Both obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we uncover dysregulated systemic alanine metabolism and hyper-expression of the alanine transaminases (ALT) in the liver of obese/diabetic mice and humans. Hepatocyte-selective silencing of both ALT enzymes revealed a clear role in systemic alanine clearance which related to glycemic control. In obese/diabetic mice, not only did silencing both ALT enzymes retard hyperglycemia, but also reversed skeletal muscle atrophy. This was due to a rescue of depressed skeletal muscle protein synthesis, with a liver-skeletal muscle amino acid metabolic crosstalk exemplified by ex vivo experiments. Mechanistically, chronic liver glucocorticoid and glucagon signaling driven liver alanine catabolism promoted hyperglycemia and skeletal muscle wasting. Taken together, here we reveal an endocrine-hepato-muscular metabolic cycle linking hyperglycemia and skeletal muscle atrophy in type 2 diabetes.

中文翻译：

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内分泌-肝-肌肉代谢循环将2型糖尿病的骨骼肌萎缩和高血糖联系起来

肥胖和肌肉减少症经常与衰老相关，并且一起可以促进诸如糖尿病和虚弱之类的相关疾病的发展。然而，关于这种关联的病理生理机制知之甚少。在这里，我们发现肥胖/糖尿病小鼠和人类肝脏中的全身丙氨酸代谢失调和丙氨酸转氨酶（ALT）的过度表达。两种ALT酶的肝细胞选择性沉默均显示在与血糖控制有关的全身丙氨酸清除中具有明显作用。在肥胖/糖尿病小鼠中，不仅沉默两种ALT酶都可以抑制高血糖症，而且还可以逆转骨骼肌萎缩。这是由于挽救了骨骼肌蛋白质合成降低，并通过体外实验证明了肝脏骨骼肌氨基酸代谢串扰。从机理上讲，慢性肝糖皮质激素和胰高血糖素信号传导驱动的肝丙氨酸分解代谢促进高血糖症和骨骼肌消耗。两者合计，在这里我们揭示了一种内分泌-肝-肌肉代谢循环，将高血糖与2型糖尿病的骨骼肌萎缩联系起来。