Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice

Takayoshi Sasako, Toshihiro Umehara, Kotaro Soeda, Kazuma Kaneko, Miho Suzuki, Naoki Kobayashi, Yukiko Okazaki, Miwa Tamura-Nakano, Tomoki Chiba, Domenico Accili, C. Ronald Kahn, Tetsuo Noda, Hiroshi Asahara, Toshimasa Yamauchi, Takashi Kadowaki () and Kohjiro Ueki ()
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Takayoshi Sasako: The University of Tokyo
Toshihiro Umehara: The University of Tokyo
Kotaro Soeda: The University of Tokyo
Kazuma Kaneko: The University of Tokyo
Miho Suzuki: The University of Tokyo
Naoki Kobayashi: National Center for Global Health and Medicine
Yukiko Okazaki: The University of Tokyo
Miwa Tamura-Nakano: National Center for Global Health and Medicine
Tomoki Chiba: Tokyo Medical and Dental University
Domenico Accili: Columbia University College of Physicians & Surgeons, Department of Medicine
C. Ronald Kahn: Harvard Medical School
Tetsuo Noda: Japanese Foundation of Cancer Research
Hiroshi Asahara: Tokyo Medical and Dental University
Toshimasa Yamauchi: The University of Tokyo
Takashi Kadowaki: The University of Tokyo
Kohjiro Ueki: National Center for Global Health and Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33008-2

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DOI: 10.1038/s41467-022-33008-2

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