Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Ave, MSB, G609, Newark, NJ, 07103, USA.
J Muscle Res Cell Motil. 2013 Dec;34(5-6):349-56. doi: 10.1007/s10974-013-9350-0. Epub 2013 Jun 8.
Abnormal intracellular Ca(2+) handling is an important factor in the progressive functional decline of dystrophic muscle. In the present study, we investigated the function of sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase (SERCA) in various dystrophic muscles of mouse models of Duchenne muscular dystrophy. Our studies show that the protein expression of sarcolipin, a key regulator of the SERCA pump is abnormally high and correlates with decreased maximum velocity of SR Ca(2+) uptake in the soleus, diaphragm and quadriceps of mild (mdx) and severe (mdx:utr-/-) dystrophic mice. These changes are more pronounced in the muscles of mdx:utr-/- mice. We also found increased expression of SERCA2a and calsequestrin specifically in the dystrophic quadriceps. Immunostaining analysis further showed that SERCA2a expression is associated both with fibers expressing slow-type myosin and regenerating fibers expressing embryonic myosin. Together, our data suggest that sarcolipin upregulation is a common secondary alteration in all dystrophic muscles and contributes to the abnormal elevation of intracellular Ca(2+) concentration via SERCA inhibition.
异常的细胞内 Ca(2+) 处理是进行性肌营养不良肌肉功能逐渐下降的一个重要因素。在本研究中，我们研究了肌营养不良小鼠模型中各种肌营养不良肌肉中的肌浆网（SR）Ca(2+)ATP 酶（SERCA）的功能。我们的研究表明，肌浆素是 SERCA 泵的关键调节蛋白，其蛋白表达异常升高，并与比目鱼肌、横膈膜和四头肌中 SR Ca(2+)摄取的最大速度降低相关，在轻度（mdx）和重度（mdx:utr-/-）肌营养不良小鼠中更为明显。在 mdx:utr-/- 小鼠的肌肉中，这些变化更为明显。我们还发现，特异性地在四头肌中，SERCA2a 和 calsequestrin 的表达增加。免疫染色分析进一步表明，SERCA2a 的表达与表达慢型肌球蛋白的纤维和表达胚胎肌球蛋白的再生纤维都有关。总之，我们的数据表明，肌浆素上调是所有肌营养不良肌肉中的常见继发性改变，并通过 SERCA 抑制导致细胞内 Ca(2+)浓度的异常升高。
