Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways
Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways
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DOI：
10.1128/mcb.00983-10
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发表时间：
2011-02-01
影响因子：
5.3
通讯作者：
White, Morris F.
中科院分区：
文献类型：
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作者：
Long, Yun Chau;Cheng, Zhiyong;White, Morris F.
骨骼肌的生长和代谢与营养的有效性的协调是代谢稳态的关键。为了确定胰岛素样信号在这一过程中的作用，我们使用肌肉肌酸激酶（MCK）-Cre来破坏小鼠骨骼肌/心肌中胰岛素受体底物Irs 1和Irs 2的表达。在2周龄的小鼠中，骨骼肌质量和胰岛素反应受到Irs 1的轻微影响，但不受Irs 2缺乏的影响。相反，Irs 1和Irs 2的联合缺乏（MDKO小鼠）严重降低了骨骼肌生长和Akt -> mTOR信号传导，并导致3周龄死亡。MDKO小鼠的尸检揭示了扩张型心肌病，反映了已知的心脏功能对胰岛素样信号传导的需求（P.G. Laustsen等人，摩尔Cell. 27：1649-1664，2007）。MDKO骨骼肌的生长和功能受损伴随着Foxo依赖性atrogene表达和氨基酸释放增加。MDKO小鼠对注射的胰岛素有抗性，其分离的骨骼肌显示胰岛素刺激的葡萄糖摄取减少。MDKO小鼠和分离的骨骼肌中的葡萄糖利用从氧化转变为乳酸产生，伴随着AMP/ATP比率的升高，这增加了AMP活化蛋白激酶（AMPK）->乙酰辅酶A羧化酶（ACC）磷酸化和脂肪酸氧化。因此，胰岛素样信号通过Irs 1/2是必不可少的终止骨骼肌分解代谢/禁食途径在存在足够的营养。
Coordination of skeletal muscle growth and metabolism with nutrient availability is critical for metabolic homeostasis. To establish the role of insulin-like signaling in this process, we used muscle creatine kinase (MCK)-Cre to disrupt expression of insulin receptor substrates Irs1 and Irs2 in mouse skeletal/cardiac muscle. In 2-week-old mice, skeletal muscle masses and insulin responses were slightly affected by Irs1, but not Irs2, deficiency. In contrast, the combined deficiency of Irs1 and Irs2 (MDKO mice) severely reduced skeletal muscle growth and Akt -> mTOR signaling and caused death by 3 weeks of age. Autopsy of MDKO mice revealed dilated cardiomyopathy, reflecting the known requirement of insulin-like signaling for cardiac function (P. G. Laustsen et al., Mol. Cell. Biol. 27:1649-1664, 2007). Impaired growth and function of MDKO skeletal muscle were accompanied by increased Foxo-dependent atrogene expression and amino acid release. MDKO mice were resistant to injected insulin, and their isolated skeletal muscles showed decreased insulin-stimulated glucose uptake. Glucose utilization in MDKO mice and isolated skeletal muscles was shifted from oxidation to lactate production, accompanied by an elevated AMP/ATP ratio that increased AMP-activated protein kinase (AMPK)-> acetyl coenzyme A carboxylase (ACC) phosphorylation and fatty acid oxidation. Thus, insulin-like signaling via Irs1/2 is essential to terminate skeletal muscle catabolic/fasting pathways in the presence of adequate nutrition.