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

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.

• Authors: Simon Hauerslev, Marie-Louise Sveen, Morten Duno, Corrado Angelini, John Vissing, Thomas O Krag
• Journal: BMC musculoskeletal disorders (BMC Musculoskelet Disord) Vol. 13 Pg. 43 (Mar 23 2012) ISSN: 1471-2474 [Electronic] England
• PMID: 22443334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Dystrophin
• MYOG protein, human
• Muscle Proteins
• MyoD Protein
• MyoD1 myogenic differentiation protein
• Myogenin
• Proteins
• Vimentin
• FKRP protein, human
• Pentosyltransferases
• CAPN3 protein, human
• Calpain
• Myosin Heavy Chains

Topics

• Adolescent
• Adult
• Apoptosis
• Biomarkers (analysis)
• Biopsy
• Blotting, Western
• Calpain (analysis, genetics)
• Denmark
• Dystrophin (genetics)
• Female
• Genetic Predisposition to Disease
• Humans
• Immunohistochemistry
• Linear Models
• Male
• Middle Aged
• Muscle Proteins (analysis, genetics)
• Muscle, Skeletal (chemistry, pathology, physiopathology)
• Muscular Dystrophies, Limb-Girdle (genetics, metabolism, pathology, physiopathology)
• Muscular Dystrophy, Duchenne (genetics, metabolism, pathology, physiopathology)
• Mutation
• MyoD Protein (analysis)
• Myogenin (analysis)
• Myosin Heavy Chains (analysis)
• Pentosyltransferases
• Phenotype
• Proteins (genetics)
• Regeneration (genetics)
• Severity of Illness Index
• Vimentin (analysis)
• Young Adult