Department of Neurology, Neuromuscular Research Unit, The Copenhagen Muscle Research Center, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark.
BMC Musculoskelet Disord. 2012 Mar 23;13:43. doi: 10.1186/1471-2474-13-43.
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.
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.
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.
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.
肢带型肌营养不良症 2A 型（LGMD2A）是由 CAPN3 基因突变引起的，完全缺乏功能性钙蛋白酶 3 会导致最严重的肌肉萎缩。钙蛋白酶 3 被认为参与肌肉退化后的收缩成分成熟。本研究旨在探讨钙蛋白酶 3 的四个功能域中的突变如何影响肌肉再生。
我们研究了 22 名钙蛋白酶 3 缺乏的 LGMD2A 患者、5 名钙蛋白酶 3 继发性减少的 LGMD2I 患者和 5 名贝克型肌营养不良症（BMD）患者的肌肉再生情况，这些患者的钙蛋白酶 3 水平正常。通过使用发育标志物新生儿肌球蛋白重链（nMHC）、波形蛋白、MyoD 和肌细胞生成素以及计数内部核纤维来评估再生。
我们发现，与 LGMD2I 和 BMD 患者相比，严重受影响的 LGMD2A 患者的近期再生（通过 nMHC/vimentin 阳性纤维的数量确定）大大减少。与仍有残余钙蛋白酶 3 的患者相比，完全缺乏钙蛋白酶 3 的患者的扭曲纤维（异常再生的标志）高度升高。钙蛋白酶 3 的突变位置不影响再生。
我们的发现表明，钙蛋白酶 3 可能是再生过程所必需的，可能在肌节重塑过程中需要，因为完全缺乏功能性钙蛋白酶 3 会导致最严重的表型。
