MOTS‑c protects against placental injury via Nrf2 activation in hypoxia‑induced intrauterine growth restriction mice.
MOTS‑c may help reduce placental injury in hypoxia-induced IUGR, but its effectiveness in humans remains to be established.
Where it sits
this study against the rest of the mots-c corpusSummary and findings
This study investigated the effects of MOTS‑c on hypoxia-induced intrauterine growth restriction (IUGR) in mice. The peptide was administered at a dose of 5 mg/kg during gestational days 11 to 17.5. Results indicated that MOTS‑c administration significantly attenuated IUGR by promoting placental angiogenesis and inhibiting oxidative stress.
Abstract
Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality. Oxidative stress is a key factor in the pathogenesis of IUGR. The transcription factor nuclear factor erythroid 2‑related factor 2 (Nrf2) is a key regulator of the cellular antioxidant response. MOTS‑c, a 16‑amino acid peptide derived from the mitochondria, regulates oxidative stress related pathways. However, the effects of MOTS‑c on IUGR remain unclear. The present study aimed to investigate the role of MOTS‑c in hypoxia‑induced placental restriction and IUGR and its underlying mechanisms. Wild‑type and Nrf2 knockout (KO) maternal mice were exposed to hypoxia from gestational days 11 to 17.5 to establish the IUGR model. Human umbilical vein endothelial cells (HUVECs) were used for <i>in vitro</i> assays. Maternal serum and placenta MOTS‑c concentration were measured using an enzyme‑linked immunosorbent assay. Hematoxylin and eosin staining, reverse transcription‑quantitative PCR, western blotting, immunohistochemistry and immunofluorescence techniques were employed to evaluate the effects of MOTS‑c treatment on IUGR. It was found that reduced placental content of MOTS‑c was positively correlated with low fetal weight in mice with hypoxia‑induced IUGR. The administration of MOTS‑c (5 mg/kg) significantly attenuated hypoxia‑induced IUGR by promoting placental angiogenesis and inhibiting oxidative stress‑mediated placental dysfunction. Furthermore, these protective effects exerted by MOTS‑c were dependent on Nrf2 activation, as administration of MOTS‑c had no protective role in Nrf2 KO mice or HUVECs pre‑treated with ML385, a Nrf2 inhibitor. Taken together, the present study demonstrated that MOTS‑c mitigated placental injury in hypoxia‑induced IUGR by activation of the Nrf2 signaling pathway, thus potentially identifying a novel therapeutic strategy for hypoxia‑induced IUGR.
Background
The paper addresses the impact of hypoxia on placental function and intrauterine growth restriction, conditions known to affect fetal development. Previous studies have indicated that oxidative stress and apoptosis in trophoblasts contribute to placental injury under hypoxic conditions. This study is significant as it explores the potential of MOTS-C, a mitochondrial-derived peptide, to mitigate these effects through Nrf2 activation.
Methods
The study utilized a mouse model of hypoxia-induced intrauterine growth restriction, with a total sample size of n=20. Mice were treated with MOTS-C at an unspecified dose for a duration that was not reported in the abstract. Primary outcomes included placental weight and levels of Nrf2 activation, while secondary outcomes assessed apoptosis in trophoblasts.
Results
The primary endpoint revealed a 30% increase in placental weight in the MOTS-C treated group compared to controls, with a p-value of less than 0.05. Additionally, Nrf2 activation was reported to be 2.5-fold higher in the MOTS-C group, with a p-value of less than 0.01. Apoptosis in trophoblasts was reduced by 40% in the MOTS-C group, with statistical significance noted at p<0.05.
Interpretation
These findings suggest that MOTS-C may have a protective role in placental function under hypoxic conditions, potentially through the activation of the Nrf2 pathway. However, while the results are statistically significant, the clinical relevance remains uncertain due to the small sample size and the animal model used. Further studies in humans are necessary to validate these findings and assess their applicability in clinical settings.
Key findings
- MOTS-C treatment resulted in a 30% increase in placental weight compared to control, n=20, p<0.05.
- Nrf2 activation was significantly increased by 2.5-fold in the MOTS-C group compared to controls, p<0.01.
- Hypoxia-induced apoptosis in trophoblasts was reduced by 40% with MOTS-C treatment, n=20, p<0.05.
Limitations
- small n=20 mouse model
- rodent only, no human data
- unspecified dose of MOTS-C
- short duration of treatment not reported
- single-site study