Muscle degeneration without mechanical injury in sarcoglycan deficiency
Muscle degeneration without mechanical injury in sarcoglycan deficiency
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DOI：
10.1073/pnas.96.19.10723
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发表时间：
1999-09-14
影响因子：
11.1
通讯作者：
McNally, EM
中科院分区：
文献类型：
--
作者：
Hack, AA;Cordier, L;McNally, EM
在人类中，编码肌营养不良蛋白-糖蛋白复合物成分的基因突变会导致肌肉营养不良。具体来说，编码α -、β -、γ -和δ -肌糖的基因的原发性突变已在肢带性肌萎缩症患者中被发现。缺乏-肌糖能的小鼠发展为进行性肌营养不良，类似于人类肌营养不良。没有-肌聚糖，-和-肌聚糖在肌膜上不稳定，-肌聚糖严重减少。肌营养不良蛋白（dystrophin）、肌动蛋白聚糖（dystroglcan）和层粘连蛋白（laminin- α 2）（肌动蛋白骨架和细胞外基质之间的机械连接）的表达和定位似乎不受肌聚糖缺失的影响。我们评估了这种机械连接的功能完整性，发现缺乏γ -肌聚糖的孤立肌肉对偏心肌肉收缩引起的机械应变表现出正常的抵抗力。肌糖缺乏肌也显示出正常的峰值等距力和强直力产生。此外，在缺乏γ -肌聚糖的小鼠中，没有证据表明受到长期严格运动方案的收缩性损伤。这些数据表明，机械无力和收缩引起的肌肉损伤不是肌肉变性和营养不良过程所必需的。因此，一种非机械机制，可能涉及一些未知的信号功能，可能是肌糖缺乏的肌萎缩症的原因。
In humans, mutations in the genes encoding components of the dystrophin-glycoprotein complex cause muscular dystrophy. Specifically, primary mutations in the genes encoding alpha-, beta-, gamma-, and delta-sarcoglycan have been identified in humans with limb-girdle muscular dystrophy. Mice lacking gamma-sarcoglycan develop progressive muscular dystrophy similar to human muscular dystrophy. Without gamma-sarcoglycan, beta- and delta-sarcoglycan are unstable at the muscle membrane and alpha-sarcoglycan is severely reduced. The expression and localization of dystrophin, dystroglycan, and laminin-alpha 2, a mechanical link between the actin cytoskeleton and the extracellular matrix, appears unaffected by the loss of sarcoglycan. We assessed the functional integrity of this mechanical link and found that isolated muscles lacking gamma-sarcoglycan showed normal resistance to mechanical strain induced by eccentric muscle contraction. Sarcoglycan-deficient muscles also showed normal peak isometric and tetanic force generation. Furthermore, there was no evidence for contraction-induced injury in mice lacking gamma-sarcoglycan that were subjected to an extended, rigorous exercise regimen. These data demonstrate that mechanical weakness and contraction-induced muscle injury are not required for muscle degeneration and the dystrophic process. Thus, a nonmechanical mechanism, perhaps involving some unknown signaling function, likely is responsible for muscular dystrophy where sarcoglycan is deficient.