Abstract
Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease. Research in contextDuchenne muscular dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a “cure” for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ), an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.
Highlights
Duchenne Muscular Dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births
This study demonstrates that pharmacological inhibition of Protein Kinase C-theta (PKCθ) in 4-week-old mdx mice, significantly prevents muscle wasting and inflammatory response, while maintains muscle regeneration and improves function and performance
Its eventual clinical application should be further investigated, our data provide proof of principle that pharmacological targeting of PKCθ in muscular dystrophy would be effective in ameliorating the disease, as our previous genetic studies suggested
Summary
Duchenne Muscular Dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. Numerous other anti-inflammatory therapies, aimed to target more specific mediators of inflammation, have been proposed to improve healing (Heier et al, 2013; Pelosi et al, 2015) In this context, we previously showed that lack of PKCθ in mdx, the mouse model of DMD, in the mdx/PKCθ−/− mouse model we generated, was associated with reduced muscle wasting, improved muscle regeneration and maintenance of performance compared to mdx mice (Madaro et al, 2012). PKCθ−/− mice may still mount a normal protective immune response to clear viral infections (Giannoni et al, 2005), and maintain Treg function (Gupta et al, 2008; Ma et al, 2012; Sun, 2012; Zanin-Zhorov et al, 2010) Taken together, these evidences validate PKCθ as a attractive target to selectively manipulate Teff cell functions that are relevant to pathogenesis of different diseases, including, as our results suggested, muscular dystrophy. Employing PKCθ−/− mice, we showed that PKCθ maintains the correct structure and function of the heart by preventing cardiomyocyte cell death in response to work demand and to neuro-hormonal signals, to which heart cells are continuously exposed (Paoletti et al, 2010)
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