Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy
Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy
Skeletal muscle requires an efficient and active membrane repair system to overcome the rigours of frequent contraction. Dysferlin is a component of that system and absence of dysferlin causes muscular dystrophy (dysferlinopathy) characterized by adult onset muscle weakness, high serum creatine kinase levels and a prominent inflammatory infiltrate. We have observed that dysferlinopathy patient biopsies show an excess of immature fibres and therefore investigated the role of dysferlin in muscle regeneration. Using notexin-induced muscle damage, we have shown that regeneration is attenuated in a mouse model of dysferlinopathy, with delayed removal of necrotic fibres, an extended inflammatory phase and delayed functional recovery. Satellite cell activation and myoblast fusion appear normal, but there is a reduction in early neutrophil recruitment in regenerating and also needle wounded muscle in dysferlin-deficient mice. Primary mouse dysferlinopathy myoblast cultures show reduced cytokine release upon stimulation, indicating that the secretion of chemotactic molecules is impaired. We suggest an extension to the muscle membrane repair model, where in addition to fusing patch repair vesicles with the sarcolemma dysferlin is also involved in the release of chemotactic agents. Reduced neutrophil recruitment results in incomplete cycles of regeneration in dysferlinopathy which combines with the membrane repair deficit to ultimately trigger dystrophic pathology. This study reveals a novel pathomechanism affecting muscle regeneration and maintenance in dysferlinopathy and highlights enhancement of the neutrophil response as a potential therapeutic avenue in these disorders.
- Polish Academy of Sciences Poland
- University of Newcastle Australia Australia
- Newcastle University United Kingdom
- Institute of Human Genetics Poland
- Centre for Life United Kingdom
Mice, Knockout, Satellite Cells, Skeletal Muscle, Neutrophils, Membrane Proteins, Muscle Proteins, Articles, Muscular Dystrophies, Mice, Inbred C57BL, Disease Models, Animal, Mice, Animals, Humans, Muscle, Skeletal, Dysferlin, Cells, Cultured
Mice, Knockout, Satellite Cells, Skeletal Muscle, Neutrophils, Membrane Proteins, Muscle Proteins, Articles, Muscular Dystrophies, Mice, Inbred C57BL, Disease Models, Animal, Mice, Animals, Humans, Muscle, Skeletal, Dysferlin, Cells, Cultured
28 Research products, page 1 of 3
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
- 2017IsRelatedTo
chevron_left - 1
- 2
- 3
chevron_right
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).94 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
