a-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway
a-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway
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α-酮戊二酸通过 PHD3/ADRB2 途径防止骨骼肌蛋白降解和肌肉萎缩
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Gang Shu
中科院分区：
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作者：
Xingcai Cai;Yexian Yuan;Zhengrui Liao;Kongping Xing;Canjun Zhu;Yaqiong Xu;Lulu Yu;Lina Wang;Songbo Wang;Xiaotong Zhu;Ping Gao;Yongliang Zhang;Qingyan Jiang;Pingwen Xu;Gang Shu
由于过度蛋白质降解导致的骨骼肌萎缩是肌肉功能障碍、疲劳以及运动能力减弱的主要原因。耐力运动对减轻肌肉萎缩是有效的，但其潜在机制尚未得到充分研究。α - 酮戊二酸（AKG）是三羧酸循环的关键中间产物，在耐力运动过程中产生。在此，我们证明了AKG能有效减轻皮质酮诱导的蛋白质降解，并挽救杜氏肌营养不良小鼠模型中的肌肉萎缩和功能障碍。有趣的是，AKG还抑制了脯氨酸羟化酶3（PHD3）的表达，PHD3是在缺氧条件下表达的重要氧化还原酶之一。随后，我们确定β2 - 肾上腺素能受体（ADRB2）是PHD3的下游靶点。我们发现AKG抑制了PHD3/ADRB2相互作用，从而增加了ADRB2的稳定性。此外，通过结合药理学和遗传学方法，我们表明AKG通过PHD3/ADRB2介导的机制挽救骨骼肌萎缩和蛋白质降解。综上所述，这些数据揭示了AKG对肌肉萎缩和蛋白质降解的抑制作用机制。这些发现不仅为运动产生的代谢物AKG在肌肉萎缩治疗中的潜在应用提供了分子基础，还确定了PHD3作为开发治疗肌肉萎缩疗法的潜在靶点。
Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction,fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. a-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3),one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the b2.adrenergic receptor (ADRB2) as a downstreamtarget for PHD3.We foundAKG inhibitedPHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated.mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise-generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.