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Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1

Author

Listed:
  • Karla E. Merz

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope
    Irell and Manella Graduate School of Biological Sciences, City of Hope
    Amgen)

  • Jinhee Hwang

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Chunxue Zhou

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Rajakrishnan Veluthakal

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Erika M. McCown

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Angelica Hamilton

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Eunjin Oh

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Wenting Dai

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Patrick T. Fueger

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope
    Comprehensive Metabolic Phenotyping Core, Beckman Research Institute of City of Hope)

  • Lei Jiang

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

  • Janice. M. Huss

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope
    Washington University School of Medicine)

  • Debbie C. Thurmond

    (Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope)

Abstract

Mitochondrial dysfunction is implicated in skeletal muscle insulin resistance. Syntaxin 4 (STX4) levels are reduced in human diabetic skeletal muscle, and global transgenic enrichment of STX4 expression improves insulin sensitivity in mice. Here, we show that transgenic skeletal muscle-specific STX4 enrichment (skmSTX4tg) in mice reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress. Specifically, skmSTX4tg reversed insulin resistance caused by high-fat diet (HFD) without altering body weight or food consumption. Electron microscopy of wild-type mouse muscle revealed STX4 localisation at or proximal to the mitochondrial membrane. STX4 enrichment prevented HFD-induced mitochondrial fragmentation and dysfunction through a mechanism involving STX4-Drp1 interaction and elevated AMPK-mediated phosphorylation at Drp1 S637, which favors fusion. Our findings challenge the dogma that STX4 acts solely at the plasma membrane, revealing that STX4 localises at/proximal to and regulates the function of mitochondria in muscle. These results establish skeletal muscle STX4 enrichment as a candidate therapeutic strategy to reverse peripheral insulin resistance.

Suggested Citation

  • Karla E. Merz & Jinhee Hwang & Chunxue Zhou & Rajakrishnan Veluthakal & Erika M. McCown & Angelica Hamilton & Eunjin Oh & Wenting Dai & Patrick T. Fueger & Lei Jiang & Janice. M. Huss & Debbie C. Thur, 2022. "Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28061-w
    DOI: 10.1038/s41467-022-28061-w
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    Cited by:

    1. Xiaofan Yu & Gabrielle Benitez & Peter Tszki Wei & Sofia V. Krylova & Ziyi Song & Li Liu & Meifan Zhang & Alus M. Xiaoli & Henna Wei & Fenfen Chen & Simone Sidoli & Fajun Yang & Kosaku Shinoda & Jeffr, 2024. "Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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