![]() ![]() ![]() Thus, it is assumed that not only insulin signaling but also IGF-1 signaling are impaired in patients with insulin resistance. Most transducers of the signaling cascade are shared by insulin and IGF-1: insulin receptor (IR) and IGF-1 receptor (IGF1R) phosphorylate insulin receptor substrates (IRSs), which activate phosphoinositide 3-kinase and its downstream Akt, resulting in inactivation of FoxOs involved in protein degradation, as well as in activation of mTOR involved in protein synthesis 10, 11. Sarcopenia, in its turn, is thought to be one of the main causes of insulin resistance in older subjects because glucose uptake in an absorptive state is attributed in large part to skeletal muscle, while it is known to be impaired in patients with diabetes, resulting in glucose intolerance and hyperglycemia 8, 9. ![]() Moreover, restoration, not inhibition, of IGF-1 was assumed to represent a promising therapeutic approach to sarcopenia 5. Sarcopenia is known to be promoted in patients with diabetes in which insulin action is impaired but likely to be ameliorated by treatment with insulin sensitizers 7. Indeed, impaired action of insulin/IGF-1 signaling is counted among the potential mechanisms underlying the development of sarcopenia, a major phenomenon associated with aging, which is characterized by decreased mass and impaired function of skeletal muscle 3, 4, 5, 6. 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.įindings from lower organisms have shown that insulin and insulin-like growth factor-1 (IGF-1) signaling accelerates aging 1, 2, but it remains unclear whether this could also be entirely true for mammals. 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. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. 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. Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. ![]()
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