Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Physiology and Pharmacology

Collaborative Specialization

Developmental Biology

Supervisor

Regnault, Timothy RH.

Abstract

Intrauterine growth restriction (IUGR) affects 10-15% of births and is associated with placental insufficiency (PI), resulting in fetal oxidative stress (OS). This OS is a factor in the predisposition to postnatal noncommunicable disease (NCD) of which muscle mitochondrial dysfunctional is a key aspect. Pyrroloquinoline quinone (PQQ), an antioxidant-like compound, is capable of OS reduction and promotes mitochondrial function, though limited research has focused on its effects in in utero skeletal muscle. This study sought to investigate the impact of in vitro H2O2, a model of OS, and an in vivo model of OS associated IUGR, with PQQ administration, on fetal myogenesis and muscle mitochondrial function. H2O2, IUGR, and unexpectedly PQQ, reduced expression of myogenic and mitochondrial genes. Therefore, PQQ does not appear to attenuate OS-induced myogenic and mitochondrial dysfunction and instead negatively altered associated genes. These changes have unknown long-term consequences for altered muscle metabolism and its contribution to NCD.

Summary for Lay Audience

Babies grow quickly in the womb before birth, and when oxygen and nutrients are not properly received, these babies have been shown to have an increased risk of later life metabolic disease, such as diabetes or heart disease. This risk is specifically associated with those who experience the hypoxia-associated pregnancy complication “placental insufficiency” and endure intrauterine growth restriction (IUGR). A key reason for development of these diseases after IUGR is the characteristic reduction in skeletal muscle mass, as the organ plays an important role in whole body metabolism. The reduction is the result of diminished blood delivery, as flow is shunted to more important organs to promote survival after birth. It is predicted that early muscle mitochondrial dysfunction is the underlying pathology that leads to development of metabolic deficits and oxidative stress due to the hypoxic growth environment may be responsible for the organelle’s deterioration. This study aimed to investigate the muscle mitochondrial impairments associated with exposure to oxidative stress. Furthermore, it set out to determine if the antioxidant-like compound, pyrroloquinoline quinone (PQQ), could prevent oxidative stress from damaging mitochondria and instead promote function. A muscle cell culture model was utilized to isolate the effects of oxidative stress and PQQ on skeletal muscle development and mitochondrial function. A second study utilized an IUGR fetal guinea pig model to determine the effects of IUGR and PQQ on skeletal muscle development, including but not limited to, muscle mitochondrial effects. Cells exposed to oxidative stress had reduced expression of genes associated with muscle development and mitochondrial function, however, the addition of PQQ did not lessen this decrease. Instead, PQQ itself decreased expression of the same genes. Similarly, IUGR animals had reduced gene expression of muscle development, mitochondrial, and metabolism markers, none of which showed increase after PQQ exposure but instead were negatively affected by exposure to the compound. Previous research has shown PQQ to have a positive effect on mitochondrial function in the liver, though this finding was not replicated within the skeletal muscle. Therefore, this study highlights the compound’s opposing effects in different organ systems and underlines the need for further research.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Download

Share

COinS