Why AMPK agonists not known to be stressors may surprisingly contribute to miscarriage or hinder IVF/ART

Abstract

Here we examine recent evidence suggesting that many drugs and diet supplements (DS), experimental AMP-activated protein kinase (AMPK) agonists as well as energy-depleting stress, lead to decreases in anabolism, growth or proliferation, and potency of cultured oocytes, embryos, and stem cells in an AMPK-dependent manner. Surprising data for DS and drugs that have some activity as AMPK agonists in in vitro experiments show possible toxicity. This needs to be balanced against a preponderance of evidence in vivo that these drugs and DS are beneficial for reproduction. We here discuss and analyze data that leads to two possible conclusions: First, although DS and drugs that have some of their therapeutic mechanisms mediated by AMPK activity associated with low ATP levels, some of the associated health problems in vivo and in vitro fertilization/assisted reproductive technologies (IVF/ART) may be better-treated by increasing ATP production using CoQ10 (Ben-Meir et al., Aging Cell 14:887-895, 2015). This enables high developmental trajectories simultaneous with solving stress by energy-requiring responses. In IVF/ART, it is ultimately best to maintain handling and culture of gametes and embryos in the quietest state with low metabolic activity (Leese et al., Mol Hum Reprod 14:667-672, 2008; Leese, Bioessays 24 (9):845-849, 2002) using back-to-nature or simplex algorithms to identify optima (Biggers, Reprod Biomed Online 4 Suppl 1:30-38, 2002). Stress markers, such as checkpoint proteins like TRP53 (aka p53) (Ganeshan et al., Exp Cell Res 358:227-233, 2017); Ganeshan et al., Biol Reprod 83:958-964, 2010) and a small set of kinases from the protein kinome that mediate enzymatic stress responses, can also be used to define optima. But, some gametes or embryos may have been stressed in vivo prior to IVF/ART or IVF/ART optimized for one outcome may be suboptimal for another. Increasing nutrition or adding CoQ10 to increase ATP production (Yang et al., Stem Cell Rev 13:454-464, 2017), managing stress enzyme levels with inhibitors (Xie et al., Mol Hum Reprod 12:217-224, 2006), or adding growth factors such as GM-CSF (Robertson et al., J Reprod Immunol 125:80-88, 2018); Chin et al., Hum Reprod 24:2997-3009, 2009) may increase survival and health of cultured embryos during different stress exposure contexts (Puscheck et al., Adv Exp Med Biol 843:77-128, 2015). We define "stress" as negative stimuli which decrease normal magnitude and speed of development, and these can be stress hormones, reactive oxygen species, inflammatory cytokines, or physical stimuli such as hypoxia. AMPK is normally activated by high AMP, commensurate with low ATP, but it was recently shown that if glucose is present inside the cell, AMPK activation by low ATP/high AMP is suppressed (Zhang et al., Nature 548:112-116, 2017). As we discuss in more detail below, this may also lead to greater AMPK agonist toxicity observed in two-cell embryos that do not import glucose. Stress in embryos and stem cells increases AMPK in large stimulation indexes but also dir...

Capture and metabolomic analysis of the human endometrial epithelial organoid secretome

“…Proper AMPK function is paramount to early embryo development, as perturbed activity is correlated to retarded murine blastocyst trophectoderm differentiation and poor tight junction formation (59,60). Further, there are compelling data to suggest that pharmacological and environmental AMPK agonists contribute to miscarriages and assisted reproductive technology failures (61). Moreover, bovine early conceptus development has been recently hypothesized to revolve around a glucose-AMPK-PPARG (proliferator-activated receptor gamma) axis, modulated by uterine secretions of glucose, adenosine phosphates, and lipids (62)(63)(64)(65).…”

The placental transcriptome of the first-trimester placenta is affected by in vitro fertilization and embryo transfer

“…As expected, the first group of pathways comprise metabolic pathways. The IVF-ET process changes the physiological hypoxic environment of the trophoblast in vivo [50]. Metabolic disturbances may lead to metabolic reprogramming of the trophoblast in the first-trimester placenta [51].…”

Metformin in Reproductive Biology

“…In utero metformin exposure has been described safe for the fetus. Some evidence suggests that the beneficial effects of metformin are partly AMPK-dependent to counteract stress ( 114 ). However, it is important to follow the development of the offspring until adulthood to evaluate the risk to develop metabolic disorders through epigenetic information ( 114 ).…”

“…Some evidence suggests that the beneficial effects of metformin are partly AMPK-dependent to counteract stress ( 114 ). However, it is important to follow the development of the offspring until adulthood to evaluate the risk to develop metabolic disorders through epigenetic information ( 114 ). Thus, if metformin is provided with a high-fat diet, then a significant increase in visceral fat depot of the offspring is observed during adulthood ( 99 ).…”