Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1/2, key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1/4, but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan.

人们认为低等生物体中的胰岛素信号会加速衰老，但尚不清楚这是否适用于哺乳动物。在这里，我们展示了具有骨骼肌特异性双基因敲除Akt1 / 2（胰岛素信号传导的关键下游分子）的小鼠，作为具有胰岛素抵抗的过早肌肉减少症的模型。敲除小鼠表现出骨骼肌质量逐渐减少、运动功能受损和全身胰岛素敏感性。他们还表现出骨质减少和寿命缩短，这主要是由于正常饮食导致的虚弱死亡和高脂肪饮食导致的肿瘤死亡。这些表型几乎可以通过额外敲除Foxo1 / 4来逆转，但只能部分通过额外敲除Tsc2激活 mTOR 通路。总体而言，我们的数据表明，与低等生物不同，与胰岛素抵抗和衰老相关的哺乳动物骨骼肌中 Akt 活性的抑制可能会加速骨质疏松症，从而缩短寿命。