Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis
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DOI：
10.1172/jci86522
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
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作者：
O'Neill, Brian T.;Lee, Kevin Y.;Kahn, C. Ronald
糖尿病严重影响蛋白质代谢，特别是骨骼肌。胰岛素和IGF-1通过它们的受体增强肌肉蛋白质合成，但它们各自在肌肉蛋白质稳态中的相对作用尚未完全阐明。使用肌肉特异性缺失胰岛素受体（M-IR-/-小鼠）、IGF-1受体（M-IGF 1 R（-/-）小鼠）或两者（MIGIRKO小鼠）的小鼠，我们评估了IR和IGF 1 R信号传导对肌肉蛋白质稳态的相对贡献。在分化的肌肉中，IR表达占主导地位，IGF 1 R的表达，相应地，M-IR-/-小鼠显示肌肉质量中度减少，而M-IGF 1 R（-/-）小鼠没有。然而，这些受体发挥互补作用，使得双敲除MIGIRKO小鼠显示肌肉质量显著减少，这与蛋白酶体和自噬-溶酶体降解增加有关，并伴有高蛋白质周转状态。MIGIRKO小鼠中Fox 01、Fox 03和Fox 04的组合肌肉特异性缺失逆转了增加的自噬并完全挽救了肌肉质量，而不改变蛋白酶体活性。这些数据表明，通过IR的信号比IGF 1 R在控制分化的肌肉中的蛋白质稳态中更重要。尽管如此，IR和IGF 1 R信号的重叠对于肌肉蛋白质周转的调节至关重要，并且这种调节依赖于FoxO调节的自噬介导的蛋白质降解的抑制。
Diabetes strongly impacts protein metabolism, particularly in skeletal muscle. Insulin and IGF-1 enhance muscle protein synthesis through their receptors, but the relative roles of each in muscle proteostasis have not been fully elucidated. Using mice with muscle-specific deletion of the insulin receptor (M-IR-/- mice), the IGF-1 receptor (M-IGF1R(-/-) mice), or both (MIGIRKO mice), we assessed the relative contributions of IR and IGF1R signaling to muscle proteostasis. In differentiated muscle, IR expression predominated over IGF1R expression, and correspondingly, M-IR-/- mice displayed a moderate reduction in muscle mass whereas M-IGF1R(-/-) mice did not. However, these receptors serve complementary roles, such that double-knockout MIGIRKO mice displayed a marked reduction in muscle mass that was linked to increases in proteasomal and autophagy-lysosomal degradation, accompanied by a high-protein-turnover state. Combined muscle-specific deletion of Fox01, Fox03, and Fox04 in MIGIRKO mice reversed increased autophagy and completely rescued muscle mass without changing proteasomal activity. These data indicate that signaling via IR is more important than IGF1R in controlling proteostasis in differentiated muscle. Nonetheless, the overlap of IR and IGF1R signaling is critical to the regulation of muscle protein turnover, and this regulation depends on suppression of FoxO-regulated, autophagy-mediated protein degradation.