Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Timothy Regnault

Abstract

Using the C2C12 mouse myoblast cell line, I investigated how prolonged hypoxia affected components of the insulin signalling and FAO/PGC-1α/PPARs pathways, as they might impact insulin sensitivity in skeletal muscle cells.

Hypoxia resulted in lower p-Akt (Thr 308) and higher total cellular GLUT4 protein levels after 7 days of differentiation. This coincided with higher triglyceride content and alterations of the FAO/PGC-1α/PPARs components, both of which could contribute to the changes observed in the components of the insulin signalling pathway. Specifically, cells differentiating in 1% O2 had lower SIRT1, PPAR- α, FATP4 and MCAD mRNA; accompanied by lower SIRT1, PGC-1α and higher PPAR- γ protein following 7 days of differentiation. Additionally, cells in prolonged hypoxia had significantly higher phosphorylation of PGC-1α, AMPKα and ACC; concurrent with higher PGC-1α acetylation. However, none of these alterations above persisted following an additional 2-day re-oxygenation treatment (recovery).

In conclusion, prolonged hypoxia impairs components of the insulin signalling and FAO/PGC-1α/PPARs pathways, although the degree of this impairment is reduced followed re-oxygenation. An altered FAO/PGC-1α/ PPARs interaction contributes to depress FAO, resulting in increased triglyceride content, which likely impairs insulin signaling, specifically Akt phosphorylation (Thr 308). It is important to note that the alterations of FAO/PGC-1α/ PPARs observed here are similar to those reported in insulin resistant adults. The changes obtained during hypoxia may partly explain the in utero factors contributing to decreased insulin sensitivity in intrauterine growth restriction offspring.

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