Biology subjects

Duque, G.

Publications and source records attributed to Duque, G..

3 recordsLinked to original sources

bioRxiv2024

Advancements in Inflammation Parallels Myopenia in Winnie Mice Model of Spontaneous Chronic Colitis

BackgroundInflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation and systemic complications, including muscle wasting. Musculoskeletal conditions have remained an unappreciated aspect of IBD. This study aimed to describe the Winnie mouse models skeletal muscle phenotype and functional alterations. This model spontaneously develops chronic colitis that closely resembles human IBD. MethodsWinnie mice and C57BL/6 (littermate) controls were evaluated at 5-6 weeks (pre-colitis) and 15-16 weeks (active colitis). Assessments included disease activity, inflammation, muscle function tests, and ex vivo analyses of the soleus (SOL) and tibialis anterior (TA) muscles for mass and histology. ResultsAt 5-6 weeks, Winnie mice showed no disease activity or muscle changes. At 15 weeks, Winnie mice exhibited significantly higher disease activity index (DAI) and elevated lipocalin-2 (LCN-2) levels than controls. SOL and TA muscles showed decreased weights and fibre sizes, which correlated significantly with LCN-2 levels. Wheel-running activity was reduced, which correlated with increased LCN-2 levels and DAI. DAI negatively correlated with muscle mass and fibre size. Grip strength remained unaltered despite these changes. ConclusionThe Winnie mouse model develops significant skeletal muscle alterations paralleling intestinal inflammation progression, characterized by reduced muscle mass and size with preserved strength but impaired functional endurance capacity. These findings establish the Winnie model as a valuable tool for investigating IBD-associated muscle wasting. Key Messages1. What is already known? O_LIInflammatory bowel disease (IBD) is associated with systemic complications, including muscle dysfunction. C_LI 2. What is new here? O_LIThe Winnie mouse model of chronic colitis develops skeletal muscle alterations that correlate with the progression of intestinal inflammation. C_LIO_LIMuscle changes in Winnie mice include reduced muscle mass, decreased fibre size, and, functional decline but preserved grip strength. C_LI 3. How can this study help patient care? O_LIThis research highlights the importance of monitoring muscle health in IBD patients and suggests potential targets for interventions to preserve muscle function. C_LIO_LIThe Winnie model provides a valuable tool for testing therapies aimed at addressing muscle dysfunction in IBD. C_LI

physiology↗

bioRxiv2020

Skeletal Phenotype and Mechanisms of Bone Loss in Winnie Mice as a Model for Inflammatory Bowel Disease

ObjectiveWe aimed to investigate the skeletal phenotype of Winnie mouse model of spontaneous chronic colitis, which carries a mutation in the Muc2 gene and closely replicates IBD symptoms and pathophysiology. These mice have a high level of gut-derived serotonin (GDS), a potent osteoblastogenesis inhibitor. We explored the underlying mechanisms of bone loss associated with chronic intestinal inflammation. DesignWinnie male and female mice prior to colitis onset (6 weeks old) and progression (14 and 24 weeks) were compared to age- and sex-matched C57BL/6 controls. We assessed bone quality (static and dynamic histomorphometry, micro-CT, 3-point bending), intestinal inflammation (lipocalin-2), GDS levels, serum levels of calcium, phosphorus and vitamin D, ex vivo bone marrow analysis and molecular mechanisms inhibiting osteoblastogenesis. ResultsSignificant deterioration in trabecular and cortical microarchitecture, reductions in bone formation, mineral apposition rate, bone volume, osteoid volume and bone strength were observed in Winnie mice compared to C57BL/6 controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice. We report for the first time that elevated GDS cross-talks with molecular pathways to inhibit bone formation in Winnie mice. Increased expression of 5-HTR1B and FOXO1 mRNAs, dissociation of FOXO1/CREB1 complex and association of FOXO1 with ATF4, promoting the transcriptional activity of FOXO1, results in suppression of osteoblast proliferation in Winnie mice compared to controls. ConclusionThese findings open avenues for the development of targeted therapies for IBD-related bone loss. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABS- Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD). - Currently available treatments are not effective for IBD-associated bone loss. - The mechanisms of bone loss are poorly understood. A major limitation has been the lack of an appropriate animal model for IBD-associated bone loss. What are the new findings?- We report for the first-time the skeletal phenotype in Winnie mouse model of IBD - This study presents a novel mechanism of IBD-associated bone loss, involving elevated gut-derived serotonin crosstalk with molecular pathways inhibiting bone formation. How might it impact on clinical practice in the foreseeable future- These findings open avenues for the development of targeted therapies for IBD-related bone loss.

physiology↗

bioRxiv2020

MSH2 knock-down shows CTG repeat stability and concomitant upstream demethylation at the DMPK locus in myotonic dystrophy type 1 human embryonic stem cells

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene, where expansion size and somatic mosaicism correlates with disease severity and age of onset. While it is known that the mismatch repair protein MSH2 contributes to the unstable nature of the repeat, its role on other disease-related features, such as CpG methylation upstream of the repeat, is unknown. In this study, we investigated the effect of an MSH2 knock-down (MSH2KD) on both CTG repeat dynamics and CpG methylation pattern in human embryonic stem cells (hESC) carrying the DM1 mutation. Repeat size in MSH2 wild type (MSH2WT) and MSH2KD DM1 hESC was determined by PacBio sequencing and CpG methylation by bisulfite massive parallel sequencing. We found stabilization of the CTG repeat concurrent with a gradual loss of methylation upstream of the repeat in MSH2KD cells, while the repeat continued to expand and upstream methylation remained unchanged in MSH2WT control lines. Repeat instability was re-established and biased towards expansions upon MSH2 transgenic re-expression in MSH2KD lines while upstream methylation was not consistently re-established. We hypothesize that the hypermethylation at the mutant DM1 locus is promoted by the MMR machinery and sustained by a constant DNA repair response, establishing a potential mechanistic link between CTG repeat instability and upstream CpG methylation. Our work represents a first step towards understanding how epigenetic alterations and repair pathways connect and contribute to the DM1 pathology.

genetics↗