JACOPO MORRONI

Dottore

ciclo: XXXIV


tutor: Marina Bouchè
supervisore: Biliana Lozanoska-Ochser

Titolo della tesi: Investigating dystrophic heart features in a newly established mdx model of accelerated heart pathology, and PKCθ as a possible pharmacological target

Introduction - Chronic cardiac muscle inflammation and fibrosis are key features of Duchenne Muscular Dystrophy (DMD), and cardiac failure is rising as the main cause of death among DMD patients. The treatment of choice in delaying DMD progression is the use of corticosteroids; considering their severe adverse effects, the need for novel anti-inflammatory therapies is urgent. The evaluation of novel therapies for the dystrophic heart depends on the availability of appropriate animal models, but the widely used DMD model, the mdx mouse, presents a milder cardiac pathology compared to humans, which precludes reliable studies. Objectives - In this study, we aimed at achieving two objectives: to generate a novel, reliable mouse model of DMD-related cardiomyopathy, and to use this model to evaluate the efficacy of PKCθ inhibition as an anti- inflammatory treatment aimed at ameliorating dystrophic heart phenotype and function. Methods - To this end, we applied an “endurance” treadmill exercise protocol to accelerate and worsen the cardiac pathology in mdx mice avoiding any further genetic manipulation, and we then treated the exercised mdx model with a highly specific PKCθ inhibitor, the Compound 20 (C20). Results and Conclusions - We demonstrated that subjecting young mdx mice (4-week-old) to “endurance” exercise accelerates heart pathology progression, as shown by early fibrosis deposition, increased ventricular necrosis and inflammation, and worsened heart function in terms of reduced left ventricle fractional shortening, compared to controls. C20 treatment of the exercised mdx mice resulted in a strong reduction of the number of immune cells infiltrating the heart, associated to less necrotic cardiomyocytes and decrease of fibrotic tissue deposition, compared with vehicle-treated exercised mdx mice. Functionally, C20 treatment also prevented the reduction in left ventricle fractional shortening observed in the vehicle-treated controls. Considering the already established efficacy of C20 administration in ameliorating mdx skeletal muscle phenotype and function, with this study we found that PKCθ pharmacological inhibition could represent an attractive therapeutic approach to treat the dystrophic heart as well. Furthermore, we established the exercised mdx model, which could represent a cheap and reproducible mouse model to investigate any other therapeutic approach aimed at ameliorating the pathological features of the dystrophic heart.

Produzione scientifica

  • 11573/1348219 - 2020 - Splenic Ly6Chi monocytes are critical players in dystrophic muscle injury and repair (01a Articolo in rivista)
    DI MAGGIO, ROSANNA; BENEDETTI, ANNA; MORRONI, JACOPO; BOUCHE', MARINA; LOZANOSKA OCHSER, BILIANA
  • 11573/1565089 - 2021 - Accelerating the mdx heart histo-pathology through physical exercise (01a Articolo in rivista)
    MORRONI, JACOPO; SCHIRONE, LEONARDO; VECCHIO, DANIELE; NICOLETTI, CARMINE; D'AMBROSIO, LUCA; VALENTI, VALENTINA; SCIARRETTA, SEBASTIANO; BOUCHE', MARINA
  • 11573/1612791 - 2022 - Inhibition of PKCθ Improves Dystrophic Heart Phenotype and Function in a Novel Model of DMD Cardiomyopathy (01a Articolo in rivista)
    MORRONI, JACOPO; SCHIRONE, LEONARDO; ZWERGEL, CLEMENS; SANCHEZ RIERA, CARLES; VALENTE, SERGIO; VECCHIO, DANIELE; SCHIAVON, SONIA; RAGNO, RINO; MAI, ANTONELLO; SCIARRETTA, SEBASTIANO; LOZANOSKA OCHSER, BILIANA; BOUCHE', MARINA

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