Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ−/− mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ−/− muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ−/− muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ−/− muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ−/− muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.
Highlights
Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy caused by lack of dystrophin, leading to membrane instability and increased probability of damage during contraction
The level of muscle regeneration was lower in 4-week-old mdx/θ−/− compared to mdx, but this level was maintained throughout the 12-month time period. Expressing these results as the ratio of regenerating area over damaged area (Figure 1C), we found that in mdxθ−/− muscle the ratio is higher at all the ages examined, suggesting that the regeneration process is boosted compared to mdx during the progression of the disease, independently from the level of muscle damage
The number of Paired box 7 (Pax7) positive cells in muscle is higher in mdxθ−/− mice compared to mdx mice, and the level of Pax7 and Notch1 expression in satellite cells isolated from mdxθ−/− muscle is higher than in SCs from mdx
Summary
Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy caused by lack of dystrophin, leading to membrane instability and increased probability of damage during contraction. In DMD patients, the necrotic fibers are initially replaced by new fibers generated by satellite cells (SCs), the main myogenic stem cells in adult muscle. SCs become activated, proliferate, and differentiate into myofibers while a minor subset self-renews to replenish the SCs pool [4]. Satellite cell self-renewal preserves the muscle regenerative capability following multiple injuries. SCs can generate functionally different daughter cells by asymmetric division: One daughter will undergo differentiation after a variable number of symmetric cell divisions, while the other will return to the quiescent state. The “self-renewing” satellite cell is characterized by stable expression of Paired box 7 (Pax7), while the differentiating one upregulates Myogenic Differentiation (MyoD) expression and downregulates Pax7 [5,6]
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