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Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle
Expert Reviews in Molecular Medicine ( IF 6.2 ) Pub Date : 2016-04-08 , DOI: 10.1017/erm.2016.9
Ivan Toral-Ojeda 1 , Garazi Aldanondo 1 , Jaione Lasa-Elgarresta 1 , Haizpea Lasa-Fernández 1 , Roberto Fernández-Torrón 1 , Adolfo López de Munain 1 , Ainara Vallejo-Illarramendi 1
Affiliation  

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a form of muscular dystrophy caused by mutations in calpain 3 (CAPN3). Several studies have implicated Ca2+ dysregulation as an underlying event in several muscular dystrophies, including LGMD2A. In this study we used mouse and human myotube cultures, and muscle biopsies in order to determine whether dysfunction of sarco/endoplasmatic Ca2+-ATPase (SERCA) is involved in the pathology of this disease. In CAPN3-deficient myotubes, we found decreased levels of SERCA 1 and 2 proteins, while mRNA levels remained comparable with control myotubes. Also, we found a significant reduction in SERCA function that resulted in impairment of Ca2+ homeostasis, and elevated basal intracellular [Ca2+] in human myotubes. Furthermore, small Ankyrin 1 (sAnk1), a SERCA1-binding protein that is involved in sarcoplasmic reticulum integrity, was also diminished in CAPN3-deficient fibres. Interestingly, SERCA2 protein was patently reduced in muscles from LGMD2A patients, while it was normally expressed in other forms of muscular dystrophy. Thus, analysis of SERCA2 expression may prove useful for diagnostic purposes as a potential indicator of CAPN3 deficiency in muscle biopsies. Altogether, our results indicate that CAPN3 deficiency leads to degradation of SERCA proteins and Ca2+ dysregulation in the skeletal muscle. While further studies are needed in order to elucidate the specific contribution of SERCA towards muscle degeneration in LGMD2A, this study constitutes a reasonable foundation for the development of therapeutic approaches targeting SERCA1, SERCA2 or sAnk1.

中文翻译:

钙蛋白酶 3 缺乏会影响骨骼肌中 SERCA 的表达和功能

2A 型肢带型肌营养不良症 (LGMD2A) 是一种由钙蛋白酶 3 (CAPN3) 突变引起的肌营养不良症。多项研究表明 Ca2+失调作为包括 LGMD2A 在内的几种肌营养不良症的潜在事件。在这项研究中,我们使用小鼠和人类肌管培养物和肌肉活检来确定是否存在肌瘤/内质钙功能障碍2+-ATPase (SERCA) 参与了这种疾病的病理学。在 CAPN3 缺陷肌管中,我们发现 SERCA 1 和 2 蛋白水平降低,而 mRNA 水平与对照肌管保持可比性。此外,我们发现 SERCA 功能显着降低,导致 Ca 受损2+稳态和升高的基础细胞内 [Ca2+] 在人类肌管中。此外,小锚蛋白 1 (sAnk1),一种与肌质网完整性有关的 SERCA1 结合蛋白,在 CAPN3 缺陷纤维中也减少了。有趣的是,SERCA2 蛋白在 LGMD2A 患者的肌肉中明显减少,而它通常在其他形式的肌营养不良症中表达。因此,SERCA2 表达的分析可能被证明可用于诊断目的,作为肌肉活检中 CAPN3 缺乏的潜在指标。总之,我们的结果表明 CAPN3 缺乏会导致 SERCA 蛋白和 Ca2+骨骼肌的失调。虽然需要进一步研究以阐明 SERCA 对 LGMD2A 肌肉退化的具体贡献,但本研究为开发针对 SERCA1、SERCA2 或 sAnk1 的治疗方法奠定了合理的基础。
更新日期:2016-04-08
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