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

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.

Smooth muscle AKG/OXGR1 signaling regulates epididymal fluid acid–base balance and sperm maturation

Infertility is a global concern attributed to genetic defects,lifestyle,nutrition,and any other factors that affect the local metabolism and niche microenvironment of the reproductive system.2-Oxoglutarate receptor 1(OXGR1)is abundantly expressed in the testis;however,its cellular distribution and biological function of OXGR1 in the male reproductive system remain unclear.In the current study,we demonstrated that OXGR1 is primarily expressed in epididymal smooth muscle cells(SMCs).Aging and heat stress significantly reduced OXGR1 expression in the epididymis.Using OXGR1 global knockout and epididymal-specific OXGR1 knockdown models,we revealed that OXGR1 is essential for epididymal sperm maturation and fluid acid–base balance.Supplementation ofα-ketoglutaric acid(AKG),the endogenous ligand of OXGR1,effectively reversed epididymal sperm maturation disorders caused by aging and heat stress.Furthermore,in vitro studies showed that AKG markedly stimulated the release of instantaneous intracellular calcium from epididymal SMCs and substantially reduced the pH_(i) value in the epididymal SMCs via OXGR1.Mechanistically,we discovered that AKG/OXGR1 considerably increased the expression of Na^(+)/HCO_(3)^(−)cotransporter(NBCe1)mRNA in the epididymal SMCs,mediated by intracellular calcium signaling.The local AKG/OXGR1 system changed the epididymal fluid pH value and HCO_(3)^(−)concentration,thereby regulating sperm maturation via intracellular calcium signaling and NBCe1 mRNA expression.This study for the first time reveals the crucial role of OXGR1 in male fertility and sheds light on the applicability of metabolic intermediates in the nutritional intervention of reproduction.