ZAG promotes exercise performance during endurance exercise by lipid utilization in skeletal muscle

Endurance exercise significantly enhances energy expenditure with lipids serving as a crucial energy source for skeletal muscle during exercise. The adipocytokine Zinc-α2-glycoprotein (ZAG) in endurance exercise remains largely uncertain. This study utilized ZAG knockout and overexpression mice to investigate ZAG's role in regulating lipid metabolism in skeletal muscle during endurance exercise. Results showed the serum ZAG level of mice was significantly increased after exercised, and ZAG knockout mice decreased the exercise performance. Subsequent research revealed that ZAG knockout notably elevated triglyceride (TG) level in skeletal muscle, reduced the expression of lipolysis-related factors such as adipose triglyceride lipase (ATGL), carnitine palmitoyl transferase-1b (CPT1b) and acyl-CoA synthetase long chain family member 1 (ACSL1), while enhancing the expression of lipid synthesis factor fatty acid synthase (FASN) during exercise. The expressions of mitochondrial energy metabolism related factors uncoupling protein 2 (UCP2) and cytochrome c oxidase subunit I (COX1) were reduced in ZAG knockout mice during endurance exercise. To assess ZAG’s impact on lipid metabolism in skeletal muscle, we used ZAG overexpression plasmid in mice and C2C12 cells. ZAG overexpression decreased TG levels, enhanced ATGL expression, and increased CPT1b expression. In conclusion, ZAG can improve the level of skeletal muscle lipid metabolism and mitochondrial function during exercise, and improve the endurance exercise performance of mice.