Impaired regeneration of dystrophin-deficient muscle fibers is caused by exhaustion of myogenic cells

Abstract

Duchenne muscular dystrophy is one of the most devastating myopathies. Muscle fibers undergo necrosis and lose their ability to regenerate, and this may be related to increased interstitial fibrosis or the exhaustion of satellite cells. In this study, we used mdx mice, an animal model of Duchenne muscular dystrophy, to assess whether muscle fibers lose their ability to regenerate after repeated cycles of degeneration-regeneration and to establish the role of interstitial fibrosis or exhaustion of satellite cells in this process. Repeated degenerativeregenerative cycles were induced by the injection of bupivacaine (33 mg/kg), a myotoxic agent. Bupivacaine was injected weekly into the right tibialis anterior muscle of male, 8-week-old mdx (N = 20) and C57Bl/10 (control, N = 10) mice for 20 and 50 weeks. Three weeks after the last injection, the mice were killed and the proportion of regenerated fibers was counted and reported as a fibrosis index. Twenty weekly bupivacaine injections did not change the ability of mdx muscle to regenerate. However, after 50 weekly bupivacaine injections, there was a significant decrease in the regenerative response. There was no correlation between the inability to regenerate and the increase in interstitial fibrosis. These results show that after prolonged repeated cycles of degeneration-regeneration, mdx muscle loses its ability to regenerate because of the exhaustion of satellite cells, rather than because of an increase in interstitial fibrosis. This finding may be relevant to cell and gene therapy in the treatment of Duchenne muscular dystrophy.

Genetic Background Affects Properties of Satellite Cells and mdx Phenotypes

“…During this process, at least some of the satellite cells have self-renewal potential, 14,24 but are quiescent and will respond efficiently to the next damages. In fact, Luz et al 15 indicated that C57BL/10 could regenerate after 50 bupivacaine injections without the loss of myofibers or gain of fibrotic areas in the TA muscle. Importantly, C57BL/10-mdx mice exhibited decreased numbers of myofibers after 50 bupivacaine injections 15 because C57BL10-mdx mice already have dystrophic degeneration-regeneration cycles.…”

“…This is consistent with the results of C57BL/10 previously described. 15 In contrast, among four inbred strains, DBA/2 mice exhibited the most remarkable skeletal muscle loss and impaired regeneration after repeated injury. Importantly, the self-renewal potential of DBA/2 satellite cells was significantly lower than that of C57BL/6.…”

“…14 In fact, it is reported that the satellite cell pool of C57BL/10 continues to respond efficiently even when the skeletal muscle is subjected to as many as 50 cycles of severe damage. 15 Therefore, it is thought that maintenance of the satellite cell pool is indispensable to retain the long-term regenerative potential for skeletal muscle injury, including in muscular dystrophies.…”

Formoterol May Activate Rat Muscle Regeneration During Cancer Cachexia

“…After an injury within the muscle, there is an effective restoration of its structure and function 20 . This is possible due to existence of a population of mononuclear acquired myogenic precursors, known as satellite cells 21 .…”

Influência do bloqueador de receptor de angiotensina (Losartana potássica) na função renal e pressão arterial em cães GRMD

“…O aumento progressivo da fibrose intersticial no mús-culo impede a migração das células miogênicas, que são necessárias para a formação muscular (Luz et al 2002). A fibrose é capaz de limitar a utilidade de terapias gênicas ou transplantação mioblástica para corrigir o defeito primário, já que a proliferação de tecido conectivo barra o suporte nutricional para a fibra muscular e a migração e fusão de novas células implantadas.…”