Biology subjects

Messaddeq, N.

Publications and source records attributed to Messaddeq, N..

8 recordsLinked to original sources

bioRxiv2026

TBPL2-dependent transcription controls RNA stability and cellular organization in growing oocytes

During oocyte growth, the marked increase in cell size is accompanied by robust RNA polymerase II (Pol II) transcription, generating transcripts that are either translated into proteins or stored as part of the maternal transcriptome. While the RNA decay machinery is known to critically regulate the maternal transcriptome during oocyte maturation, its contribution during the growth phase remains poorly understood. We previously identified an oocyte-specific transcription machinery dependent on the TATA-binding protein paralog TBPL2, which is required for oocyte growth. To investigate how the absence of TBPL2-mediated transcription affects the cellular state of the oocyte, we characterized the phenotypic consequences of the Tbpl2-/- mutation in growing oocytes. Our data reveal that both nuclear and cytoplasmic organizations are profoundly disrupted in the absence of TBPL2-mediated transcription. Given that cytoplasmic organization is closely linked to RNA storage capacity, we examined the expression and localization of proteins involved in mRNA regulation, stability and storage. We observed a marked impairment in the redistribution of these key factors in Tbpl2-/- oocytes. To assess the impact of TBPL2 on RNA storage, we analyzed poly(A) tail length and found a global increase in polyadenylation in mutant oocytes. Gene-specific poly(A) tail analyses revealed differential mRNA changes, with shortened tails for a downregulated transcript and elongated tails for an upregulated one, suggesting stabilization of the latter. Collectively, our findings indicate that TBPL2-mediated transcription is essential for maintaining proper cellular organization in growing oocytes, at least in part by ensuring the functional integrity of the RNA decay machinery.

developmental biology↗

bioRxiv2026

Cardiorenal and hepatic dysfunctions underlie metabolic alterations in the spinocerebellar ataxia type 7 mice

Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine expansion disorder characterized by progressive cerebellar and retinal degeneration leading to ataxia and blindness. While mutant ATXN7 is ubiquitously expressed, most studies have focused on neurological symptoms, and peripheral contributions to pathology remain poorly understood. Here, we investigated systemic abnormalities in SCA7140Q/5Q knock-in mice, a model of early-onset disease. Using longitudinal metabolic profiling, ultrasound imaging, and histopathology, we identified early and progressive dysfunction of the kidney, liver, and heart. Renal impairment was marked by uremia, polyuria with abnormal calcium and glucose excretion, tubular epithelial cell loss, and podocyte dedifferentiation, including the reappearance of primary cilia and pedicel effacement. Hepatic alterations included dysregulated lipid metabolism, elevated bilirubin, and reduced iron levels, contributing to anemia. Cardiac dysfunction manifested as reduced stroke volume as early as 11 weeks, suggesting a cardiorenal syndrome. Together, these organ-specific changes resulted in systemic metabolic disturbances such as dyslipidemia, iron deficiency anemia, thrombocytosis, and chronic inflammation, detectable before the onset of motor incoordination. Our findings demonstrate that peripheral organ dysfunction is an early and integral feature of SCA7 pathogenesis, with renal and cardiac impairments emerging prior to neurological decline. These results highlight the value of systemic biomarkers for disease monitoring and suggest that targeting peripheral pathology may provide therapeutic benefit. More broadly, they underscore the need to view SCA7 not solely as a neurodegenerative disorder but as a multi-organ disease.

pathology↗

bioRxiv2025

Androgen receptor imprints satellite cells stemness and preserves their reservoir for lifelong regeneration and optimal repair

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multi-omic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR in young adult mice disrupts this balance, precipitating premature cell-cycle entry, skewed division modalities, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.

developmental biology↗

bioRxiv2025

BIN1 overexpression rescues cardiac but not skeletal muscle defects in a mouse model of caveolinopathy

BackgroundMutations in CAV3, encoding caveolin-3, cause caveolinopathies, rare genetic disorders affecting both skeletal and cardiac muscle. Caveolin-3 contributes to T-tubule formation and excitation-contraction coupling. BIN1 (amphiphysin 2), a membrane-shaping protein critical for T-tubule integrity, has shown therapeutic promise in congenital myopathies and heart dysfunction. To date, there are no therapy for caveolinopathies. MethodsWe evaluated the therapeutic impact of BIN1 overexpression in Cav-3 knockout mice, a model recapitulating key features of human caveolinopathy. We assessed skeletal and cardiac function, T-tubule morphology, mitochondria, and gene expression using histological, physiological, and molecular approaches. ResultsWe found Cav-3-/- mice displayed skeletal muscle weakness, T-tubule disorganization, and mitochondrial abnormalities, alongside cardiac diastolic dysfunction and myofibrillar disarray. While BIN1 overexpression failed to improve skeletal muscle strength, T-tubule structure, or fiber atrophy, it corrected nuclear positioning and partially restored mitochondrial markers. In contrast, BIN1 robustly rescued cardiac performance, restoring end-diastolic volume, cardiac output, and sarcomeric integrity. Expression profiling revealed greater dysregulation of excitation-contraction coupling and atrogene pathways in skeletal than in cardiac muscle. Cavin-4, a BIN1-interacting protein, was selectively dysregulated in Cav3-/- muscle, suggesting a mechanistic barrier to BIN1-mediated rescue in this tissue. ConclusionsThese findings identify tissue-specific differences in the molecular consequences of caveolin-3 loss and demonstrate that BIN1 overexpression effectively rescues cardiac, but not skeletal, manifestations of caveolinopathy. Our results support BIN1 as a promising gene therapy target for inherited cardiomyopathies, while highlighting the need for alternative strategies in skeletal muscle.

pathology↗

bioRxiv2025

Interaction of lncRNA LENT with DHX36 regulates translation and suppresses autophagy in melanoma.

The melanocyte lineage determining Microphthalmia-associated transcription factor (MITF) drives proliferation and survival of melanocytic melanoma cells through regulation of both coding genes and long non-coding RNAs (LncRNAs). Here we characterize LINC00520 (hereafter called LncRNA ENhancer of Translation, LENT) regulated by MITF and strongly expressed in melanocytic melanoma cells. LENT is essential for proliferation and survival of cultured melanocytic melanoma cells and xenograft tumours. LENT interacts with the G4 quadruplex resolvase DHX36 and both associate with the ribosome in the 80S and light polysome fractions. LENT modulates DHX36 association with a collection of mRNAs regulating their engagement with polysomes and fine-tuning their subsequent translation. These mRNAs encode proteins involved in endoplasmic reticulum (ER) and mitochondrial homeostasis as well as autophagy. Consequently, LENT silencing leads to extensive autophagy and mitophagy, compromised oxidative metabolic capacity accompanied by an accumulation and mis-localization of mitochondrial proteins leading to proteotoxic stress and apoptosis. The LENT-DHX36 axis therefore fine-tunes translation of proteins involved in ER and mitochondrial homeostasis suppressing autophagy and promoting survival and proliferation of melanoma cells.

cancer biology↗

bioRxiv2024

Experimental myositis: an optimised version of C-protein-induced myositis

IntroductionInflammatory myopathies (IM) are a group of severe autoimmune diseases, sharing some similarities, whose cause is unknown and treatment is empirical. While C-protein-induced myositis (CIM), the most currently used model of IM, has removed some roadblock to understand and improve the treatment of IM, it has only been partially characterised and its generation limited by reproducibility issues. This study aimed at optimising the generation and the characterisation of CIM. MethodsIn silico analysis was run to identify the top-3 specific and immunogenic regions of C-protein. The cognate polypeptides were synthetised and used to immunise C57BL/6N mice. Grip strength, walking ability, serum creatine-kinase levels and muscle pathology (histological and electron microscopic features) were assessed. Immune cell proportions and interferon signature in muscles were also determined. ResultsAmong the three C-protein polypeptides with the highest immunogenic score, amino acids 965-991 induced the most severe phenotype (i.e., 37% decrease in strength, 36% increase in hind base width, 45% increase in serum creatine-kinase level, 80% increase in histological inflammatory score) from day (D) 14 to at least D31 after immunisation [experimental myositis (EM)]. Optical and electron microscopy revealed mononuclear cell infiltrate, myofibre necrosis, atrophy, MHC-I expression as well as sarcolemmal, sarcomeric and mitochondrial abnormalities. Proinflammatory T-lymphocytes, macrophages, type-I and II interferon-stimulated transcripts were found within the muscle of EM mice. ConclusionEM recapitulates the common hallmarks of IM. This costless, high throughput, reproducible and stable model, generated in the most commonly used background for genetically engineered mice, may foster pre-clinical research in IM. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSC-protein-induced myositis is currently the most used model of inflammatory myopathies but has been partially characterised and its generation is limited by reproducibility issues. What this study adds.Immunisation against the polypeptide encompassing C-protein amino acids 965-991 induces a costless, high throughput, reproducible and stable model of myositis (experimental myositis) that recapitulates the common hallmarks of inflammatory myopathies. How this study might affect research, practice or policyExperimental myositis, generated in the most used background for genetically engineered mice (C57BL/6N), might foster pre-clinical research in IM.

immunology↗

bioRxiv2023

Senescent cells deposit intracellular contents through adhesion-dependent fragmentation

Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here we identify that senescent cells dispose of large fragments of themselves through cell-to-cell adhesion, which we term senescent-cell adhesion fragments (SCAFs). Found across all senescent types examined, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreased SCAF formation but induced senescent-cell death, which was caused by an inability to shed damaged mitochondria. Dynamic analyses show that SCAFs ultimately rupture, releasing a complex proteome including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Altogether, these findings identify a new feature that facilitates senescent cell survival, but the consequence of which is external deposition of damaged intracellular contents, with implications for cancer and aging.

cell biology↗

bioRxiv2020

High levels of frataxin overexpression leads to mitochondrial and cardiac toxicity in mouse models

Friedreich ataxia (FA) is currently an incurable inherited mitochondrial disease caused by reduced levels of frataxin (FXN). Cardiac dysfunction is the main cause of premature death in FA. AAV-mediated gene therapy constitutes a promising approach for FA, as demonstrated in cardiac and neurological mouse models. While the minimal therapeutic level of FXN protein to be restored and biodistribution have recently been defined for the heart, it is unclear if FXN overexpression could be harmful. Indeed, depending on the vector delivery route and dose administrated, the resulting FXN protein level could reach very high levels in the heart, cerebellum, or in off-target organs such as the liver. The present study demonstrates safety of FXN cardiac overexpression up to 9-fold the normal endogenous level, but significant toxicity to the mitochondria and heart above 20-fold. We show gradual severity with increasing FXN overexpression, ranging from subclinical cardiotoxicity to left ventricle dysfunction. This appears to be driven by impairment of mitochondria respiratory chain, ultrastructure and homeostasis, which lead to myofilaments alteration, cell death and fibrosis. Overall, this study underlines the need, during the development of gene therapy approaches, to consider appropriately vector potency, long term safety and biomarkers to monitor such events.

bioengineering↗