Department of Integrative Biology and Physiology and 2 Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.
J Cell Biol. 2012 Jun 25;197(7):1009-27. doi: 10.1083/jcb.201110032.
Utrophin is normally confined to the neuromuscular junction (NMJ) in adult muscle and partially compensates for the loss of dystrophin in mdx mice. We show that Akt signaling and utrophin levels were diminished in sarcospan (SSPN)-deficient muscle. By creating several transgenic and knockout mice, we demonstrate that SSPN regulates Akt signaling to control utrophin expression. SSPN determined α-dystroglycan (α-DG) glycosylation by affecting levels of the NMJ-specific glycosyltransferase Galgt2. After cardiotoxin (CTX) injury, regenerating myofibers express utrophin and Galgt2-modified α-DG around the sarcolemma. SSPN-null mice displayed delayed differentiation after CTX injury caused by loss of utrophin and Akt signaling. Treatment of SSPN-null mice with viral Akt increased utrophin and restored muscle repair after injury, revealing an important role for the SSPN-Akt-utrophin signaling axis in regeneration. SSPN improved cell surface expression of utrophin by increasing transportation of utrophin and DG from endoplasmic reticulum/Golgi membranes. Our experiments reveal functions of utrophin in regeneration and new pathways that regulate utrophin expression at the cell surface.
肌联蛋白在成人肌肉中通常局限于神经肌肉接点（NMJ），并在 mdx 小鼠中部分补偿肌营养不良蛋白的缺失。我们发现肌联蛋白缺失会导致 Akt 信号和肌联蛋白水平降低。通过创建几种转基因和敲除小鼠，我们证明肌联蛋白调节 Akt 信号以控制肌联蛋白的表达。肌联蛋白通过影响 NMJ 特异性糖基转移酶 Galgt2 的水平来决定 α- 连接蛋白聚糖（α-DG）的糖基化。在心脏毒素（CTX）损伤后，再生肌纤维在肌膜周围表达肌联蛋白和 Galgt2 修饰的 α-DG。肌联蛋白缺失的小鼠在 CTX 损伤后由于肌联蛋白和 Akt 信号的缺失而表现出分化延迟。用病毒 Akt 治疗肌联蛋白缺失的小鼠可增加肌联蛋白的表达，并在损伤后恢复肌肉修复，这表明 SSPN-Akt-肌联蛋白信号轴在再生中起着重要作用。肌联蛋白通过增加内质网/高尔基体膜上肌联蛋白和 DG 的运输，提高肌联蛋白在细胞表面的表达。我们的实验揭示了肌联蛋白在再生中的功能以及调节细胞表面肌联蛋白表达的新途径。
