Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"The emerging role of eIF5A hypusination as a unique and underexplored mechanism in proteinopathies and neurological diseases","authors":"Rohan Desai ,&nbsp;Daniel C. Lee ,&nbsp;Maj-Linda B. Selenica","doi":"10.1016/j.bbadis.2025.167991","DOIUrl":"10.1016/j.bbadis.2025.167991","url":null,"abstract":"<div><div>Eukaryotic Translation Initiation Factor 5A (eIF5A) undergoes a unique post-translational modification of hypusination, converting a lysine 50 residue to hypusine (hypK50). While a few studies have investigated the role of the spermidine-hypusine-eIF5A axis in neurodegenerative diseases, including the pathological accumulation of tau and TAR DNA-binding protein 43 (TDP-43), the role of the hypusine pathway in neurological diseases remains vastly understudied. Thus, the focus of this review is highlighting emerging research on the mechanisms by which aberrant and chronic increases in hypusinated eIF5A (eIF5A^hypK50) govern nucleocytoplasmic transport, stress granule dynamics, and protein aggregation to encourage further research of this pathway in multi-etiology dementia.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167991"},"PeriodicalIF":4.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710281","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":"Elafin inhibits macrophage activation by blocking a chloride channel","authors":"Xia Li ,&nbsp;Longxin Chen ,&nbsp;Na Chen ,&nbsp;Liang Xu ,&nbsp;Xiaoli Cui ,&nbsp;Feng Wang","doi":"10.1016/j.bbadis.2025.167989","DOIUrl":"10.1016/j.bbadis.2025.167989","url":null,"abstract":"<div><div>The molecular mechanisms underlying the anti-inflammatory functions of elafin, beyond its role as a serine protease inhibitor, have garnered significant interest. In this study, we engineered an antibody-elafin fusion construct (Her-elafin) by grafting elafin into the complementarity-determining region (CDR) of the Herceptin antibody. Her-elafin retained the full inhibitory activity of elafin against neutrophil elastase and effectively suppressed lipopolysaccharide (LPS)-induced macrophage activation. Using Her-elafin as a molecular probe, we identified that elafin specifically binds to and inhibits Clic1, a chloride channel expressed on macrophages. This binding likely reduces intracellular reactive oxygen species (ROS) production, thereby attenuating downstream inflammatory cascades. Furthermore, the dual inhibitory activities of Her-elafin against neutrophil elastase and Clic1 resulted in significant anti-inflammatory effects in a murine model of acute lung injury, highlighting its potential as a promising therapeutic strategy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167989"},"PeriodicalIF":4.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676827","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":"Activation of IRF2 signaling networks facilitates podocyte pyroptosis in lupus nephritis","authors":"Fan Zhang ,&nbsp;Ying Xie ,&nbsp;Ruo-nan Dang ,&nbsp;Jie Yu ,&nbsp;Xiao-xue Tian ,&nbsp;Lin-jie Li ,&nbsp;Quan-min Zhou ,&nbsp;Xiao-min An ,&nbsp;Pei-lei Chen ,&nbsp;Ying-qin Luo ,&nbsp;Yuan-sheng Wu ,&nbsp;Jun Liu ,&nbsp;Hui-mei Zou","doi":"10.1016/j.bbadis.2025.167990","DOIUrl":"10.1016/j.bbadis.2025.167990","url":null,"abstract":"<div><div>Lupus nephritis (LN), a severe and often debilitating complication of systemic lupus erythematosus (SLE), is marked by renal inflammation and structural damage. While interferon regulatory factor 2 (IRF2) has been implicated in various immune-mediated pathologies, its precise role in LN pathogenesis remains elusive. In this study, we demonstrate a significant upregulation of IRF2 in renal biopsy specimens from patients with advanced LN, as well as in the MRL/lpr murine model of LN, with expression levels correlating positively with disease severity. Genetic ablation of IRF2 in MRL/lpr mice resulted in substantial improvements in renal function, reductions in proteinuria, and attenuation of glomerular histopathological lesions, thereby underscoring a pathogenic role for IRF2 in LN progression. In vitro experiments using podocytes exposed to serum from LN patients revealed that IRF2 silencing effectively suppressed NLRP3 inflammasome activation, a key driver of pyroptosis. Mechanistically, IRF2 exerts its effects through two primary pathways: firstly, it transcriptionally enhances the expression of critical NLRP3 inflammasome components, thereby increasing their availability for assembly; secondly, IRF2 transcriptionally represses IRBIT, leading to the release of Ca²⁺ from the endoplasmic reticulum, a process essential for the oligomerization and activation of NLRP3 inflammasome components. By orchestrating both the expression and assembly of NLRP3 inflammasome members, IRF2 ultimately promotes podocyte pyroptosis and accelerates LN progression. Collectively, these findings identify IRF2 as a central regulator of NLRP3 inflammasome-mediated podocyte injury in LN, suggesting novel therapeutic strategies aimed at interrupting LN pathogenesis through dual modulation of inflammatory gene networks and Ca²⁺-dependent signaling pathways.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167990"},"PeriodicalIF":4.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144676826","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":"Identification and validation of BCL11A as a neural and immune vulnerability factor in pancreatic adenocarcinoma","authors":"Aotian Chen ,&nbsp;Jialun Wang ,&nbsp;Jiaying Yang ,&nbsp;Yue Wang ,&nbsp;Chenchen Wu ,&nbsp;Huaina Yang ,&nbsp;Yaoyao Fan ,&nbsp;Qing Gao ,&nbsp;Yiqiao Hu ,&nbsp;Xihan Li ,&nbsp;Xiaoping Zou","doi":"10.1016/j.bbadis.2025.167988","DOIUrl":"10.1016/j.bbadis.2025.167988","url":null,"abstract":"<div><div>As a highly malignant tumor, pancreatic adenocarcinoma (PAAD) has nonspecific symptoms and a poor prognosis. Previous studies have demonstrated that perineural invasion (PNI) and neurotrophic factors (NFs) play essential roles in PAAD. Nevertheless, the prognostic significance and functions of NF-related genes (NFRGs) in PAAD remain unclear. In this research, we conducted an intersection analysis utilizing differentially expressed genes (DEGs) found in the TCGA-PAAD cohort along with NFRGs from the Genecard. Using machine learning (ML) techniques, including LASSO regression, SVM-RFE and random forest algorithms, we developed a highly accurate prognostic model centered on NFRGs, ultimately pinpointing BCL11A as the crucial prognostic NFRG. Via analysis of the TCGA cohort, immunohistochemistry of 20 pairs of clinical samples and western blot of PAAD cell lines, BCL11A was found to be low-expressed in PAAD and associated with a poor prognosis. Experiments conducted both in vitro and in vivo revealed that the increased expression of BCL11A suppressed tumor growth and triggered apoptosis through endoplasmic reticulum (ER) stress. Moreover, immune infiltration analysis found increased CD8⁺ T cells in the BCL11A^high group. Flow cytometry demonstrated that overexpression of BCL11A in vivo promoted intratumoral CD8⁺ T cell infiltration and activation, and increased PD-L1 expression. Our study confirmed BCL11A as a potential biomarker of clinical prognosis, immune infiltration, and neural-tumor interactions in PAAD, and might provide new insights for diagnosis and treatment of this tumor.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167988"},"PeriodicalIF":4.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669071","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":"Pharmacologic interventions targeting ovarian aging, cancer, and mitochondrial dysfunction: An updated evidence","authors":"Alejandro Teppa-Garrán ,&nbsp;Efraín Pérez-Peña ,&nbsp;Luis Sobrevia ,&nbsp;Reinaldo Marín","doi":"10.1016/j.bbadis.2025.167987","DOIUrl":"10.1016/j.bbadis.2025.167987","url":null,"abstract":"<div><div>Ovarian aging is a major determinant of female reproductive longevity, characterized by declining oocyte quality and reduced ovarian reserve. With more women delaying childbearing, age-related infertility has become an urgent biomedical concern. Mitochondrial dysfunction plays a central role in this process, leading to oxidative damage and metabolic disturbances that impair oocyte competence. These alterations are linked to poorer outcomes in assisted reproductive technology (ART), particularly for women over 35, who face significantly reduced success rates. This review examines the key mechanisms of ovarian aging, including oxidative stress, DNA damage, telomere shortening, and mitochondrial dysfunction, all contributing to diminished oocyte quality and quantity. Special focus is given to sirtuins, especially SIRT1 and SIRT3, as critical regulators of redox balance in oocytes and granulosa cells. The review also addresses the impact of age-related changes on chromosomal cohesion and ovarian fibrosis. Importantly, mitochondrial insufficiency is increasingly recognized as a factor in broader age-related diseases, such as metabolic disorders and cancer, suggesting shared molecular pathways between reproductive aging and systemic health. Recent advances highlight the potential of targeted nutrient supplementation to modulate redox homeostasis, enhance sirtuin activity, and preserve mitochondrial function—strategies that may benefit both ovarian health and overall aging. This intersection of reproductive biology and mitochondrial medicine is driving interest in pharmacologic interventions to improve oocyte quality and mitigate age-related comorbidities.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167987"},"PeriodicalIF":4.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669072","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":"Interplay between O-GlcNAcylation and 5-FU response in colorectal cancer: Novel insights from an examination of primary and metastatic cell lines","authors":"Ninon Very ,&nbsp;Ferdinand Trinel ,&nbsp;Nicolas Szydlowski ,&nbsp;Tony Lefebvre ,&nbsp;Ikram El Yazidi-Belkoura","doi":"10.1016/j.bbadis.2025.167986","DOIUrl":"10.1016/j.bbadis.2025.167986","url":null,"abstract":"<div><div>5-fluorouracil (5-FU) is the cornerstone of colorectal cancer (CRC) chemotherapy. <em>O</em>-linked β-N-<em>Acetyl</em>-glucosaminylation (<em>O</em>-GlcNAcylation) plays an essential role in cancer biology, including CRC, but its impact on chemotherapy response remains underexplored. Our previous study revealed that <em>O</em>-GlcNAcylation enhances 5-FU sensitization <em>in vivo</em> and <em>in vitro</em> in HT-29 colon primary cancer cells by reducing Thymidylate Synthase (TS) degradation, the main 5-FU target. The present study analyzed the impact of <em>O</em>-GlcNAcylation on HT-29 and LoVo metastatic colon cancer cells response to 5-FU and further explored its effect on Thymidine Phosphorylase (TP) and Thymidine Kinase (TK), key-actors of 5-FU conversion into active compounds.</div><div>Using Human Protein Atlas (HPA) and GEPIA2 databases, combined with comparative analysis of non-cancerous colon CCD841CoN, HT-29 and LoVo cells, we showed elevated <em>TK1</em> and <em>TYMS</em> expressions in CRC tissues and cell lines, alongside increased <em>O-</em>GlcNAcylation, OGA, OGT, TK and TS levels. Notably, TP overexpression was specific to LoVo. 5-FU treatment induced a time-dependent decrease of OGT and <em>O</em>-GlcNAcylation in LoVo, as previously observed in HT-29; but this was not correlated with <em>OGT</em> mRNA drop. Functionally, <em>OGT</em> knockdown reduced 5-FU sensitivity in HT-29 <em>via</em> decreased TK and TS levels, while enhancing LoVo sensitivity, correlated with increased TP levels. Importantly, we identified TP, TK and TS as <em>O</em>-GlcNAcylated in both cell lines.</div><div>These findings reveal distinct regulatory effects of <em>O</em>-GlcNAcylation on 5-FU metabolic enzymes and on chemotherapy response between primary and metastatic colon cancer cells. This underscores the potential for tailored therapeutic strategies considering the unique enzymatic profile of different tumor stages.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167986"},"PeriodicalIF":4.2,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644338","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":"FBXW8-mediated degradation of PPT1 suppresses epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma","authors":"Jingliang He ,&nbsp;Xun Zou ,&nbsp;Dan Wang ,&nbsp;Lili Zhou ,&nbsp;Xiuming Li ,&nbsp;Shaojie Ma ,&nbsp;Xiaozhu Shen ,&nbsp;Shunfang Liu ,&nbsp;Bin Liu","doi":"10.1016/j.bbadis.2025.167985","DOIUrl":"10.1016/j.bbadis.2025.167985","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by its aggressive growth, high metastatic potential, and resistance to therapeutic interventions. Dysregulation of the ubiquitin-proteasome system (UPS) is recognized as a hallmark of cancer; however, its precise functional contributions to HCC pathogenesis remain incompletely elucidated. In the present study, we identify F-box and WD repeat domain-containing 8 (FBXW8), an F-box protein component of the Cullin-RING ligase (CRL) complex, as a pivotal tumor suppressor in HCC. Through a combination of in vitro and in vivo models, we demonstrate that FBXW8 depletion facilitates HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas FBXW8 overexpression exerts inhibitory effects on these malignant phenotypes. Proteomic and mechanistic analyses reveal that FBXW8 targets palmitoyl-protein thioesterase 1 (PPT1), a lysosomal hydrolase, for ubiquitination and subsequent proteasomal degradation. Elevated PPT1 expression correlates with poor clinical prognosis in HCC patients and is positively associated with the activation of EMT and oncogenic signaling pathways. Our data further reveal that PPT1 promotes EMT in part by enhancing the expression of critical EMT transcription factors, notably Snail Family Transcriptional Repressor 1 (SNAIL) and Zinc Finger E-box Binding Homeobox 1 (ZEB1), with a more pronounced effect on SNAIL. Mechanistically, FBXW8-mediated degradation of PPT1 inhibits EMT, reducing metastatic potential, whereas PPT1 silencing reverses the tumor-promoting effects of FBXW8 loss. These findings establish the FBXW8-PPT1 axis as a pivotal regulatory pathway linking UPS-mediated proteostasis to HCC progression and metastasis. Our study highlights the therapeutic potential of targeting PPT1 or restoring FBXW8 activity to disrupt oncogenic signaling and improve outcomes in HCC patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167985"},"PeriodicalIF":4.2,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144634001","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":"MicroRNA-126: A key regulator of angiogenesis, inflammation, and tumorigenesis — Exploring its multifaceted functions in vascular health and cancer","authors":"Oliwia Woźniak ,&nbsp;Bartosz Mierzejewski ,&nbsp;Edyta Brzoska","doi":"10.1016/j.bbadis.2025.167984","DOIUrl":"10.1016/j.bbadis.2025.167984","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) are small, noncoding RNA molecules (20 to 24 nucleotides) that serve as essential regulators of gene expression through post-transcriptional mechanisms. Among these miRNAs, microRNA-126 (miR-126) has emerged as a key player in angiogenesis, vascular biology, inflammation, and fibrosis. Encoded in the intron of the epidermal growth factor-like domain 7 <em>(EGFL7</em>) gene, miR-126 undergoes canonical biogenesis and forms complexes that repress target messenger RNAs (mRNAs) by binding to complementary sequences in their 3′-untranslated regions (UTRs). MiR-126 have two distinct mature subtypes, namely miR-126-3p and miR-126-5p. The key miR-126 targets include factors such as <em>SPRED1, PIK3R2, PTEN, VEGF, EGFL7, CXCL12,</em> and others. Importantly, changes in miR-126 expression are associated with numerous diseases affecting vascular functions, which highlights its therapeutic potential to improve neovascularisation and underlines its importance as a biomarker for assessing disease risk. This review integrates the current understanding of miR-126 mechanisms of action, its implications in vascular pathologies, and therapeutic strategies, highlighting its importance in cardiovascular health and cancer biology.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167984"},"PeriodicalIF":4.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621460","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":"Ras association domain family member 1 (RASSF1): Molecular characteristics, clinical relevance and therapeutic interventions in cancer","authors":"Muhammad Omer Iqbal ,&nbsp;Qianqian Wang ,&nbsp;Imran Ahmad Khan ,&nbsp;Yuchao Gu ,&nbsp;Jin Chen ,&nbsp;Xiao Wu","doi":"10.1016/j.bbadis.2025.167977","DOIUrl":"10.1016/j.bbadis.2025.167977","url":null,"abstract":"<div><div>Ras Association Domain Family 1 (RASSF1) proteins are key modulators of tumor suppression, apoptosis, and cell cycle regulation. Among its isoforms, RASSF1A is the most extensively studied due to its crucial role in maintaining cellular homeostasis and preventing cancer progression. It primarily functions as a scaffold protein, orchestrating critical signaling pathways such as Ras, Hippo, and p53 to regulate cell proliferation and apoptosis. Epigenetic silencing of RASSF1A, predominantly through promoter hypermethylation, is a hallmark of numerous human cancers, including those of the lung, breast, and liver. Structural studies have identified conserved domains within RASSF1A, such as the Ras-association (RA) and SARAH domains, which mediate interactions with Ras-GTP and MST kinases to modulate tumor suppressor pathways. Additionally, post-translational modifications (PTMs), such as phosphorylation, influence RASSF1A stability and activity. Dysregulation of RASSF1A impairs several cellular processes, leading to unchecked cell proliferation and tumorigenesis. Understanding the molecular mechanisms regulating RASSF1A—both epigenetically and post-translationally—provides critical insights into potential therapeutic strategies aimed at restoring its tumor-suppressive functions. This review highlights current knowledge of RASSF1A's role in tumorigenesis and explores emerging approaches to target its dysregulation in cancer therapy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167977"},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621461","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":"Distinct systemic metabolic features in limb-girdle muscular dystrophy type R1 mouse models as a potential early pathogenic signature","authors":"Fumiko Shinkai-Ouchi ,&nbsp;Yoshiki Itoh ,&nbsp;Mayumi Shindo ,&nbsp;Kyohei Mikami ,&nbsp;Yoshinobu Iguchi ,&nbsp;Shoji Hata ,&nbsp;Rie Tsutsumi ,&nbsp;Yuna Izumi-Mishima ,&nbsp;Kyoka Machida ,&nbsp;Yuki Suzuki ,&nbsp;Hiroshi Sakaue ,&nbsp;Yasuko Ono","doi":"10.1016/j.bbadis.2025.167983","DOIUrl":"10.1016/j.bbadis.2025.167983","url":null,"abstract":"<div><div>Limb-girdle muscular dystrophy type R1 (LGMDR1, formerly LGMD2A) is a genetic disorder caused by mutations in <em>CAPN3</em> and is characterized by progressive proximal limb muscle weakness. The <em>CAPN3</em> gene product, calpain-3/CAPN3/p94, is a member of the intracellular cysteine protease superfamily predominantly expressed in the skeletal muscle. LGMDR1 pathogenesis has been investigated separately using mouse models: CAPN3:C129S [knock-in (KI)] mice, which express a proteolytically inactive variant, and CAPN3 knockout (KO) mice. These studies propose that CAPN3 bears both proteolytic activity-dependent and -independent functions and that the loss of either or both affects phenotypes.</div><div>Here, we report a side-by-side, long-term analysis of KI and KO mice to comprehensively understand the LGMDR1 pathology in terms of CAPN3 function. Their physiques were comparable to those of wild-type animals, but age-dependent LGMDR1 symptoms were observed by histochemical analysis, with more severe symptoms observed in KO mice. Quantitative muscle proteomics and gene ontology analyses revealed more diverse changes in the KO mice than in the KI mice. Of the associated terms, “metabolic process” was the most affected across the genotype and age groups. Metabolomic analysis suggested that the skeletal muscles of these mice had an imbalance in the branched-chain amino acid catabolic pathway. Furthermore, a reduction in lipids and glycogen was observed in the liver of KO mice, suggesting that a systemic energy deficit occurs during CAPN3 deficiency.</div><div>Altogether, our results suggest that muscular dysfunction in LGMDR1 models is associated with compromised systemic energy balance and that the extent of perturbation is implicated in disease severity.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167983"},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621458","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}