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Mechanistic Control of The Coldinduced Augmentation of The Transcriptional Co-Activator PGC-1α

Allan, RJ (2017) Mechanistic Control of The Coldinduced Augmentation of The Transcriptional Co-Activator PGC-1α. Doctoral thesis, Liverpool John Moores University.

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Cold water immersion is commonly used to alleviate the stress and damage that ensues following strenuous exercise. Alongside its purported performance and analgesic benefits recent literature highlights the positive impact it may have towards endurance adaptive responses, particularly on key markers of mitochondrial biogenesis. Despite these recent advances showing PGC-1α, the ‘master regulator’ of mitochondrial biogenesis, being augmented in its post-exercise response by cold water immersion, the precise controlling mechanisms remain to be determined. However, it has been suggested that local cooling effects on AMPK and p38 MAPK related signalling and/or increased systemic β-adrenergic stimulation are involved. Study 1 (Chapter 4) examined whether post-exercise cold-water immersion induced augmentation of PGC-1α mRNA is mediated through local or systemic mechanisms. Participants completed acute cycling followed by seated-rest (CON) or single-leg cold-water immersion (CWI; 10 min, 8°C) with muscle biopsies obtained pre-, post- and 3 h post-exercise from a single limb in the CON condition but from both limbs in CWI (thereby providing tissue from a CWI and non-immersed limb, NOT). Muscle temperature decreased following CWI (-5°C), with lesser changes observed in CON and NOT (-3°C; P<0.05). A significant interaction effect was present for AMPK phosphorylation (P=0.031). Exercise (CON) increased gene expression of PGC-1α 3 h post-exercise (~5-fold; P<0.001). Post-exercise CWI augmented PGC-1α expression above CON in immersed (CWI; ~9-fold; P=0.003) and NOT limbs (~12-fold; P=0.001). Plasma Normetanephrine concentration was higher in CWI vs. CON post-immersion (860 vs. 665 pmol·L-1; P=0.034). Data herein reports for the first time that local cooling of the immersed limb evokes transcriptional control of PGC1-α in the non-immersed limb, suggesting increased systemic β-adrenergic activation of AMPK may mediate, in part, post-exercise cold-induction of PGC-1α mRNA. Study 2 (Chapter 5) assessed the impact of combining a post-exercise cooling stimulus with prior low glycogen as both stressors are shown to separately enhance the post-exercise PGC-1α response. A single-leg depletion protocol and bi-lateral muscle biopsies with and without post-exercise CWI were utilised to give the following conditions: High glycogen control (HI CON), Low glycogen control (LO CON), High glycogen CWI (HI CWI) and Low glycogen CWI (LO CWI). HI limbs began the experimental day ~190 mmol·kg-1dry weight (dw) with low limbs at ~85 mmol·kg-1dw glycogen before undergoing the same relative exercise protocol as Chapter 4. PGC-1α mRNA was different between conditions (P = 0.039) with HI glycogen limbs showing greater expression than contralateral LO glycogen limbs (P < 0.05). PGC-1α mRNA increased to a greater extent in CWI HI vs. CON HI (ES 0.67 Large). Data herein supports previous research that shows post-exercise CWI is able to augment PGC-1α above the exercise response alone, however this response was not evident in heavily depleted limbs (~85 mmol·kg-1dw), suggesting a critical threshold may exist for the expected enhancement of PGC-1α to occur when exercise is commenced in a low glycogen state. Chapter 6 sought to examine the contribution of CWI (Chapter 4, Experiment 1) and/or low muscle glycogen (Chapter 5, Experiment 2) in the activation of PGC-1α via either the canonical (Exon 1a) or the alternative promoter (Exon 1b) regions. Data was obtained using muscle biopsy samples collected from the previous chapters (Chapter 4 and 5). Exercise increased the expression of promoter specific PGC-1α, with greater fold changes seen in Exon 1b. Experiment 1 (Chapter 4) showed PGC-1α Exon 1b expression closely matched the pattern of expression seen for total-PGC-1α, with large, systemic cold-induced increases in the non-immersed (NOT, 2344 fold change from Pre, P = 0.010) and immersed (CWI, 1860 fold change from Pre, P = 0.07), compared with the control limb (CON, 579 fold change from Pre). Results from experiment 2 (Chapter 5) saw PGC-1α Exon 1a and 1b gene expression increase post-exercise, with the Exon 1b response showing lower fold-changes at 3h post-exercise compared to those from Experiment 1 (chapter 4), despite the same exercise protocol being utilised (~200 fold increases in experiment 2 vs. ~2000 fold increases in experiment 1). The data suggests that depletion exercise in the days prior to the experimental day may have raised basal RNA levels, which may have therefore contributed to dampened fold-changes seen post-exercise when relativized to pre-exercise values. The lack of a cold augmentation in promoter specific PGC-1α gene expression in experiment 2 suggests this response may be extremely acute, and may not occur when cooling is undertaken on the third day of exercise. This thesis provides a novel insight into the influence of local, systemic and upstream activating mechanisms regulating the post-exercise, post-cooling and exercising in low glycogen states upon PGC-1α. These findings provide mechanistic application for future study designs and practical application in the support for the use of CWI when the intended target is an upregulation of the gene PGC-1α.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Cold water immersion; PGC-1α
Subjects: R Medicine > RC Internal medicine > RC1200 Sports Medicine
Divisions: Sport & Exercise Sciences
Date Deposited: 29 Sep 2017 09:48
Last Modified: 23 Nov 2022 10:00
DOI or ID number: 10.24377/LJMU.t.00007178
Supervisors: Gregson, W, Morton, JP and Sharples, AP
URI: https://researchonline.ljmu.ac.uk/id/eprint/7178
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