KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction

Cortes‐Araya, Yennifer; Stenhouse, Claire; Salavati, Mazdak; Dan-Jumbo, Susan O.; Ho, William; Ashworth, Cheryl; Clark, Emily L.; Esteves, Cristina L.; Donadeu, F.X.

doi:10.1113/jp281647

Cited by 13 publications

(24 citation statements)

References 55 publications

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“…Recent studies examining periconceptional maternal exposures suggest that EtOH may impact brain weights in the developing offspring ( Steane et al, 2021 ). Further, increased proportional brain to body weight is a reliable indicator of intrauterine growth restriction (IUGR) ( Cortes-Araya et al, 2022 ). Therefore, we examined the ratio of brain to total bodyweight in the male and female offspring.…”

Section: Resultsmentioning

confidence: 99%

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

Thomas

Zimmel

Basel

et al. 2022

Front. Cell Dev. Biol.

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Hormesis refers to graded adaptive responses to harmful environmental stimuli where low-level toxicant exposures stimulate tissue growth and responsiveness while, in contrast, higher-level exposures induce toxicity. Although the intergenerational inheritance of programmed hormetic growth responses is described in plants and insects, researchers have yet to observe this phenomenon in mammals. Using a physiologically relevant mouse model, we demonstrate that chronic preconception paternal alcohol exposures program nonlinear, dose-dependent changes in offspring fetoplacental growth. Our studies identify an inverse j-shaped curve with a threshold of 2.4 g/Kg per day; below this threshold, paternal ethanol exposures induce programmed increases in placental growth, while doses exceeding this point yield comparative decreases in placental growth. In male offspring, higher paternal exposures induce dose-dependent increases in the placental labyrinth layer but do not impact fetal growth. In contrast, the placental hypertrophy induced by low-level paternal ethanol exposures associate with increased offspring crown-rump length, particularly in male offspring. Finally, alterations in placental physiology correlate with disruptions in both mitochondrial-encoded and imprinted gene expression. Understanding the influence of ethanol on the paternally-inherited epigenetic program and downstream hormetic responses in offspring growth may help explain the enormous variation observed in fetal alcohol spectrum disorder (FASD) phenotypes and incidence.

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Section: Resultsmentioning

confidence: 99%

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

Thomas

Zimmel

Basel

et al. 2022

Front. Cell Dev. Biol.

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“…Thus far, there have been many studies on the pathogenesis of IUA, but the role of KLB in this disease has not been clear. Previous studies have shown that KLB is necessary for FGF19 and FGF21 to bind to their homologous receptors with high affinity and is associated with a variety of physiological activities and diseases [ 30 , 31 ]. Immunohistochemistry, immunofluorescence, and Western blot experiments demonstrated that KLB protein is significantly overexpressed in the ESCs of IUA patients.…”

Section: Discussionmentioning

confidence: 99%

β-Klotho Promotes the Development of Intrauterine Adhesions via the PI3K/AKT Signaling Pathway

Guo

Wang

Wen

et al. 2022

IJMS

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Intrauterine adhesion (IUA) refers to injury to the basal layer of the endometrium, which can be caused by various factors. It is often accompanied by clinical symptoms such as abnormal menstruation, infertility, recurrent abortion, and periodic abdominal pain. In recent years, a number of studies have reported the effects of β-Klotho (KLB) on the occurrence and development of human tumors and fibrotic diseases, but its relationship with endometrial fibroblasts and endometrial fibrosis has not been elucidated. In this study, we compared the expression of KLB in endometrial stromal cells (ESCs) from patients with IUA and normal controls. We constructed animal and cell models of IUA and conducted expression verification and functional experiments on KLB. We found that the expression of KLB was significantly increased in the ESCs of IUA patients and rat models compared with the controls. The overexpression of KLB could promote the proliferation and fibrosis of ESCs. In addition, the overexpression of KLB activated the PI3K/AKT signaling pathway in ESCs. Our study shows that KLB protein is highly expressed in the ESCs of patients with IUA and can enhance stromal cell proliferation and cell fibrosis by activating the PI3K/AKT pathway, thus promoting the development of IUA.

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“…Cells were differentiated as per a previously published protocol 63 with minor changes. In short, MDPCs (5 × 10 4 ) were seeded in triplicate on rh-Laminin 521 (0.5 µg/cm 2 , Life Technologies)-coated 24-well or 96-well plates plates with growth media (DMEM supplemented with 10% FBS, 5 ng/ml bFGF and 1% PS).…”

Section: Methodsmentioning

confidence: 99%

Derivation and long-term maintenance of porcine skeletal muscle progenitor cells

Dan-Jumbo,

Riley,

Cortes-Araya

et al. 2024

Sci Rep

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Culture of muscle cells from livestock species has typically involved laborious enzyme-based approaches that yield heterogeneous populations with limited proliferative and myogenic differentiation capacity, thus limiting their use in physiologically-meaningful studies. This study reports the use of a simple explant culture technique to derive progenitor cell populations from porcine muscle that could be maintained and differentiated long-term in culture. Fragments of semitendinosus muscle from 4 to 8 week-old piglets (n = 4) were seeded on matrigel coated culture dishes to stimulate migration of muscle-derived progenitor cells (MDPCs). Cell outgrowths appeared within a few days and were serially passaged and characterised using RT-qPCR, immunostaining and flow cytometry. MDPCs had an initial mean doubling time of 1.4 days which increased to 2.5 days by passage 14. MDPC populations displayed steady levels of the lineage-specific markers, PAX7 and MYOD, up until at least passage 2 (positive immunostaining in about 40% cells for each gene), after which the expression of myogenic markers decreased gradually. Remarkably, MDPCs were able to readily generate myotubes in culture up until passage 8. Moreover, a decrease in myogenic capacity during serial passaging was concomitant with a gradual increase in the expression of the pre-adipocyte markers, CD105 and PDGFRA, and an increase in the ability of MDPCs to differentiate into adipocytes. In conclusion, explant culture provided a simple and efficient method to harvest enriched myogenic progenitors from pig skeletal muscle which could be maintained long-term and differentiated in vitro, thus providing a suitable system for studies on porcine muscle biology and applications in the expanding field of cultured meat.

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KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction

Abstract: support-information-section).

Cited by 13 publications

References 55 publications

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

β-Klotho Promotes the Development of Intrauterine Adhesions via the PI3K/AKT Signaling Pathway

Derivation and long-term maintenance of porcine skeletal muscle progenitor cells

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