The Function And Mechanisms Of Insulin-like Growth Factor 1 Receptor(IGF1R)in Human Sperm Motility

Clinical studies have shown that about 15 to 20 percent of married couples suffer from infertility,nearly half of which are due to male fertility problems,and sperm motility is a major cause of male infertility.Previous studies have found that insulin-like growth factor 1 receptor(IGF1R)can affect sperm capacitation,but the role and mechanism of IGF1R in sperm motility is not clear.IGF1R is a member of the tyrosine kinase family,which is expressed in almost all kinds of cells and has important functions in the process of sperm production.In order to systematically explore the function and molecular mechanisms of IGF1R in human sperm motility,we use activators and inhibitors independently or in combination during human sperm culture,and analyzed sperm movement parameters using the computer assisted sperm analysis(CASA)system.We found that the sperm motility was improved when IGF1 was added to normal sperm,while the sperm motility drops when IGF1R inhibitor GSK1904529A or NVP-AEW541 was added.In large sample-size experiments,we added IGF1 to 131 cases of normal sperm and 104 cases of asthenozoospermic sperm during culture and found that IGF1 could effectively improve the movement of both normal and asthenozoospermia sperm.In addition,we added IGF1 to 68 cases of normal sperm and 57 cases of asthenozoospermia sperm,and found that IGF1 could effectively improve the penetration ability of the normal sperm and asthenozoospermia sperm.These results suggest that IGF1R is closely related to sperm motility.Intracellular calcium regulation is closely associated with sperm movement,we analyzed the sperm intracellular calcium levels after culture using flow cytometry,and found that IGF1 had an enhanced effect on sperm calcium level,and IGF1R inhibitor had an inhibitory effect.Therefore,IGF1R can regulate sperm motility by changing the calcium levels.1,4,5-triphosphate(IP3)is produced by hydrolysis of phosphatidylinositol 4 and 5-diphosphate(PIP2)in the presence of PLC,and can induce the release of intracellular calcium.We found that IP3R inhibitor 2-APB could inhibit the motility and the progressive motility of sperm,while IP3 could improve the motility and the progressive motility,and could also partially rescue the inhibitory effects of 2-APB.Flow cytometry analysis showed that the calcium and sperm motility changed in a consistent way:IP3 inhibitor 2-APB reduced sperm intracellular calcium levels,while IP3 increased calcium levels and partially rescued the inhibitory effects of 2-APB on calcium levels.IP3 could rescue the inhibitory effects of NVP-AEW541 on both calcium levels and sperm motility.Thus,IGF1R changed sperm motility by regulating intracellular calcium levels through IP3.In addition,IP3 could rescue the inhibitory effects of U73122 on both sperm motility and calcium levels.These results show that PLC are involved in the IGF1R pathway regulating sperm motility.In conclusion,sperm motility can be regulated by IGF1R/PLC/IP3/Ca2+pathway,IGF1 can improve the motility and the penetration ability of asthenozoospermic sperm,which provides a new way in developing treatments of asthenozoospermia.