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Pharmacological inhibition of PKCθ counteracts muscle disease in a mouse model of Duchenne muscular dystrophy

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.

Researchers previously showed that genetic ablation of Protein Kinase C θ ( PKCθ; PKC Theta ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation.

To establish whether pharmacological targeting of PKCθ in Duchenne muscular dystrophy can be proposed as a therapeutic option, in this study researchers have treated young mdx mice with the PKCθ inhibitor Compound 20 ( C20 ).

C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration.

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 Duchenne muscular dystrophy can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.

Duchenne muscular dystrophy is a severe muscle disease affecting 1:3500 male births, and it 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 Duchenne muscular dystrophy.

Glucocorticoids, which have anti-inflammatory properties, are being used to treat Duchenne muscular dystrophy 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. ( Xagena )

Marrocco V et al, EBioMedicine 2017;16:150-161