use of the Hu97/18 model for investigation of pathophysiology in HD in multiple organ systems. It also highlights the importance of studying both sexes in HD research.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fuelling repair: metabolic regulation of alveolar type 2 cell fate in lung regeneration and disease. 燃料修复：肺再生和疾病中肺泡2型细胞命运的代谢调节。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-30 DOI: 10.1242/dmm.052978

Sophia Wugk, Sarah Kenny, Filza Masood, Ei Thant Htoo, Suzanne M Cloonan

{"title":"Fuelling repair: metabolic regulation of alveolar type 2 cell fate in lung regeneration and disease.","authors":"Sophia Wugk, Sarah Kenny, Filza Masood, Ei Thant Htoo, Suzanne M Cloonan","doi":"10.1242/dmm.052978","DOIUrl":"10.1242/dmm.052978","url":null,"abstract":"There is growing scientific interest in uncovering the mechanisms of lung regeneration, aiming to inform the development of innovative therapies for irreversible lung damage associated with chronic diseases. Cellular metabolism and its associated metabolites are increasingly recognised as active regulators of stem cell behaviour and tissue repair in other organs, yet little is known about how metabolic programmes and metabolite-mediated processes influence lung progenitor cell fate decisions. This Review explores current knowledge of how cellular metabolism directs the stem cell functions of alveolar type 2 (AT2) cells, the main epithelial progenitor cells of the distal lungs. Recent studies suggest that AT2 cell regenerative functions are linked to shifts in glycolytic and oxidative metabolism and require tight regulation of mitochondrial function and lipid metabolism for effective repair. Dysregulation of AT2 cell metabolism, as observed in chronic lung diseases, such as pulmonary fibrosis and chronic obstructive pulmonary disease, is emerging as a mechanism of regenerative failure and associated with respiratory disease progression. Improving our understanding of how AT2 cell metabolism 'fails to fuel' and starts 'fuelling to fail' lung repair is paramount for the development of innovative therapies that may slow or reverse the progression of chronic lung diseases.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in diagnosis of mitochondrial dysfunction and primary mitochondrial disease. 线粒体功能障碍与原发性线粒体疾病的诊断进展。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-10-01 DOI: 10.1242/dmm.052804

Melis Kose, Elizabeth McCormick, James T Peterson, Colleen Muraresku, Angela Viaene, Zarazuela Zolkipli-Cunningham, Marni J Falk

{"title":"Advances in diagnosis of mitochondrial dysfunction and primary mitochondrial disease.","authors":"Melis Kose, Elizabeth McCormick, James T Peterson, Colleen Muraresku, Angela Viaene, Zarazuela Zolkipli-Cunningham, Marni J Falk","doi":"10.1242/dmm.052804","DOIUrl":"10.1242/dmm.052804","url":null,"abstract":"Mitochondria are critical cellular organelles engaged in energy production, diverse intermediary metabolic functions and signaling. Inherited genetic disorders directly affecting mitochondrial structure and/or function, known collectively as primary mitochondrial diseases, are among the most complex and heterogeneous inherited conditions, involving dual-genome origin, multisystem manifestations and widely variable clinical severity. These diseases can follow different inheritance patterns and are caused by pathogenic variants in nearly 400 genes encoded by either the mitochondrial or nuclear genome, which commonly impair proteins or RNAs in distinct molecular pathways, resulting in defective energy production by disrupting oxidative phosphorylation. Mitochondrial diseases are challenging to accurately diagnose because of their extensive clinical variability and common features with other metabolic and neuromuscular disorders, as well as limitations in existing diagnostic tools. However, advances in molecular genetics, imaging and systems biology have transformed the diagnostic landscape, enabling more comprehensive and integrative approaches. This Review provides an overview of mitochondrial physiology and outlines the current state of diagnostic strategies, ranging from conventional biochemical assessments and tissue-based analyses to next-generation genome-wide sequencing and the emerging omics technologies. We discuss how combining classical and modern methods can improve diagnostic accuracy and inform clinical decision making. Additionally, we highlight the need for continued refinement of diagnostic frameworks to better support personalized management and future therapeutic development in mitochondrial medicine.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with a human actin variant. 人类肌动蛋白突变斑马鱼的早期症状前和性别特异性心脏重构先于心力衰竭。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-29 DOI: 10.1242/dmm.052692

Kendal Prill, John F Dawson

{"title":"Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with a human actin variant.","authors":"Kendal Prill, John F Dawson","doi":"10.1242/dmm.052692","DOIUrl":"10.1242/dmm.052692","url":null,"abstract":"Dilated cardiomyopathy (DCM) is a leading cause of heart failure with notable sex differences in susceptibility and progression. Although mutations within the sarcomere, such as the change of threonine (T) to isoleucine (I) at position 126 of actin alpha cardiac muscle 1 (ACTC1) p.T126I, contribute to familial DCM, the in vivo effects and sex-specific consequences remain unclear. We generated a zebrafish model carrying the orthologous Acta1b p.T126I mutation and conducted longitudinal sex-stratified analyses of cardiac function, morphology and gene expression. Mutants showed variable onset of cardiac dysfunction, with progressive DCM, pericardial effusion, ventricular dilation and reduced survival in adults. Female mutants exhibited earlier and sustained diastolic dysfunction, greater cardiac remodeling and significantly lower survival compared to males, revealing pronounced sexual dimorphism. Molecular profiling at a pre-symptomatic stage identified upregulation of nppb, downregulation of hypertrophic transcription factors (gata4, mef2ca), and sex-specific alterations in Ca2+-handling genes (serca2, pln1, slc8a1a) and proteostasis regulators (hsf1, bag3). Assessment at later stages demonstrated a variable shift of gene expression to cardiac remodeling and decompensation in individual fish. These findings demonstrate that the Acta1b p.T126I mutation drives progressive sex-specific DCM in zebrafish, highlighting the biological sex as a critical modifier of sarcomeric cardiomyopathy progression and targeted therapy development.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Paediatric Genetic Diseases: Models, Mechanisms and Therapies. 儿科遗传疾病：模型、机制和治疗。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-08 DOI: 10.1242/dmm.053177

Kirsty Hooper

引用次数: 0

Fixed-dose streptozotocin combined with high-fat diet induces a stable type 2 diabetes-like phenotype in C57BL/6J mice. 固定剂量链脲佐菌素联合高脂饮食可诱导C57BL/6J小鼠稳定的2型糖尿病样表型。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-17 DOI: 10.1242/dmm.053071

Claes Fryklund, Christian Simonsson, Alexandra Hellberg, Josefin Malmberg, Karin G Stenkula, Maria Swanberg

{"title":"Fixed-dose streptozotocin combined with high-fat diet induces a stable type 2 diabetes-like phenotype in C57BL/6J mice.","authors":"Claes Fryklund, Christian Simonsson, Alexandra Hellberg, Josefin Malmberg, Karin G Stenkula, Maria Swanberg","doi":"10.1242/dmm.053071","DOIUrl":"10.1242/dmm.053071","url":null,"abstract":"High-fat diet (HFD) combined with streptozotocin (STZ) is widely used to model type 2 diabetes (T2D) in rodents, but is often associated with high mortality, non-responders and inconsistent outcomes. STZ is conventionally administered using body weight-adjusted dosing (mg/kg), despite evidence that heavier animals, including HFD-fed mice, exhibit more severe glycaemic responses. Here, we performed metabolic phenotyping in chow- and HFD-fed C57BL/6J mice treated with low or high fixed doses (mg instead of mg/kg) of anomer-equilibrated STZ. HFD combined with low-dose STZ induced a stable T2D-like phenotype characterized by sustained obesity, moderate hyperglycaemia, insulin resistance and partial β-cell loss, with low inter-individual variability. In contrast, high-dose STZ induced a type 1 diabetes-like phenotype, with extensive β-cell loss. A semi-mechanistic mathematical model was developed and validated against independent experimental data, reproducing the observed dynamics of fasting glucose in response to fixed-dose STZ. The model further predicted that weight-adjusted (mg/kg) dosing could introduce variability in glycaemic responses, particularly in HFD-fed mice. Together, these results demonstrate that fixed-dose, anomer-equilibrated STZ induces a stable T2D-like phenotype, providing an alternative to conventional weight-adjusted dosing in HFD-fed mice.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Female-specific alterations in insulin dynamics are associated with glucose tolerance in a Glut1DS mouse model. 在Glut1DS小鼠模型中，女性特异性胰岛素动力学改变与葡萄糖耐量有关。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-21 DOI: 10.1242/dmm.052836

Tamio Furuse, Tomoko Kushida, Akiko Shinogi, Mao Ozaki, Ryoko Yanagisawa, Masaru Tamura

{"title":"Female-specific alterations in insulin dynamics are associated with glucose tolerance in a Glut1DS mouse model.","authors":"Tamio Furuse, Tomoko Kushida, Akiko Shinogi, Mao Ozaki, Ryoko Yanagisawa, Masaru Tamura","doi":"10.1242/dmm.052836","DOIUrl":"10.1242/dmm.052836","url":null,"abstract":"Glucose transporter type 1 deficiency syndrome (Glut1DS) is a rare autosomal dominant genetic disorder caused by mutations in SLC2A1, which results in impaired glucose transport across the blood-brain barrier. Patients with Glut1DS present with various symptoms, including seizures, delayed development and movement disorders. The current first-line therapy - ketogenic diet - has shown variable efficacy, highlighting the need to explore alternative therapeutic strategies. This study aimed to investigate comprehensive phenotypic characteristics of the Glut1DS mouse model B6(D2)-Slc2a1<Rgsc200>/1Rbrc to establish foundational data for identifying novel therapeutic targets. The Slc2a1Rgsc200 mutant mouse was phenotypically characterized at the Japan Mouse Clinic of the RIKEN BioResource Research Center by using a phenotyping pipeline that included intraperitoneal glucose tolerance test (IPGTT) and clinical blood chemistry analyses. Heterozygous Glut1DS mutants exhibited no differences in basal plasma glucose or glycosylated hemoglobin A1c levels when compared to wild-type controls. However, female heterozygous mutants showed decreased glucose levels during IPGTT, accompanied by increased plasma insulin levels following glucose administration. These findings support recent evidence linking insulin signaling to seizure control in patients with Glut1DS, as demonstrated in human studies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiac magnetic resonance imaging reveals myocardial fibrosis and systolic dysfunction in mitochondrial trifunctional protein-deficient mice. 心脏MRI显示线粒体三功能蛋白缺陷小鼠心肌纤维化和收缩功能障碍。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-25 DOI: 10.1242/dmm.052921

Eduardo Vieira Neto, Shakuntala Basu, Thomas J Becker-Szurszewski, Sean Hartwick, Kristina E Schwab, Yijen Wu, Jerry Vockley

{"title":"Cardiac magnetic resonance imaging reveals myocardial fibrosis and systolic dysfunction in mitochondrial trifunctional protein-deficient mice.","authors":"Eduardo Vieira Neto, Shakuntala Basu, Thomas J Becker-Szurszewski, Sean Hartwick, Kristina E Schwab, Yijen Wu, Jerry Vockley","doi":"10.1242/dmm.052921","DOIUrl":"10.1242/dmm.052921","url":null,"abstract":"Cardiomyopathy is an important manifestation in patients with fatty acid oxidation disorders and represents a major cause of morbidity and early mortality in mitochondrial trifunctional protein (TFP) deficiency. Although a mouse model carrying the TFP β-subunit p.Met404Lys mutation (βTFP-deficient mice) has been described, cardiac involvement in this model has not been systematically characterized. Here, we combined cardiac histology and multiparametric cardiac magnetic resonance imaging (CMR) to define myocardial structure, function and tissue characteristics in this mouse model. Histological analysis with automated whole-slide collagen quantification revealed myocardial fibrosis with collagen deposition in mutant hearts, and CMR demonstrated increased myocardial extracellular volume in both male and female homozygous mutants. Homozygous males showed reduced ejection fraction, impaired systolic strain and increased left ventricular end-systolic volume, indicating systolic dysfunction. Male mice were more severely affected than females and exhibited reduced survival. Together, these findings demonstrate that βTFP-deficient mice develop fibrotic cardiomyopathy with systolic dysfunction, reproducing important cardiac features observed in human TFP deficiency. This work establishes the model as a relevant platform for investigating disease mechanisms and therapeutic strategies for cardiomyopathy in TFP deficiency.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A bioengineered platform reveals progressive impairment of skeletal muscles by metabolic dysfunction-associated steatotic liver disease-derived factors. masld衍生因子对生物工程骨骼肌进行性损伤：肝脏诱导肌肉萎缩模型平台。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-17 DOI: 10.1242/dmm.052820

Armando Cortés-Reséndiz, Juan M Fernández-Costa, Maria Sabater-Arcís, Francesco De Chiara, Javier Ramón-Azcón

{"title":"A bioengineered platform reveals progressive impairment of skeletal muscles by metabolic dysfunction-associated steatotic liver disease-derived factors.","authors":"Armando Cortés-Reséndiz, Juan M Fernández-Costa, Maria Sabater-Arcís, Francesco De Chiara, Javier Ramón-Azcón","doi":"10.1242/dmm.052820","DOIUrl":"10.1242/dmm.052820","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) affects >30% of the global population and is increasing in prevalence to become the most common liver disorder. MASLD can influence distal organs via secreted mediators, and up to 43% of patients show sarcopenia or related muscle-wasting phenotypes. We developed a modular human three-dimensional bioengineered liver-muscle platform to dissect causal liver-muscle crosstalk. Liver constructs recapitulated steatosis and transition to metabolic dysfunction-associated steatohepatitis (MASH), with inflammatory, apoptotic, immune cell-recruiting and pro-fibrotic signatures. Transferring liver-derived conditioned media to engineered muscles revealed severity-dependent impairment of contractile performance, altered protein balance and myogenic regulation. Contractility declined progressively from steatosis to MASH. Steatotic liver conditioned media reduced myotube size, whereas MASH conditioned media triggered a compensatory program that partially preserved size despite functional loss. Muscle exposure to MASLD mediators was associated with disrupted autophagic degradation, consistent with impaired flux and accumulation of autophagosomes and lysosomes. This scalable human platform enables systematic investigation of MASLD extrahepatic mechanisms and provides a testbed for perturbations and interventions targeting liver-driven muscle wasting.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0