Chandraskeharan Kumaran, Martin Paul T
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Ohio State University College of Medicine, Columbus, Ohio 43205, USA.
Muscle Nerve. 2009 Jan;39(1):25-41. doi: 10.1002/mus.21198.
Many proteins that affect skeletal muscle growth are secreted glycoproteins, yet the nature of how glycosylation regulates the expression and growth-promoting properties of such factors is not well understood. One type of glycosylation that affects muscle growth is that controlled by the CT GalNAc transferase (Galgt2), the enzyme responsible for the synthesis of the beta1,4GalNAc linkage on the CT carbohydrate antigen (GalNAcbeta1,4[Neu5Ac(or Gc)alpha2,3]Galbeta1,4GlcNAcbeta-R). In the mouse, both Galgt2 protein and the CT carbohydrate become confined to the neuromuscular synapse in skeletal muscle by the second postnatal week. Galgt2 transgenic mice that overexpress the CT carbohydrate from embryonic time-points onward in skeletal muscle had profoundly impaired muscle growth that was maintained throughout adulthood. Transgenic overexpression of Galgt2 increased myostatin protein expression and stimulated myostatin signaling, whereas expression of follistatin protein, a myostatin inhibitor, was decreased. Changed myostatin and follistatin protein levels were controlled at a posttranslational level, and inhibition of muscle growth was overcome if serum follistatin levels were normalized to wild-type levels. In contrast to embryonic Galgt2 overexpression, postnatal overexpression of Galgt2 had no effect on either myostatin or follistatin expression or muscle growth. These experiments demonstrate that Galgt2 can control growth by modulating the expression of myostatin and myostatin inhibitors during particular periods of muscle development.
许多影响骨骼肌生长的蛋白质都是分泌型糖蛋白，然而糖基化如何调节这些因子的表达和促进生长特性的本质尚未得到充分理解。一种影响肌肉生长的糖基化类型是由CT GalNAc转移酶（Galgt2）控制的，该酶负责在CT碳水化合物抗原（GalNAcbeta1,4[Neu5Ac(或Gc)alpha2,3]Galbeta1,4GlcNAcbeta-R）上合成β1,4GalNAc连接。在小鼠中，到出生后第二周时，Galgt2蛋白和CT碳水化合物都局限于骨骼肌的神经肌肉突触。从胚胎期开始就在骨骼肌中过表达CT碳水化合物的Galgt2转基因小鼠，其肌肉生长受到严重损害，且这种损害在成年期一直持续。Galgt2的转基因过表达增加了肌肉生长抑制素蛋白的表达并刺激了肌肉生长抑制素信号传导，而肌肉生长抑制素抑制剂卵泡抑素蛋白的表达则降低。肌肉生长抑制素和卵泡抑素蛋白水平的变化是在翻译后水平受到控制的，如果血清卵泡抑素水平恢复到野生型水平，则可以克服对肌肉生长的抑制。与胚胎期Galgt2过表达相反，出生后Galgt2过表达对肌肉生长抑制素或卵泡抑素的表达以及肌肉生长均无影响。这些实验表明，Galgt2可以在肌肉发育的特定时期通过调节肌肉生长抑制素和肌肉生长抑制素抑制剂的表达来控制生长。
