Browsing by Author "Casar, Juan Carlos"

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    beta 4 Integrin Marks Interstitial Myogenic Progenitor Cells in Adult Murine Skeletal Muscle
    (SAGE PUBLICATIONS LTD, 2012) Liadaki, Kalliopi; Casar, Juan Carlos; Wessen, McKenzie; Luth, Eric S.; Jun, Susan; Gussoni, Emanuela; Kunkel, Louis M.
    Skeletal muscle growth and its regeneration following injury rely on myogenic progenitor cells, a heterogeneous population that includes the satellite cells and other interstitial progenitors. The present study demonstrates that surface expression of beta 4 integrin marks a population of vessel-associated interstitial muscle progenitor cells. Muscle beta 4 integrin-positive cells do not express myogenic markers upon isolation. However, they are capable of undergoing myogenic specification in vitro and in vivo: beta 4 integrin cells differentiate into multinucleated myotubes in culture dishes and contribute to muscle regeneration upon delivery into diseased mice. Subfractionation of beta 4 integrin-expressing cells based on CD31 expression does not further enrich for myogenic precursors. These findings support the expression of beta 4 integrin in interstitial, vessel-associated cells with myogenic activity within adult skeletal muscle. (J Histochem Cytochem 60:31-44, 2012)
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    Denervation Drives YAP/TAZ Activation in Muscular Fibro/Adipogenic Progenitors
    (2023) Gallardo, Felipe S.; Cordova-Casanova, Adriana; Bock-Pereda, Alexia; Rebolledo, Daniela L.; Ravasio, Andrea; Casar, Juan Carlos; Brandan, Enrique
    Loss of motoneuron innervation (denervation) is a hallmark of neurodegeneration and aging of the skeletal muscle. Denervation induces fibrosis, a response attributed to the activation and expansion of resident fibro/adipogenic progenitors (FAPs), i.e., multipotent stromal cells with myofibroblast potential. Using in vivo and in silico approaches, we revealed FAPs as a novel cell population that activates the transcriptional coregulators YAP/TAZ in response to skeletal muscle denervation. Here, we found that denervation induces the expression and transcriptional activity of YAP/TAZ in whole muscle lysates. Using the Pdgfra(H2B:EGFP/+) transgenic reporter mice to trace FAPs, we demonstrated that denervation leads to increased YAP expression that accumulates within FAPs nuclei. Consistently, re-analysis of published single-nucleus RNA sequencing (snRNA-seq) data indicates that FAPs from denervated muscles have a higher YAP/TAZ signature level than control FAPs. Thus, our work provides the foundations to address the functional role of YAP/TAZ in FAPs in a neurogenic pathological context, which could be applied to develop novel therapeutic approaches for the treatment of muscle disorders triggered by motoneuron degeneration.
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    Involvement of lysophosphatidic acid-LPA1-YAP signaling in healthy and pathological FAPs migration
    (2024) Bock-Pereda, Alexia; Cruz-Soca, Meilyn; Gallardo, Felipe S.; Cordova-Casanova, Adriana; Gutierrez-Rojas, Cristian; Faundez-Contreras, Jennifer; Chun, Jerold; Casar, Juan Carlos; Brandan, Enrique
    Skeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration. Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA(1)) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs. Moreover, we found that FAPs derived from the mdx4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA(1) or YAP transcriptional coactivator activity in mdx4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA(1)-YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies.
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    LPA-induced expression of CCN2 in muscular fibro/adipogenic progenitors (FAPs): Unraveling cellular communication networks
    (2024) Cordova-Casanova, Adriana; Cruz-Soca, Meilyn; Gallardo, Felipe S.; Faundez-Contreras, Jennifer; Bock-Pereda, Alexia; Chun, Jerold; Vio, Carlos P.; Casar, Juan Carlos; Brandan, Enrique
    Cellular Communication Network Factor 2, CCN2, is a profibrotic cytokine implicated in physiological and pathological processes in mammals. The expression of CCN2 is markedly increased in dystrophic muscles. Interestingly, diminishing CCN2 genetically or inhibiting its function improves the phenotypes of chronic muscular fibrosis in rodent models. Elucidating the cell-specific mechanisms behind the induction of CCN2 is a fundamental step in understanding its relevance in muscular dystrophies. Here, we show that the small lipids LPA and 2S-OMPT induce CCN2 expression in fibro/adipogenic progenitors (FAPs) through the activation of the LPA1 receptor and, to a lower extent, by also the LPA6 receptor. These cells show a stronger induction than myoblasts or myotubes. We show that the LPA/LPARs axis requires ROCK kinase activity and organized actin cytoskeleton upstream of YAP/TAZ signaling effectors to upregulate CCN2 levels, suggesting that mechanical signals are part of the mechanism behind this process. In conclusion, we explored the role of the LPA/LPAR axis on CCN2 expression, showing a strong cytoskeletal-dependent response in muscular FAPs.
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    Sympathetic and electrochemical skin responses in the assessment of sudomotor function: a comparative study
    (2023) Idiaquez, Juan; Casar, Juan Carlos; Fadic, Ricardo; Iturriaga, Rodrigo
    Objectives: The sympathetic skin response (SSR) is a well-established test, whereas the electro-chemical skin conductance (ESC) is still under evaluation. Our aim was therefore to assess the diagnostic accuracy of ESC to detect abnormal sudomotor function, using SSR as a reference test.Methods: A cross sectional observational study was performed of 61 neurological patients assessed for possible sudomotor dysfunction and 50 age-matched healthy controls (HC). Patients with diagnoses of vasovagal syncope (VVS, n=25), Parkinson's disease (PD, n=15), multiple system atrophy (MSA, n=11) and peripheral neuropathies (PN, n=10) were included. Sudomotor function was assessed with SSR and ESC tests in all participants. The absence of SSR in the palms or soles indicates abnormal sudomotor function. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic value of the ESC. Cardiovascular autonomic (CV-Aut) function was evaluated through the Ewing score, based on the following tests: Heart rate change with deep breathing, Valsalva ratio, 30:15 ratio, blood pressure changes on standing and during isometric exercise. A Ewing score > 2 indicates the presence of CV-Aut dysfunction.Results: Mean SSR amplitudes and ESC values showed differences between HC and patients with MSA or PN (p < 0.05), but not in patients with VVS or PD. Absence of SSR was associated with abnormal ESC (p < 0.05). Patients with abnormal CV-Aut dysfunction had lower ESC (p< 0.05). Palm ESC (P-ESC) and sole ESC (S-ESC) assessment had a sensitivity of 0.91 and 0.95 to predict sudomotor dysfunction, with a specificity of 0.78 and 0.85, respectively. The area under ROC curve was 0.905 and 0.98, respectively.Conclusions: ESC in palms and soles has a high diagnostic accuracy for sudomotor dysfunction as detected by absent SSR in patients with MSA and PN. (c) 2022 Elsevier Masson SAS. All rights reserved.