Browsing by Author "Cruz Soca, Meilyn"

Now showing 1 - 4 of 4
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    Blockade of Bradykinin receptors worsens the dystrophic phenotype of mdx mice: differential effects for B1 and B2 receptors
    (2018) Acuña, María José; Salas, Daniela; Córdova Casanova, Adriana Paz; Cruz Soca, Meilyn; Céspedes, Carlos; Vio Lagos, Carlos P.; Brandan, Enrique
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    Cross-talk between TGF-β and PDGFRα signaling pathways regulates the fate of stromal fibro–adipogenic progenitors
    (2019) Contreras Saavedra, Osvaldo Isaías; Cruz Soca, Meilyn; Theret, Marine; Soliman, Hesham; Wei Tung, Lin; Groppa, Elena; Rossi, Fabio M.; Brandan, Enrique
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    Dysregulated ATX-LPA and YAP/TAZ signaling in dystrophic Sgcd−/− mice with early fibrosis and inflammation
    (2025) Gutiérrez Rojas, Cristián Armando; Córdova Casanova, Adriana Paz; Faundez-Contreras, Jennifer; Cruz Soca, Meilyn; Gallardo, Felipe S.; Bock-Pereda, Alexia; Casar Leturia, Juan Carlos; Barton, Elisabeth R.; Brandan, Enrique
    Background Sarcoglycanopathies are muscle dystrophies caused by mutations in the genes encoding sarcoglycans (α, β, γ, and δ) that can destabilize the dystrophin-associated glycoprotein complex at the sarcolemma, leaving muscle fibers vulnerable to damage after contraction, followed by inflammatory and fibrotic responses and resulting in muscle weakness and atrophy. Two signaling pathways have been implicated in fibrosis and inflammation in various tissues: autotaxin/lysophosphatidic acid (ATX-LPA) and yes-associated protein 1/transcriptional co-activator with PDZ-binding motif (YAP/TAZ). LPA, synthesized by ATX, can act as a pleiotropic molecule due to its multiple receptors. Two Hippo pathway effectors, YAP/TAZ, can be dephosphorylated by LPA and translocated to the nucleus. They induce several target genes, such as CCN2/CTGF, involved in fibrosis and inflammation. However, no detailed characterization of these processes or whether these pathways change early in the development of sarcoglycanopathy has been evaluated in skeletal muscle. Methods Using the δ-sarcoglycan knockout mouse model (Sgcd−/−), we investigated components of these pathways, inflammatory and fibrotic markers, and contractile properties of different skeletal muscles (triceps-TR, gastrocnemius-GST, diaphragm-DFG, tibialis anterior-TA, and extensor digitorum longus-EDL) at one and two months of age. Results We found that Sgcd−/− mice show early dystrophic features (fiber damage/necrosis, centrally nucleated fibers, inflammatory infiltrate, and regenerated fibers) followed by later fiber size reduction in TR, GST, and DFG. These changes are concomitant with an early inflammatory and fibrotic response in these muscles. Sgcd−/− mice also have early impaired force generation in the TA and EDL, and resistance to mechanical damage in the EDL. In addition, an early dysregulation of the ATX-LPA axis and the YAP/TAZ signaling pathway in the TR, GST, and DFG was observed in these mice. Conclusions The ATX-LPA axis and the YAP/TAZ signaling pathway, which are involved in inflammation and fibrosis, are dysregulated in skeletal muscle from an early age in Sgcd−/− mice. These changes are concomitant with a fibrotic and inflammatory response in these mice. Unraveling the role of the LPA axis and YAP/TAZ in sarcoglycanopathy holds great promise for improving our understanding of disease pathogenesis and identifying novel therapeutic targets for this currently incurable group of muscle disorders.
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    Role of αV integrins in the cellular response of fibro/adipogenic progenitors to lysophosphatidic acid
    (2022) Cruz Soca, Meilyn; Brandan, Enrique; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    La fibrosis se caracteriza por la acumulación excesiva de componentes de la matriz extracelular (ECM) en respuesta al daño o patología. La ECM reemplaza el tejido funcional por tejido conectivo, comprometiendo la arquitectura y función de este. En el músculo esquelético, la fibrosis se asocia principalmente con distrofias musculares, incluida la distrofia muscular de Duchenne (DMD). Los progenitores fibro/adipogénicos (FAPs) son una población de células progenitoras mesenquimales, no miogénicas, que poseen un potencial fibrogénico y adipogénico intrínseco. En condiciones patológicas y crónicas, como la DMD, los FAPs se activan a través de la proliferación y diferenciación a miofibroblastos, las principales células secretoras de ECM, causando la infiltración intramuscular del tejido fibroso. Algunas proteínas de la ECM incrementadas, como fibronectina y periostina, son reconocidas por integrinas αv, reguladores clave de la fibrogénesis en una amplia gama de modelos. El ácido lisofosfatídico (LPA) es un lisofosfolípido que señaliza a través de seis receptores acoplados a proteína G (LPARs). Señalización aberrante del LPA se ha relacionado con varias patologías fibróticas, como la fibrosis dérmica, pulmonar idiopática y hepática. Además, LPA induce la expresión del factor de crecimiento de tejido conectivo (CTGF/CCN2), factor pro fibrótico fuertemente relacionado con la patogénesis de trastornos fibróticos como la DMD. Esta evidencia sitúa al LPA como un potente modulador de la fibrosis en diferentes tejidos. Sin embargo, se desconoce el rol del LPA en el músculo, lo cual hace atractivo su estudio en el desarrollo de fibrosis en el músculo esquelético.