Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice.
Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice.
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Serpina3n 的基因过度表达可减轻小鼠的肌营养不良症。
DOI：
10.1093/hmg/ddw005
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发表时间：
2016
影响因子：
3.5
通讯作者：
Molkentin,JefferyD
中科院分区：
文献类型：
--
作者：
Tjondrokoesoemo,Andoria;Schips,Tobias;Kanisicak,Onur;Sargent,MichelleA;Molkentin,JefferyD
肌营养不良（MD）与稳定肌纤维质膜的基因突变有关，例如通过肌营养不良蛋白-糖蛋白复合物（DGC）。这种复合物的不稳定性或膜修复/完整性的缺陷导致钙内流和肌纤维坏死，从而导致进行性营养不良性疾病。MD发病机制还与骨骼肌蛋白酶水平和活性增加有关，这可能通过细胞附着复合物的更大降解来增强肌膜的弱化。在这里，我们观察到的补偿性增加丝氨酸蛋白酶抑制剂Serpina 3 n在小鼠模型的MD和急性肌肉组织损伤后。产生Serpina 3 n肌肉特异性转基因小鼠来模拟这种表达的增加，这降低了营养不良骨骼肌中选择蛋白酶的活性，并保护肌肉免受心脏毒素的急性损伤和mdxorSgcd −/−MD遗传背景中的慢性肌肉疾病。Serpina 3 n转基因减轻了肌肉变性和纤维化，降低了血清肌酸激酶水平，恢复了在跑步机上的跑步能力，并减少了mdx和Sgcd −/−小鼠体内的肌膜渗漏。从机制上讲，我们表明，增加Serpina 3 n促进更大的肌膜膜的完整性和稳定性，在营养不良的小鼠模型与增加膜驻留的整合素，DGC/utrophin-糖蛋白复合物的蛋白质和膜联蛋白A1。因此，Serpina 3 n在损伤或营养不良疾病期间阻断选择的骨骼肌驻留蛋白酶活性的内源性增加，这稳定了肌膜，导致较少的肌纤维变性和增加的再生。这些结果表明使用选择的蛋白酶抑制剂作为治疗MD的策略。
Muscular dystrophy (MD) is associated with mutations in genes that stabilize the myofiber plasma membrane, such as through the dystrophin–glycoprotein complex (DGC). Instability of this complex or defects in membrane repair/integrity leads to calcium influx and myofiber necrosis leading to progressive dystrophic disease. MD pathogenesis is also associated with increased skeletal muscle protease levels and activity that could augment weakening of the sarcolemma through greater degradation of cellular attachment complexes. Here, we observed a compensatory increase in the serine protease inhibitor Serpina3n in mouse models of MD and after acute muscle tissue injury. Serpina3n muscle-specific transgenic mice were generated to model this increase in expression, which reduced the activity of select proteases in dystrophic skeletal muscle and protected muscle from both acute injury with cardiotoxin and from chronic muscle disease in themdxorSgcd−/−MD genetic backgrounds. The Serpina3n transgene mitigated muscle degeneration and fibrosis, reduced creatine kinase serum levels, restored running capacity on a treadmill and reduced muscle membrane leakinessin vivothat is characteristic ofmdxandSgcd−/−mice. Mechanistically, we show that increased Serpina3n promotes greater sarcolemma membrane integrity and stability in dystrophic mouse models in association with increased membrane residence of the integrins, the DGC/utrophin–glycoprotein complex of proteins and annexin A1. Hence, Serpina3n blocks endogenous increases in the activity of select skeletal muscle resident proteases during injury or dystrophic disease, which stabilizes the sarcolemma leading to less myofiber degeneration and increased regeneration. These results suggest the use of select protease inhibitors as a strategy for treating MD.