Abstract
Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C θ (PKCθ) is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKCθ could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/θ−/−, where PKCθ expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/θ−/− mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKCθ expression in hematopoietic cells.These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKCθ activity in the development of DMD. Although the immune cell population(s) involved remain unidentified, our findings reveal that PKCθ can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches.
Highlights
Duchenne muscular dystrophy (DMD) is one of the most common X-linked lethal diseases, and results from the mutation within the gene encoding dystrophin, a large cytoskeletal protein, whose ablation leads to membrane instability [1]
Lack of Protein kinase C h (PKCh) in mdx mice reduces muscle degeneration and inflammation To verify whether inhibition of PKCh may improve healing in muscular dystrophy, we crossed the PKCh knock out model (PKCh2/2) with mdx, the mouse model of DMD
The mdx mouse strain is the most widely used animal model for DMD; it presents a milder phenotype compared to DMD, the immune cell populations in their muscles resemble those seen in DMD patients [6]
Summary
Duchenne muscular dystrophy (DMD) is one of the most common X-linked lethal diseases, and results from the mutation within the gene encoding dystrophin, a large cytoskeletal protein, whose ablation leads to membrane instability [1]. Up-regulated inflammatory gene expression and activated immune cell infiltrates are evident during early disease stages in dystrophic muscle, and the identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Numerous other anti-inflammatory therapies have been proposed to improve healing [9,10,11,12,13] In this context, it has been recently shown that rapamycin treatment reduced dystrophic phenotype in mdx mice and that this effect was associated to a significant reduction in infiltration of Teff cells in skeletal muscle tissue, while Treg cells were preserved [14]. It is worth noting that PKCh has been recently immunofluorescence (c–d), in TA muscles from mdx (a and c) or mdx/ h2/2 (b and d). (E) Representative western Blot analysis of IgG accumulation in TA muscles from mdx or mdx/h2/2
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