AKG/OXGR1 promotes skeletal muscle blood flow and metabolism by relaxing vascular smooth muscle

Abstract

Abstract In response to contraction during exercise, skeletal muscle growth and metabolism are dynamically regulated by nerve action, blood flow, and metabolic feedback. α-Ketoglutarate (AKG), a bioactive intermediate in the tricarboxylic acid cycle released during exercise, has been shown to promote skeletal muscle hypertrophy. However, the underlying mechanism of AKG in regulating skeletal muscle development and metabolism is still less known. 2-Oxoglutarate receptor 1 (OXGR1), the endogenous AKG receptor, is found to be distributed in the vascular smooth muscle (VSM) of skeletal muscles. OXGR1 knockout results in skeletal muscle atrophy, accompanied by decreased expression of myosin heavy chain I (MyHC I), capillary density, and endurance exercise capacity. Furthermore, the study found that dietary AKG supplementation increased mice endurance exercise distance, MyHC I/MyHC IIb ratio, arteriole, and capillary densities in skeletal muscle. Meanwhile, acute AKG administration gradually increased the blood flow in the lower limbs. Further, by using OXGR1 global knockout and OXGR1 VSM-specific (MYH11-Cre × OXGR1-FloxP) knockdown models, we found that OXGR1 in VSM is essential for AKG-induced improvement of skeletal muscle performances. According to the in vitro study, AKG expanded the cell area in VSM with a decreased intracellular pH by OXGR1. Our results demonstrated a novel role of AKG/OXGR1 in VSM of skeletal muscle to regulate blood flow and then enhance slow muscle fiber conversion and capillarization. These findings provide a theoretical basis for the AKG/OXGR1 signaling pathway to maintain human muscle function and improve meat production and livestock and poultry meat quality.