dysferlin deficient muscular dystrophy

[David Feder]

Hum. Mol. Genet., Mar 2009

Attenuated muscle regeneration is a key factor in dysferlin deficient muscular dystrophy
Yen-Hui Chiu1, Mark A. Hornsey1, Lars Klinge1,2, Louise H. Jørgensen, Steven H. Laval, Richard Charlton, Rita Barresi, Volker Straub, Hanns Lochmüller and Kate Bushby*

Newcastle University, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ, United Kingdom

* To whom correspondence should be addressed at: Newcastle University, Institute of Human Genetics, International Centre for Life, Newcastle, NE1 3BZ, UK, Tel: [phone] Fax: [phone] Email: [e-mail]

Received January 23, 2009; Revised March 11, 2009; Accepted March 11, 2009

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) characterised 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 disorder.