Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
PLoS One. 2013 Aug 1;8(8):e71017. doi: 10.1371/journal.pone.0071017. Print 2013.
Genetic disruption of myostatin or its related signaling is known to cause strong protection against diet-induced metabolic disorders. The translational value of these prior findings, however, is dependent on whether such metabolically favorable phenotype can be reproduced when myostatin blockade begins at an adult age. Here, we reported that AAV-mediated delivery of a myostatin pro-peptide D76A mutant in adult mice attenuates the development of hepatic steatosis and arteriosclerosis, two common diet-induced metabolic diseases. A single dose of AAV-D76A in adult Ldlr null mice resulted in sustained expression of myostatin pro-peptide in the liver. Compared to vehicle-treated mice, D76A-treated mice gained similar amount of lean and fat mass when fed a high fat diet. However, D76A-treated mice displayed significantly reduced aortic lesions and liver fat, in association with a reduction in hepatic expression of lipogenic genes and improvement in liver insulin sensitivity. This suggests that muscle and fat may not be the primary targets of treatment under our experimental condition. In support to this argument, we show that myostatin directly up-regulated lipogenic genes and increased fat accumulation in cultured liver cells. We also show that both myostatin and its receptor were abundantly expressed in mouse aorta. Cultured aortic endothelial cells responded to myostatin with a reduction in eNOS phosphorylation and an increase in ICAM-1 and VCAM-1 expression.
AAV-mediated expression of myostatin pro-peptide D76A mutant in adult Ldlr null mice sustained metabolic protection without remarkable impacts on body lean and fat mass. Further investigations are needed to determine whether direct impact of myostatin on liver and aortic endothelium may contribute to the related metabolic phenotypes.
已知肌抑素或其相关信号的遗传破坏会导致强烈的保护作用，防止饮食引起的代谢紊乱。然而，这些先前发现的转化价值取决于在成年期开始阻断肌抑素时，是否可以再现这种代谢有利的表型。在这里，我们报告说，在成年小鼠中，AAV 介导的肌抑素前肽 D76A 突变体的传递可减轻两种常见的饮食诱导的代谢疾病——肝脂肪变性和动脉硬化的发展。在成年 LDLR 基因敲除小鼠中单次给予 AAV-D76A 可导致肝脏中肌抑素前肽的持续表达。与载体处理的小鼠相比，D76A 处理的小鼠在喂食高脂肪饮食时获得了相似数量的瘦体重和脂肪量。然而，与对照组相比，D76A 处理的小鼠的主动脉病变和肝脂肪明显减少，与肝内脂质生成基因的表达减少和肝胰岛素敏感性的改善有关。这表明，在我们的实验条件下，肌肉和脂肪可能不是治疗的主要靶点。为了支持这一观点，我们表明肌抑素可直接上调脂质生成基因并增加培养的肝细胞中的脂肪积累。我们还表明，肌抑素及其受体在小鼠主动脉中均大量表达。培养的主动脉内皮细胞对肌抑素的反应是 eNOS 磷酸化减少，ICAM-1 和 VCAM-1 表达增加。
在成年 LDLR 基因敲除小鼠中，AAV 介导的肌抑素前肽 D76A 突变体的表达可维持代谢保护，而对瘦体重和脂肪量没有显著影响。需要进一步研究以确定肌抑素对肝脏和主动脉内皮细胞的直接影响是否有助于相关的代谢表型。
