PGC-1α alternative promoter (Exon 1b) controls augmentation of total PGC-1α gene expression in response to cold water immersion and low glycogen availability

AbstractThis investigation sought to determine whether post-exercise cold water immersion and low glycogen availability, separately and in combination, would preferentially activate either the Exon 1a or Exon 1b Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter. Through a reanalysis of sample design, we identified that the systemic cold-induced augmentation of total PGC-1α gene expression observed previously (Allan et al. in J Appl Physiol 123(2):451–459, 2017) was largely a result of increased expression from the alternative promoter (Exon 1b), rather than canonical promoter (Exon 1a). Low glycogen availability in combination with local cooling of the muscle (Allan et al. in Physiol Rep 7(11):e14082, 2019) demonstrated that PGC-1α alternative promoter (Exon 1b) expression continued to rise at 3 h post-exercise in all conditions; whilst, expression from the canonical promoter (Exon 1a) decreased between the same time points (post-exercise–3 h post-exercise). Importantly, this increase in PGC-1α Exon 1b expression was reduced compared to the response of low glycogen or cold water immersion alone, suggesting that the combination of prior low glycogen and CWI post-exercise impaired the response in gene expression versus these conditions individually. Data herein emphasise the influence of post-exercise cooling and low glycogen availability on Exon-specific control of total PGC-1 α gene expression and highlight the need for future research to assess Exon-specific regulation of PGC-1α.

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Low pre‐exercise muscle glycogen availability offsets the effect of post‐exercise cold water immersion in augmenting PGC‐1α gene expression

Physiological Reports ◽

10.14814/phy2.14082 ◽

2019 ◽

Vol 7 (11) ◽

pp. e14082 ◽

Cited By ~ 2

Author(s):

Robert Allan ◽

Adam P. Sharples ◽

Matthew Cocks ◽

Barry Drust ◽

John Dutton ◽

...

Keyword(s):

Gene Expression ◽

Muscle Glycogen ◽

Cold Water ◽

Water Immersion ◽

Cold Water Immersion ◽

Post Exercise ◽

Exercise Muscle

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Adaptations to Post-exercise Cold Water Immersion: Friend, Foe, or Futile?

Frontiers in Sports and Active Living ◽

10.3389/fspor.2021.714148 ◽

2021 ◽

Vol 3 ◽

Author(s):

Mohammed Ihsan ◽

Chris R. Abbiss ◽

Robert Allan

Keyword(s):

Exercise Performance ◽

Cold Water ◽

Water Immersion ◽

Endurance Performance ◽

Cold Water Immersion ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Post Exercise ◽

Exercise Induced ◽

Post Exercise Recovery

In the last decade, cold water immersion (CWI) has emerged as one of the most popular post-exercise recovery strategies utilized amongst athletes during training and competition. Following earlier research on the effects of CWI on the recovery of exercise performance and associated mechanisms, the recent focus has been on how CWI might influence adaptations to exercise. This line of enquiry stems from classical work demonstrating improved endurance and mitochondrial development in rodents exposed to repeated cold exposures. Moreover, there was strong rationale that CWI might enhance adaptations to exercise, given the discovery, and central role of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in both cold- and exercise-induced oxidative adaptations. Research on adaptations to post-exercise CWI have generally indicated a mode-dependant effect, where resistance training adaptations were diminished, whilst aerobic exercise performance seems unaffected but demonstrates premise for enhancement. However, the general suitability of CWI as a recovery modality has been the focus of considerable debate, primarily given the dampening effect on hypertrophy gains. In this mini-review, we highlight the key mechanisms surrounding CWI and endurance exercise adaptations, reiterating the potential for CWI to enhance endurance performance, with support from classical and contemporary works. This review also discusses the implications and insights (with regards to endurance and strength adaptations) gathered from recent studies examining the longer-term effects of CWI on training performance and recovery. Lastly, a periodized approach to recovery is proposed, where the use of CWI may be incorporated during competition or intensified training, whilst strategically avoiding periods following training focused on improving muscle strength or hypertrophy.

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Postexercise cold water immersion modulates skeletal muscle PGC-1α mRNA expression in immersed and nonimmersed limbs: evidence of systemic regulation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00096.2017 ◽

2017 ◽

Vol 123 (2) ◽

pp. 451-459 ◽

Cited By ~ 14

Author(s):

Robert Allan ◽

Adam P. Sharples ◽

Graeme L. Close ◽

Barry Drust ◽

Sam O. Shepherd ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

P38 Mapk ◽

Cold Water ◽

Water Immersion ◽

Cold Water Immersion ◽

Peak Power Output ◽

Adrenergic Stimulation ◽

Local Cooling ◽

First Time

Mechanisms mediating postexercise cold-induced increases in PGC-1α gene expression in human skeletal muscle are yet to be fully elucidated but may involve local cooling effects on AMPK and p38 MAPK-related signaling and/or increased systemic β-adrenergic stimulation. Therefore, we aimed to examine whether postexercise cold water immersion enhancement of PGC-1α mRNA is mediated through local or systemic mechanisms. Ten subjects completed acute cycling (8 × 5 min at ~80% peak power output) followed by seated-rest (CON) or single-leg cold water immersion (CWI; 10 min, 8°C). Muscle biopsies were obtained preexercise, postexercise, and 3 h postexercise from a single limb in the CON condition but from both limbs in CWI [thereby providing tissue from a CWI and nonimmersed limb (NOT)]. Muscle temperature decreased up to 2 h postexercise following CWI (−5°C) in the immersed limb, with lesser changes observed in CON and NOT (−3°C, P < 0.05). No differences between limbs were observed in p38 MAPK phosphorylation at any time point ( P < 0.05), whereas a significant interaction effect was present for AMPK phosphorylation ( P = 0.031). Exercise (CON) increased gene expression of PGC-1α 3 h postexercise (~5-fold, P < 0.001). CWI augmented PGC-1α expression above CON in both the immersed (CWI; ~9-fold, P = 0.003) and NOT limbs (~12-fold, P = 0.001). Plasma normetanephrine concentration was higher in CWI vs. CON immediately postimmersion (860 vs. 665 pmol/l, P = 0.034). We report for the first time that local cooling of the immersed limb evokes transcriptional control of PGC-1α in the nonimmersed limb, suggesting increased systemic β-adrenergic activation of AMPK may mediate, in part, postexercise cold induction of PGC-1α mRNA. NEW & NOTEWORTHY We report for the first time that postexercise cold water immersion of one limb also enhances PGC-1α expression in a contralateral, nonimmersed limb. We suggest that increased systemic β-adrenergic stimulation, and not localized cooling per se, exerts regulatory effects on local signaling cascades, thereby modulating PGC-1α expression. Therefore, these data have important implications for research designs that adopt contralateral, nonimmersed limbs as a control condition while also increasing our understanding of the potential mechanisms underpinning cold-mediated PGC-1α responses.

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Changes in myocardial myosin heavy chain isoform composition with exercise and post-exercise cold-water immersion

Journal of Muscle Research and Cell Motility ◽

10.1007/s10974-021-09603-z ◽

2021 ◽

Author(s):

Ramzi A. Al-horani ◽

Mukhallad A. Mohammad ◽

Saja Haifawi ◽

Mohammed Ihsan

Keyword(s):

Myosin Heavy Chain ◽

Heavy Chain ◽

Cold Water ◽

Water Immersion ◽

Cold Water Immersion ◽

Post Exercise ◽

Myosin Heavy Chain Isoform

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Cold-water immersion following sprint interval training does not alter endurance signaling pathways or training adaptations in human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00434.2016 ◽

2017 ◽

Vol 313 (4) ◽

pp. R372-R384 ◽

Cited By ~ 13

Author(s):

James R. Broatch ◽

Aaron Petersen ◽

David J. Bishop

Keyword(s):

Mitochondrial Biogenesis ◽

Molecular Mechanisms ◽

Cold Water ◽

P53 Protein ◽

Water Immersion ◽

Interval Training ◽

Cold Water Immersion ◽

Peroxisome Proliferator ◽

Sprint Interval Training ◽

Single Session

We investigated the underlying molecular mechanisms by which postexercise cold-water immersion (CWI) may alter key markers of mitochondrial biogenesis following both a single session and 6 wk of sprint interval training (SIT). Nineteen men performed a single SIT session, followed by one of two 15-min recovery conditions: cold-water immersion (10°C) or a passive room temperature control (23°C). Sixteen of these participants also completed 6 wk of SIT, each session followed immediately by their designated recovery condition. Four muscle biopsies were obtained in total, three during the single SIT session (preexercise, postrecovery, and 3 h postrecovery) and one 48 h after the last SIT session. After a single SIT session, phosphorylated (p-)AMPK, p-p38 MAPK, p-p53, and peroxisome proliferator-activated receptor-γ coactivator-1α ( PGC-1α) mRNA were all increased ( P < 0.05). Postexercise CWI had no effect on these responses. Consistent with the lack of a response after a single session, regular postexercise CWI had no effect on PGC-1α or p53 protein content. Six weeks of SIT increased peak aerobic power, maximal oxygen consumption, maximal uncoupled respiration (complexes I and II), and 2-km time trial performance ( P < 0.05). However, regular CWI had no effect on changes in these markers, consistent with the lack of response in the markers of mitochondrial biogenesis. Although these observations suggest that CWI is not detrimental to endurance adaptations following 6 wk of SIT, they question whether postexercise CWI is an effective strategy to promote mitochondrial biogenesis and improvements in endurance performance.

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Promoter-specific regulation of PPARGC1A gene expression in human skeletal muscle

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0150 ◽

2015 ◽

Vol 55 (2) ◽

pp. 159-168 ◽

Cited By ~ 12

Author(s):

Daniil V Popov ◽

Evgeny A Lysenko ◽

Tatiana F Vepkhvadze ◽

Nadia S Kurochkina ◽

Pavel A Maknovskii ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Human Skeletal Muscle ◽

Stop Codon ◽

Constitutive Expression ◽

Alternative Promoter ◽

Specific Expression ◽

Post Exercise ◽

Specific Regulation ◽

Intensity Of Exercise

The goal of this study was to identify unknown transcription start sites of thePPARGC1A(PGC-1α) gene in human skeletal muscle and investigate the promoter-specific regulation ofPGC-1αgene expression in human skeletal muscle. Ten amateur endurance-trained athletes performed high- and low-intensity exercise sessions (70 min, 70% or 50%o2max). High-throughput RNA sequencing and exon–exon junction mapping were applied to analyse muscle samples obtained at rest and after exercise.PGC-1αpromoter-specific expression and activation of regulators of PGC-1α gene expression (AMPK, p38 MAPK, CaMKII, PKA and CREB1) after exercise were evaluated using qPCR and western blot. Our study has demonstrated that during post-exercise recovery, human skeletal muscle expresses thePGC-1αgene via two promoters only. As previously described, the additional exon 7a that contains a stop codon was found in all samples. Importantly, only minor levels of other splice site variants were found (and not in all samples). Constitutive expressionPGC-1αgene occurs via the canonical promoter, independent of exercise intensity and exercise-induced increase of AMPKThr172phosphorylation level. Expression ofPGC-1αgene via the alternative promoter is increased of two orders after exercise. This post-exercise expression is highly dependent on the intensity of exercise. There is an apparent association between expression via the alternative promoter and activation of CREB1.

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Cold water immersion attenuates anabolic signaling and skeletal muscle fiber hypertrophy, but not strength gain, following whole-body resistance training

Journal of Applied Physiology ◽

10.1152/japplphysiol.00127.2019 ◽

2019 ◽

Vol 127 (5) ◽

pp. 1403-1418 ◽

Cited By ~ 7

Author(s):

Jackson J. Fyfe ◽

James R. Broatch ◽

Adam J. Trewin ◽

Erik D. Hanson ◽

Christos K. Argus ◽

...

Keyword(s):

Skeletal Muscle ◽

Resistance Training ◽

Protein Content ◽

Muscle Fiber ◽

Cold Water ◽

Water Immersion ◽

Cold Water Immersion ◽

Post Exercise ◽

Leg Press ◽

Before And After

We determined the effects of cold water immersion (CWI) on long-term adaptations and post-exercise molecular responses in skeletal muscle before and after resistance training. Sixteen men (22.9 ± 4.6 y; 85.1 ± 17.9 kg; mean ± SD) performed resistance training (3 day/wk) for 7 wk, with each session followed by either CWI [15 min at 10°C, CWI (COLD) group, n = 8] or passive recovery (15 min at 23°C, control group, n = 8). Exercise performance [one-repetition maximum (1-RM) leg press and bench press, countermovement jump, squat jump, and ballistic push-up], body composition (dual X-ray absorptiometry), and post-exercise (i.e., +1 and +48 h) molecular responses were assessed before and after training. Improvements in 1-RM leg press were similar between groups [130 ± 69 kg, pooled effect size (ES): 1.53 ± 90% confidence interval (CI) 0.49], whereas increases in type II muscle fiber cross-sectional area were attenuated with CWI (−1,959 ± 1,675 µM2 ; ES: −1.37 ± 0.99). Post-exercise mechanistic target of rapamycin complex 1 signaling (rps6 phosphorylation) was blunted for COLD at post-training (POST) +1 h (−0.4-fold, ES: −0.69 ± 0.86) and POST +48 h (−0.2-fold, ES: −1.33 ± 0.82), whereas basal protein degradation markers (FOX-O1 protein content) were increased (1.3-fold, ES: 2.17 ± 2.22). Training-induced increases in heat shock protein (HSP) 27 protein content were attenuated for COLD (−0.8-fold, ES: −0.94 ± 0.82), which also reduced total HSP72 protein content (−0.7-fold, ES: −0.79 ± 0.57). CWI blunted resistance training-induced muscle fiber hypertrophy, but not maximal strength, potentially via reduced skeletal muscle protein anabolism and increased catabolism. Post-exercise CWI should therefore be avoided if muscle hypertrophy is desired. NEW & NOTEWORTHY This study adds to existing evidence that post-exercise cold water immersion attenuates muscle fiber growth with resistance training, which is potentially mediated by attenuated post-exercise increases in markers of skeletal muscle anabolism coupled with increased catabolism and suggests that blunted muscle fiber growth with cold water immersion does not necessarily translate to impaired strength development.

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