Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin.
Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin.
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DOI：
10.1083/jcb.142.5.1279
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发表时间：
1998-09-07
期刊：
影响因子：
--
通讯作者：
McNally EM
中科院分区：
文献类型：
--
作者：
Hack AA;Ly CT;Jiang F;Clendenin CJ;Sigrist KS;Wollmann RL;McNally EM
γ-肌聚糖是一种跨膜肌营养不良蛋白相关蛋白，在骨骼肌和心肌中表达。使用同源重组破坏小鼠 γ-肌聚糖基因。缺乏γ-肌聚糖的小鼠在生命早期表现出明显的营养不良性肌肉变化。到 20 周时，这些小鼠出现心肌病并过早死亡。 γ-肌聚糖的损失导致β-和δ-肌聚糖的二次减少，同时部分保留α-和ε-肌聚糖，这表明β-、γ-和δ-肌聚糖作为一个单元发挥作用。重要的是，缺乏γ-肌聚糖的小鼠表现出正常的肌营养不良蛋白含量和定位，这表明肌纤维变性的发生与肌营养不良蛋白的改变无关。此外，β-肌营养不良聚糖和层粘连蛋白保持完整，这意味着肌营养不良蛋白-肌营养不良聚糖-层粘连蛋白机械连接未受到肌聚糖缺乏的影响。缺乏γ-肌聚糖的骨骼肌中存在丰富的凋亡肌核，表明程序性细胞死亡导致肌纤维变性。伊文思蓝染料活体染色显示，缺乏 γ-肌聚糖的肌肉会出现膜破裂，就像肌营养不良蛋白缺陷肌肉中所见的那样。我们的数据表明，肌聚糖损失是足够的，并且肌营养不良蛋白损失并不是导致膜缺陷和细胞凋亡所必需的。作为各种肌营养不良症的常见分子特征，肌聚糖损失可能是病理学的介质。
γ-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine γ-sarcoglycan gene was disrupted using homologous recombination. Mice lacking γ-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of γ-sarcoglycan produced secondary reduction of β- and δ-sarcoglycan with partial retention of α- and ε-sarcoglycan, suggesting that β-, γ-, and δ-sarcoglycan function as a unit. Importantly, mice lacking γ-sarco- glycan showed normal dystrophin content and local- ization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, β-dystroglycan and laminin were left intact, implying that the dystrophin–dystroglycan–laminin mechanical link was unaffected by sarcoglycan deficiency. Apoptotic myonuclei were abundant in skeletal muscle lacking γ-sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking γ-sarcoglycan developed membrane disruptions like those seen in dystrophin-deficient muscle. Our data demonstrate that sarcoglycan loss was sufficient, and that dystrophin loss was not necessary to cause membrane defects and apoptosis. As a common molecular feature in a variety of muscular dystrophies, sarcoglycan loss is a likely mediator of pathology.
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DOI：
10.1083/jcb.122.4.809
发表时间：
1993-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ervasti JM;Campbell KP
通讯作者：
Campbell KP
影响因子：
16
作者：
Holt, KH;Lim, LE;Campbell, KP
通讯作者：
Campbell, KP
影响因子：
64.8
作者：
MONACO, AP;NEVE, RL;KUNKEL, LM
通讯作者：
KUNKEL, LM
影响因子：
158.5
作者：
Duggan, DJ;Gorospe, JR;Kunel, RW
通讯作者：
Kunel, RW
影响因子：
64.8
作者：
BURGHES, AHM;LOGAN, C;RAY, PN
通讯作者：
RAY, PN