Molecular Regulation of Mitochondrial Biogenesis in Exercised and Fasted Human Skeletal Muscle: an Examination of Emerging Regulatory Protein
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The transcriptional co-activator PGC-1alpha is widely accepted as the “master regulator” of mitochondrial biogenesis – an increase in mitochondrial content – and much research has been devoted to understanding PGC-1alpha's role in mitochondrial remodeling. However, several studies have demonstrated the dispensability of PGC-1alpha for exercise-induced increases in mitochondrial content, highlighting redundancies in the molecular control of mitochondrial biogenesis. This dissertation attempts to advance our understanding of the molecular regulation of mitochondrial biogenesis in human muscle by examining the impact of exercise and fasting on regulatory protein with emerging roles in mitochondrial biogenesis. We first review the literature to critically evaluate the ability of PGC-1alpha to coordinate mitochondrial biogenesis in human muscle and highlight a number of regulatory protein that also appear important in the regulation of mitochondrial gene expression. Subsequent chapters examine how the expression of these protein is altered in skeletal muscle under various physiological conditions (e.g. rest, exercise, fasting). We demonstrate that the activation of Nrf2 – a transcription factor with an emerging role in mitochondrial biogenesis – coincides with the induction of genes involved in mitochondrial biogenesis after a single exercise bout and that changes in Nrf2 protein associate with changes in mitochondrial content after training. We also find that the expression of LRP130 – another emerging regulatory protein – is highest in human muscle fibers with a high mitochondrial content, localized to the mitochondria within individual fibers, and correlated with mitochondrial content at the whole-muscle level. Finally, although fasting does not robustly activate mitochondrial biogenic pathways in human muscle, Nrf2 protein expression is increased and changes in LRP130 and PGC-1alpha are coordinated in fasted muscle. Collectively, this dissertation highlights Nrf2 and LRP130 as important emerging regulators of mitochondrial biogenesis in human muscle, thereby warranting the further study of these protein in future work.
URI for this recordhttp://hdl.handle.net/1974/27997
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