Publication Date

2012-07-18

Availability

Embargoed

Embargo Period

2014-02-11

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular Cell and Developmental Biology (Medicine)

Date of Defense

2012-06-22

First Committee Member

Carlos T. Moraes

Second Committee Member

Teresa Zimmers

Third Committee Member

Wayne E. Balkan

Fourth Committee Member

Theodore J. Lampidis

Abstract

Aging is the progressive decline in cellular, tissue and organ function. The mitochondrial theory of aging suggests that the accumulation of mitochondrial DNA (mtDNA) mutations leads to mitochondrial dysfunction, loss of organ function and consequently a decrease in lifespan. This theory is appealing as there is a correlation between age-dependent alterations in mtDNA and an increased risk for developing cardiovascular diseases, neurodegenerative disorders and myopathy. To further investigate the role of mtDNA mutations in aging, the mtDNA mutator mouse, a mouse model with a proof-reading deficient mtDNA polymerase γ (POLG) was created. These mice have a premature aging phenotype and develop hair loss, anemia, kyphosis, sarcopenia, cardiomyopathy and decreased lifespan. This phenotype was associated with an accumulation of mtDNA mutations and mitochondrial dysfunction, suggesting that there is a link between mtDNA mutations, mitochondrial dysfunction and the aging phenotype in mammals. The work presented in this dissertation demonstrates three strategies employed to compensate for mitochondrial dysfunction in aging using the mutator mouse as a model system. We illustrate that increased mitochondrial biogenesis and activation of peroxisome proliferator-activated receptor (PPAR) pathways can improve some aging phenotypes in the mutator mouse. In chapter 2, we show that increased expression of PPAR γ coactivator-1α (PGC-1α), a crucial regulator of mitochondrial biogenesis and function, in muscle of mutator mice increased mitochondrial biogenesis and function, and also improved the skeletal muscle and heart phenotypes of the mice. However, deep sequencing analysis of mtDNA showed that the increased mitochondrial biogenesis did not reduce the accumulation of mtDNA mutations in the mutator mouse but rather caused a small increase. Therefore, our results indicate that increased muscle PGC-1α expression is able to improve some premature aging phenotypes in the mutator mice without reverting the accumulation of mtDNA mutations. Bezafibrate is pharmacological agent that activates peroxisome proliferator-activated receptors (PPARs) and PGC-1α pathways that has been shown to improve mitochondrial function and energy metabolism. In chapter 3 we show that mutator mice treated with bezafibrate for 8-months had delayed hair loss and improved skin and spleen phenotypes. Bezafibrate did not induce global mitochondrial biogenesis/function in mutator mice; instead it increased mostly markers of fatty acid oxidation. Although we observed positive effects, bezafibrate induced hepatomegaly and did not slow the development of sarcopenia or increased the lifespan of the mutator mice. Our results show that despite its toxic effects, bezafibrate improved some aging phenotypes in the mutator mouse. Because increased PGC-1α expression in muscle conferred benefits to mutator mice, in chapter 4 we created wild-type and mutator mice that inducibly and ubiquitously express either PGC-1α or its family member PGC-1β. We found that increased systemic expression of PGC-1β was toxic and caused lethality, however, ubiquitous induction of PGC-1α did not appear to be deleterious. These animals are valuable tools for studying the effects of systemic increases in mitochondrial biogenesis during aging.

Keywords

Aging; Mitochondria; Mitochondrial Biogenesis; PGC-1; Skeletal Muscle; Heart

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