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Open Access Research article

Calpain 3 is important for muscle regeneration: Evidence from patients with limb girdle muscular dystrophies

Simon Hauerslev1, Marie-Louise Sveen1, Morten Duno2, Corrado Angelini34, John Vissing1 and Thomas O Krag1*

Author Affiliations

1 Department of Neurology, Neuromuscular Research Unit, The Copenhagen Muscle Research Center, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark

2 Department of Clinical Genetics, University of Copenhagen, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark

3 Department of Neurosciences, University of Padova, Via 8 Febbraio 1848, Padova, Italy

4 IRCSS S. Camillo, Via Alberoni 7, Venice, Italy

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BMC Musculoskeletal Disorders 2012, 13:43  doi:10.1186/1471-2474-13-43

Published: 23 March 2012

Abstract

Background

Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration.

Methods

We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers.

Results

We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the CAPN3 gene.

Conclusions

Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.

Keywords:
Limb girdle muscular dystrophy; Calpain 3; Muscle regeneration; INF; Neonatal myosin heavy chain; Vimentin