Regulation of SIRT1, SIRT3, PGC-1α, and LRP130 in Response to Energetic Stress in Human Skeletal Muscle
The purpose of this dissertation was to investigate how the regulation of transcriptional coactivators (PGC-1α, LRP130) and protein deacetylases (SIRT1, SIRT3), which are shown to regulate mitochondrial adaptations in cell and animal models, respond to energy stressors in human skeletal muscle. In Chapter 3, we investigated whether changes in fatty acid oxidation known to occur during fasting and exercise occur in concert with changes in SIRT3 mitochondrial localization and expression. We found that 48 hours of fasting and acute endurance exercise modestly decreased SIRT3 mRNA expression but did not alter SIRT3 mitochondrial localization, despite increases in fatty acid oxidation. This suggests that if SIRT3 is involved in the acute regulation of fatty acid oxidation in human skeletal muscle, this is not accomplished by alterations in mitochondrial localization. In Chapter 4, we investigated the impact of a 48-hour fast on the regulation of SIRT1 and GCN5 in human skeletal muscle. In addition, we examined the relationship between SIRT1/GCN5 and the expression of PGC-1α target genes. SIRT1 mRNA expression slightly increased, while GCN5 was unchanged. However, protein content and nuclear localization of SIRT1 and GCN5 did not change, suggesting that, in contrast with previous animal studies, SIRT1 and GCN5 are unaltered in response to fasting in human skeletal muscle. We also found that individual changes in nuclear GCN5 and SIRT1 predicted changes in PGC-1α mRNA expression, but not PDK4, which suggests that SIRT1 and GCN5 may specifically regulate the PGC-1α gene. In Chapter 5, we examined changes in LRP130 gene and protein expression in response to 6 weeks of sprint-interval training (SIT) in human skeletal muscle. We also investigated the relationships between changes in LRP130, SIRT3, and PGC-1α expression in response to exercise. We found that expression of these proteins was unaltered following 2 and 6 weeks of SIT, although there were significant positive relationships between changes in LRP130, PGC-1α, and SIRT3 protein content. These results suggest that the regulation of these proteins may be coordinated in human skeletal muscle. Collectively, these studies demonstrate that physiological models derived from cells and animals do not always directly translate to human physiology.
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