Hosaka Yukio, Yokota Toshifumi, Miyagoe-Suzuki Yuko, Yuasa Katsutoshi, Imamura Michihiro, Matsuda Ryoichi, Ikemoto Takaaki, Kameya Shuhei, Takeda Shin'ichi
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira 187-8502, Tokyo, Japan.
J Cell Biol. 2002 Sep 16;158(6):1097-107. doi: 10.1083/jcb.200204076. Epub 2002 Sep 9.
Alpha1-syntrophin is a member of the family of dystrophin-associated proteins; it has been shown to recruit neuronal nitric oxide synthase and the water channel aquaporin-4 to the sarcolemma by its PSD-95/SAP-90, Discs-large, ZO-1 homologous domain. To examine the role of alpha1-syntrophin in muscle regeneration, we injected cardiotoxin into the tibialis anterior muscles of alpha1-syntrophin-null (alpha1syn-/-) mice. After the treatment, alpha1syn-/- muscles displayed remarkable hypertrophy and extensive fiber splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change. In the hypertrophied muscles of the mutant mice, the level of insulin-like growth factor-1 transcripts was highly elevated. Interestingly, in an early stage of the regeneration process, alpha1syn-/- mice showed remarkably deranged neuromuscular junctions (NMJs), accompanied by impaired ability to exercise. The contractile forces were reduced in alpha1syn-/- regenerating muscles. Our results suggest that the lack of alpha1-syntrophin might be responsible in part for the muscle hypertrophy, abnormal synapse formation at NMJs, and reduced force generation during regeneration of dystrophin-deficient muscle, all of which are typically observed in the early stages of Duchenne muscular dystrophy patients.
α1- syntrophin是肌营养不良蛋白相关蛋白家族的成员之一；研究表明，它通过其PSD - 95/SAP - 90、盘状大蛋白、ZO - 1同源结构域将神经元型一氧化氮合酶和水通道蛋白-4募集到肌膜上。为了研究α1- syntrophin在肌肉再生中的作用，我们将心脏毒素注射到α1- syntrophin基因敲除（α1syn-/-）小鼠的胫前肌中。处理后，与野生型再生肌肉相比，α1syn-/-肌肉出现了明显的肥大和广泛的肌纤维分裂，尽管突变小鼠未处理的肌肉没有明显的组织学变化。在突变小鼠的肥大肌肉中，胰岛素样生长因子-1转录本水平显著升高。有趣的是，在再生过程的早期阶段，α1syn-/-小鼠表现出明显紊乱的神经肌肉接头（NMJ），同时伴有运动能力受损。α1syn-/-再生肌肉的收缩力降低。我们的结果表明，α1- syntrophin的缺失可能部分导致了肌营养不良蛋白缺乏的肌肉在再生过程中的肌肉肥大、NMJ处异常突触形成以及力产生减少，所有这些都是杜兴氏肌营养不良患者早期阶段的典型表现。
