Abstract
Chronic cardiac muscle inflammation and subsequent fibrotic tissue deposition are key features in Duchenne Muscular Dystrophy (DMD). The treatment of choice for delaying DMD progression both in skeletal and cardiac muscle are corticosteroids, supporting the notion that chronic inflammation in the heart plays a pivotal role in fibrosis deposition and subsequent cardiac dysfunction. Nevertheless, considering the adverse effects associated with long-term corticosteroid treatments, there is a need for novel anti-inflammatory therapies. In this study, we used our recently described exercised mdx (ex mdx) mouse model characterised by accelerated heart pathology, and the specific PKCθ inhibitor Compound 20 (C20), to show that inhibition of this kinase leads to a significant reduction in the number of immune cells infiltrating the heart, as well as necrosis and fibrosis. Functionally, C20 treatment also prevented the reduction in left ventricle fractional shortening, which was typically observed in the vehicle-treated ex mdx mice. Based on these findings, we propose that PKCθ pharmacological inhibition could be an attractive therapeutic approach to treating dystrophic cardiomyopathy
Highlights
Introduction published maps and institutional affilDuchenne Muscular Dystrophy (DMD) is a severe X-linked genetic uncurable disease that leads to progressive skeletal and cardiac muscle wasting, affecting roughly 1:3000–5000 of males
Heart Function Is Preserved in Compound 20 (C20)-Treated Exercised Mdx together, these results showed that C20 treatment reduces fibrotic tissue deposition in the In DMD-related cardiomyopathy, fibrotic tissue deposition is associated with ventricudystrophic heart
We used this approach since it is well established that the immune response plays a critical role in DMD pathology progression [28,61,62], and interfering with the onset or the amplification of the immune response can ameliorate dystrophic muscle phenotype and/or function [23,24,25,26,27,29,63] as well as heart pathology [64,65,66,67]
Summary
C20 could Cell ameliorate dystrophic heart phenotype and function, To assess whethermdx. 1A, mdx mice were divided into three groups at 3 weeks of age. A third group of non-exercised, non-treated, age-matched mdx were used as control. Vehicle and C20non-exercised, age-matched mdx were used as[46], control. C20 or vehicle were administration administered to mdx mice from 3 weeks of or vehicle werebefore administered to mdx session) mice from weeks of age (one weektwice before age (one week starting the exercise via3intraperitoneal injection, a starting exercise session) via end intraperitoneal injection, twice week mg/kg [30,31]. During the exercise sessions, we observed a decrease in exhaustion served a decrease in exhaustion among the C20-treated mice compared with vehicleamong the C20-treated mice compared with vehicle-treated (Figure 1B), suggesting that treated (Figure 1B), suggesting that treatment with the established dose and frequency of treatment with the established dose and frequency of C20 might be effective in ameliorating.
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