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- Title
Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1.
- Authors
Merz, Karla E.; Hwang, Jinhee; Zhou, Chunxue; Veluthakal, Rajakrishnan; McCown, Erika M.; Hamilton, Angelica; Oh, Eunjin; Dai, Wenting; Fueger, Patrick T.; Jiang, Lei; Huss, Janice. M.; Thurmond, Debbie C.
- 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. STX4 is a regulator of the glucose transporter GLUT4 vesicle fusion at the plasma membrane in skeletal muscle. Here, the authors show that skeletal muscle-specific STX4 enrichment reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress.
- Subjects
INSULIN resistance; EXOCYTOSIS; MITOCHONDRIA; INSULIN sensitivity; MITOCHONDRIAL membranes; PANCREATIC beta cells; FOOD consumption; SKELETAL muscle
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-28061-w