Lysophosphatidic Acid Improves Human Sperm Motility by Enhancing Glycolysis and Activating L-Type Calcium Channels

Abstract

Until now, the molecular mechanisms underlining sperm motility defect causing male infertility are still poorly understood. Safe and effective compounds or drugs that can improve sperm motility are also very limited. Lysophosphatidic acid (LPA) is a naturally occurring phospholipid and a bioactive intermediate with multiple biological activities. It has been detected in various body fluids such as serum, plasma, saliva, tears, blister fluids, hen egg white, and ascites from patients with ovarian cancer. LPA is also abundant in seminal plasma and follicular fluid. It enhances follicle stimulation, improves oocyte fertilization, and promotes early embryonic development and embryo implantation. However, the physiological role of LPA in the male reproductive system remains unknown. Here, our study showed that LPA significantly improved the motility parameters of human sperm hyperactivation in a dose-dependent manner. The LPA-induced elevation of sperm motility is dependent on bovine serum albumin (BSA) but independent of the classical BSA-induced sAC/cAMP/PKA signaling pathway. The enhancement of sperm motility by LPA could not be blocked by CCCP, a respiratory inhibitor suppressing mitochondrial ATP production. Moreover, LPA improved the activity of triosephosphate isomerase in glycolysis. Meanwhile, LPA treatment significantly increased ATP and phosphoenolpyruvate levels and decreased ADP content during sperm glycolysis. Notably, none of known or identified LPA receptors was detected in human sperm. Further investigations showed that LPA promoted sperm motility through L-type calcium channels. In summary, this study revealed the involvement of LPA in the regulation for human sperm motility by enhancing glycolysis and activating L-type calcium channels. The current findings may shed new light on the understanding of causes of asthenozoospermia, and indicate that LPA could be used as a novel therapeutic agent to improve sperm function and fertilizing capacity.

IKBA phosphorylation governs human sperm motility through ACC-mediated fatty acid beta-oxidation

“…Further, there exists no significant relationship between human sperm motility and tyrosine phosphorylation 59 . Previous studies have reported that tyrosine phosphorylation shows a slow and gradual time-dependent increase during sperm capacitation 60 – 62 . In this study, Bay117082 induced an obvious increase in protein tyrosine phosphorylation at 60 min (Supplementary Fig.…”

“…Thick arrows (up or down) indicate the alteration of substance after treatment with Bay117082 (yellow), LPS (blue), and etomoxir (purple); solid lines represent verified trends and dashed lines represent conjectural trends. The elements “sperm” and “mitochondria” were modified from our previous article 62 . …”

“…As recommended by the WHO Laboratory manual for the examination and processing of human semen (fifth edition) and our earlier study 62 , we used BWW media (94.8 mM NaCl, 4.8 mM KCl, 1.7 mM CaCl 2 , 1.2 mM MgSO 4 , 1.2 mM KH 2 PO 4 , 5.5 mM glucose, 13.21 mM sodium lactate, 0.27 mM sodium pyruvate, 25 mM NaHCO 3 , and 3.5 mg/mL BSA) for collecting and cultivating human sperm. The aforementioned reagents were purchased from Sigma-Aldrich (Saint Louis, MO, USA).…”

Alkaline Dilution Alters Sperm Motility in Dairy Goat by Affecting sAC/cAMP/PKA Pathway Activity

“…on the sperm membrane surface [ 12 , 29 ] and the phosphorylation level of the VSP protein in the sperm tail can differ widely [ 30 , 31 ]. Intracellular alkalinization is critical not only for sperm hyperactivation and acrosome reactions but also for basal sperm motility, as the ability of dynein to hydrolyze ATP and provide axial filament bending increases significantly with increasing pHi [ 32 , 33 ]. These pH-regulating proteins can be classified into two categories: (1) Membrane proteins that mediate H + transmembrane transport, including proton channels (Hv1), proton pumps, and Na + /H + exchangers (NHE); (2) Membrane proteins that mediate HCO 3 − ion transmembrane transport, including SLC4 family proteins, SLC26 family proteins, and cystic fibrosis transmembrane transduction regulators (CFTR) [ 34 ].…”

“…The ionic requirements and signaling pathways of mammalian sperm motility have been widely studied, but they are still not completely understood [ 56 , 57 ]. At the molecular level, sperm motility enhancement requires the activation of several signaling pathways, including but not limited to cAMP-dependent pathways, an increase in pHi, changes in [Ca 2+ ]i concentration, and hyperpolarization of the sperm plasma membrane potential [ 33 , 58 ].…”