IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33008-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33008-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-33008-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Giulia Milan & Vanina Romanello & Francesca Pescatore & Andrea Armani & Ji-Hye Paik & Laura Frasson & Anke Seydel & Jinghui Zhao & Reimar Abraham & Alfred L. Goldberg & Bert Blaauw & Ronald A. DePinho, 2015. "Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
    2. Takayoshi Sasako & Mitsuru Ohsugi & Naoto Kubota & Shinsuke Itoh & Yukiko Okazaki & Ai Terai & Tetsuya Kubota & Satoshi Yamashita & Kunio Nakatsukasa & Takumi Kamura & Kaito Iwayama & Kumpei Tokuyama , 2019. "Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    3. Judith Campisi & Pankaj Kapahi & Gordon J. Lithgow & Simon Melov & John C. Newman & Eric Verdin, 2019. "From discoveries in ageing research to therapeutics for healthy ageing," Nature, Nature, vol. 571(7764), pages 183-192, July.
    4. Paul Krimpenfort & Annemieke IJpenberg & Ji-Ying Song & Martin van der Valk & Martijn Nawijn & John Zevenhoven & Anton Berns, 2007. "p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a," Nature, Nature, vol. 448(7156), pages 943-946, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Scott, Andrew J., 2023. "The economics of longevity – An introduction," The Journal of the Economics of Ageing, Elsevier, vol. 24(C).
    2. Kotaro Soeda & Takayoshi Sasako & Kenichiro Enooku & Naoto Kubota & Naoki Kobayashi & Yoshiko Matsumoto Ikushima & Motoharu Awazawa & Ryotaro Bouchi & Gotaro Toda & Tomoharu Yamada & Takuma Nakatsuka , 2023. "Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Old, Jonathan & Scott, Andrew, 2023. "Healthy ageing trends in England between 2002 to 2018: Improving but slowing and unequal," Department of Economics, Working Paper Series qt759110mx, Department of Economics, Institute for Business and Economic Research, UC Berkeley.
    4. Jinjie Duan & Wenhui Dong & Guangyan Wang & Wenjing Xiu & Guangyin Pu & Jingwen Xu & Chenji Ye & Xu Zhang & Yi Zhu & Chunjiong Wang, 2023. "Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Rupesh S. Patel & Rodrigo Romero & Emma V. Watson & Anthony C. Liang & Megan Burger & Peter M. K. Westcott & Kim L. Mercer & Roderick T. Bronson & Eric C. Wooten & Arjun Bhutkar & Tyler Jacks & Stephe, 2022. "A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Zi Wang & Lina Zou & Yiyan Zhang & Mengnan Zhu & Shuxian Zhang & Di Wu & Jianfeng Lan & Xiao Zang & Qi Wang & Hanxin Zhang & Zixing Wu & Huanhu Zhu & Di Chen, 2023. "ACS-20/FATP4 mediates the anti-ageing effect of dietary restriction in C. elegans," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Hina Kosakamoto & Fumiaki Obata & Junpei Kuraishi & Hide Aikawa & Rina Okada & Joshua N. Johnstone & Taro Onuma & Matthew D. W. Piper & Masayuki Miura, 2023. "Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Qing Zou & Yingsi Lai & Zhao-Rong Lun, 2023. "Exploring the Association between Oxygen Concentration and Life Expectancy in China: A Quantitative Analysis," IJERPH, MDPI, vol. 20(2), pages 1-13, January.
    9. Jean-Philippe Leduc-Gaudet & Anais Franco-Romero & Marina Cefis & Alaa Moamer & Felipe E. Broering & Giulia Milan & Roberta Sartori & Tomer Jordi Chaffer & Maude Dulac & Vincent Marcangeli & Dominique, 2023. "MYTHO is a novel regulator of skeletal muscle autophagy and integrity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Seoyeon Lee & Mohammad Naimul Islam & Kaveh Boostanpour & Dvir Aran & Guangchun Jin & Stephanie Christenson & Michael A. Matthay & Walter L. Eckalbar & Daryle J. DePianto & Joseph R. Arron & Liam Mage, 2021. "Molecular programs of fibrotic change in aging human lung," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    11. Haiwen Li & Peipei Wang & Chen Zhang & Yuanbojiao Zuo & Yuan Zhou & Renzhi Han, 2023. "Defective BVES-mediated feedback control of cAMP in muscular dystrophy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    12. Damien S. E. Broekharst & Sjaak Bloem & Marije Blok & Mariët Raatgever & Nathascha Hanzen & Jasmien J. E. de Vette, 2023. "Determining the Appropriate Support for Older Adults with Different Levels of Vitality and Health-Related Quality of Life: An Explanatory Study," IJERPH, MDPI, vol. 20(11), pages 1-11, June.
    13. Xueqing Wang & Quanlong Jiang & Hongdao Zhang & Zhidong He & Yuanyuan Song & Yifan Chen & Na Tang & Yifei Zhou & Yiping Li & Adam Antebi & Ligang Wu & Jing-Dong J. Han & Yidong Shen, 2024. "Tissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    14. Naina Bhatia-Dey & Thomas Heinbockel, 2021. "The Olfactory System as Marker of Neurodegeneration in Aging, Neurological and Neuropsychiatric Disorders," IJERPH, MDPI, vol. 18(13), pages 1-15, June.
    15. Betz, Ulrich A.K. & Arora, Loukik & Assal, Reem A. & Azevedo, Hatylas & Baldwin, Jeremy & Becker, Michael S. & Bostock, Stefan & Cheng, Vinton & Egle, Tobias & Ferrari, Nicola & Schneider-Futschik, El, 2023. "Game changers in science and technology - now and beyond," Technological Forecasting and Social Change, Elsevier, vol. 193(C).
    16. Old, Jonathan & Scott, Andrew, 2023. "Healthy ageing trends in England between 2002 to 2018: Improving but slowing and unequal," The Journal of the Economics of Ageing, Elsevier, vol. 26(C).
    17. Cox, Lynne S., 2022. "Therapeutic approaches to treat and prevent age-related diseases through understanding the underlying biological drivers of ageing," The Journal of the Economics of Ageing, Elsevier, vol. 23(C).
    18. Jorge Navarro & Miguel Cañete & Francisco J. Olivera & Marta Gil-Lacruz & Ana Gil-Lacruz & Pedro C. Marijuán, 2022. "The Cost of Loneliness: Assessing the Social Relationships of the Elderly via an Abbreviated Sociotype Questionnaire for inside and outside the Clinic," IJERPH, MDPI, vol. 19(3), pages 1-15, January.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33008-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.