Arginase-II gene deficiency reduces skeletal muscle aging in mice

Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (<i>wt</i>) mice and mice deficient in <i>arg-ii</i> (<i>arg-ii^-/-</i>) of both sexes are investigated. We demonstrate a decreased physical performance of old <i>wt</i> mice, which is partially prevented in <i>arg-ii^-/-</i> animals, particularly in males. The improved phenotype of <i>arg-ii^-/-</i> mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in <i>arg-ii^-/-</i> mice. Finally, we demonstrate an increased <i>arg-ii</i> gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.