Morissette Michael R, Cook Stuart A, Buranasombati Cattleya, Rosenberg Michael A, Rosenzweig Anthony
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Am J Physiol Cell Physiol. 2009 Nov;297(5):C1124-32. doi: 10.1152/ajpcell.00043.2009. Epub 2009 Sep 16.
Myostatin is a highly conserved negative regulator of skeletal muscle growth. Loss of functional myostatin in cattle, mice, sheep, dogs, and humans results in increased muscle mass. The molecular mechanisms responsible for this increase in muscle growth are not fully understood. Previously, we have reported that phenylephrine-induced cardiac muscle growth and Akt activation are enhanced in myostatin knockout mice compared with controls. Here we report that skeletal muscle from myostatin knockout mice show increased Akt protein expression and overall activity at baseline secondary to an increase in Akt mRNA. We examined the functional role of myostatin modulation of Akt in C2C12 myotubes, a well-established in vitro model of skeletal muscle hypertrophy. Adenoviral overexpression of myostatin attenuated the insulin-like growth factor-I (IGF-I)-mediated increase in myotube diameter, as well as IGF-I-stimulated Akt phosphorylation. Inhibition of myostatin by overexpression of the NH(2)-terminal portion of myostatin was sufficient to increase myotube diameter and Akt phosphorylation. Coexpression of myostatin and constitutively active Akt (myr-Akt) restored the increase in myotube diameter. Conversely, expression of dominant negative Akt (dn-Akt) with the inhibitory myostatin propeptide blocked the increase in myotube diameter. Of note, ribosomal protein S6 phosphorylation and atrogin-1/muscle atrophy F box mRNA were increased in skeletal muscle from myostain knockout mice. Together, these data suggest myostatin regulates muscle growth at least in part through regulation of Akt.
肌生成抑制素是骨骼肌生长的一种高度保守的负调节因子。牛、小鼠、绵羊、狗和人类中功能性肌生成抑制素的缺失会导致肌肉量增加。导致肌肉生长增加的分子机制尚未完全明确。此前，我们报道过，与对照组相比，苯肾上腺素诱导的心肌生长和Akt激活在肌生成抑制素基因敲除小鼠中增强。在此我们报道，肌生成抑制素基因敲除小鼠的骨骼肌在基线时显示Akt蛋白表达增加且总体活性增强，这继发于Akt mRNA的增加。我们在C2C12肌管（一种成熟的骨骼肌肥大体外模型）中研究了肌生成抑制素对Akt调节的功能作用。腺病毒介导的肌生成抑制素过表达减弱了胰岛素样生长因子-I（IGF-I）介导的肌管直径增加以及IGF-I刺激的Akt磷酸化。通过肌生成抑制素氨基末端部分的过表达来抑制肌生成抑制素足以增加肌管直径和Akt磷酸化。肌生成抑制素与组成型活性Akt（myr-Akt）的共表达恢复了肌管直径的增加。相反，显性负性Akt（dn-Akt）与抑制性肌生成抑制素前肽的表达阻断了肌管直径的增加。值得注意的是，肌生成抑制素基因敲除小鼠骨骼肌中的核糖体蛋白S6磷酸化以及萎缩基因1/肌肉萎缩F盒mRNA增加。这些数据共同表明，肌生成抑制素至少部分通过对Akt的调节来调控肌肉生长。
