Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Dean Betts

2nd Supervisor

Dr. Timothy Regnault

Joint Supervisor

Abstract

Low birth weight infants have a higher risk of developing metabolic syndrome, including Type II Diabetes. Fetal muscle is growth restricted in low birth weight infants and is the main tissue for determining insulin resistance. Recent studies indicate premature senescence in low birth weight rodents, which could lead to adult disease. In utero environments may play a role in the development of senescence through increased reactive oxygen species (ROS). Telomerase is present at high levels during development and protects cells from cellular stress and apoptosis. We postulate that telomerase protects cells from DNA damage and premature senescence. A primary culture of fetal guinea pig muscle cells were grown at 20% and 2% oxygen concentrations and treated with a telomerase inhibitor for 48 hours. ROS detection was conducted with MitoSOX, Mitotracker and DCF staining. Cells cultured at 20% O2 and treated with telomerase inhibitor displayed reduced growth rates and increased levels of senescence markers, including p21 and p53. DNA damage, measured by γH2AX staining at telomeres, was significantly increased at all oxygen concentrations with telomerase inhibition. Telomerase inhibition increased phosphorylation of metabolic proteins p66Shc and S6K and increased mitochondrial ROS levels, which can lead to DNA damage and senescence. Telomerase may protect cells during development from adverse in utero environments that cause premature senescence.

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