Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass
Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass
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DOI：
10.1172/jci.insight.85477
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发表时间：
2016-04-21
期刊：
影响因子：
8
通讯作者：
Gregorevic, Paul
中科院分区：
文献类型：
--
作者：
Davey, Jonathan R.;Watt, Kevin I.;Gregorevic, Paul
转化生长因子- β (tgf - β)信号网络是骨骼肌质量和功能的关键调节因子，因此是对抗肌肉疾病的一个有吸引力的治疗靶点，但其潜在的作用机制尚不确定。我们报道基于卵泡抑素的干预（调节tgf - β网络活动）可以促进肌肉肥大，从而改善与衰老相关的肌肉萎缩。然而，与健康的年轻成人肌肉组织相比，老年肌肉减少小鼠的肌肉对卵泡抑素的反应降低。定量蛋白质组学和转录组学分析发现，暴露于卵泡抑素会引发转录/翻译特征，包括抑制锚蛋白重复序列和SOCS盒蛋白2 （Asb2）。增加ASB2的表达减少了肌肉质量，从而证明ASB2是tgf - β网络响应的肌肉质量负调节因子。与年轻人的肌肉相比，肌肉减少症的肌肉在暴露于卵泡抑素后不会表现出ASB2丰度的降低。此外，防止青壮年肌肉中ASB2的抑制可减少卵泡抑素诱导的肌肉肥大。这些发现为调控卵泡抑素介导的骨骼肌属性适应的转录和翻译事件提供了深入的见解，并确定Asb2是肌肉质量的调节剂，涉及卵泡抑素介导的年轻和老年肌肉生长之间潜在的机制功能障碍。
The transforming growth factor-beta (TGF-beta) signaling network is a critical regulator of skeletal muscle mass and function and, thus, is an attractive therapeutic target for combating muscle disease, but the underlying mechanisms of action remain undetermined. We report that follistatin-based interventions (which modulate TGF-beta network activity) can promote muscle hypertrophy that ameliorates aging-associated muscle wasting. However, the muscles of old sarcopenic mice demonstrate reduced response to follistatin compared with healthy young-adult musculature. Quantitative proteomic and transcriptomic analyses of young-adult muscles identified a transcription/translation signature elicited by follistatin exposure, which included repression of ankyrin repeat and SOCS box protein 2 (Asb2). Increasing expression of ASB2 reduced muscle mass, thereby demonstrating that Asb2 is a TGF-beta network-responsive negative regulator of muscle mass. In contrast to young-adult muscles, sarcopenic muscles do not exhibit reduced ASB2 abundance with follistatin exposure. Moreover, preventing repression of ASB2 in young-adult muscles diminished follistatin-induced muscle hypertrophy. These findings provide insight into the program of transcription and translation events governing follistatin-mediated adaptation of skeletal muscle attributes and identify Asb2 as a regulator of muscle mass implicated in the potential mechanistic dysfunction between follistatin-mediated muscle growth in young and old muscles.