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

Author

Listed:
  • Takayoshi Sasako

    (The University of Tokyo
    National Center for Global Health and Medicine)

  • Toshihiro Umehara

    (The University of Tokyo)

  • Kotaro Soeda

    (The University of Tokyo
    National Center for Global Health and Medicine)

  • 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
    Toranomon Hospital)

  • Kohjiro Ueki

    (National Center for Global Health and Medicine
    The University of Tokyo)

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.

Suggested Citation

  • 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 Nod, 2022. "Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33008-2
    DOI: 10.1038/s41467-022-33008-2
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    References listed on IDEAS

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