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

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 and Debbie C. Thurmond ()
Additional contact information
Karla E. Merz: Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope
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
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
Debbie C. Thurmond: Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28061-w

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