Role of p53 Within the Regulatory Network Controlling Muscle Mitochondrial Biogenesis

Saleem, Ayesha; Carter, Heather N.; Iqbal, Sobia; Hood, David A.

doi:10.1097/jes.0b013e31822d71be

Cited by 50 publications

(66 citation statements)

References 33 publications

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“…As noted by Saleem et al [41], if p53 does indeed play a regulatory role in contractile-induced mitochondrial biogenesis, it follows that it should exhibit post-translational modification and/or alter its subcellular location upon contraction. Indeed, Saleem et al [16] initially observed that acute muscle contraction (in the form of a fatiguing electrical stimulation protocol) induces a twofold change in phosphorylation of p53 on serine 15 (a modification that is typically associated with increased stability and activity) immediately post-exercise.…”

Section: Exercise Induces Post-translational Modification Of P53 and mentioning

confidence: 89%

“…P phosphorylation, AIF apoptosisinducing factor, AMP adenosine monophosphate, AMPK 5 0 AMPactivated protein kinase, ATP adenosine triphosphate, COX cytochrome c oxidase, Drp1 dynamin-related protein 1, HSP70 heat shock protein 70, Mfn2 mitofusion 2, p38MAPK p38 mitogen-activated protein kinase, PGC-1a peroxisome proliferator-activated receptor gamma co-activator 1-a, ROS reactive oxygen species, SCO2 synthesis of cytochrome c oxidase 2, Tfam mitochondrial transcription factor A; solid lines represent activation and dashed lines represent translocation human health and physical performance. Indeed, reduced p53 function is associated with tumour development, insulin resistance, reduced longevity and impaired exercise performance [41,46]. Furthermore, the nutritional modulation of contractile-induced p53 signalling (i.e.…”

Section: Perspectives and Future Directionsmentioning

confidence: 99%

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The Emerging Role of p53 in Exercise Metabolism

Bartlett

Drust

et al. 2013

Sports Med

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The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has been implicated as a key molecular player regulating substrate metabolism and exercise-induced mitochondrial biogenesis in skeletal muscle. In this context, the study of p53 therefore has obvious implications for both human health and performance, given that impaired mitochondrial content and function is associated with the pathology of many metabolic disorders such as ageing, type 2 diabetes, obesity and cancer, as well as reduced exercise performance. Studies on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, reduces cytochrome c oxidase (COX) activity and peroxisome proliferator-activated receptor gamma co-activator 1-a protein content whilst also reducing mitochondrial respiration and increasing reactive oxygen species production during state 3 respiration in IMF mitochondria. Additionally, p53 KO mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) during fatiguing swimming, treadmill running and electrical stimulation protocols. p53 may regulate contractile-induced increases in mitochondrial content via modulating mitochondrial transcription factor A (Tfam) content and/or activity, given that p53 KO mice display reduced skeletal muscle mitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon muscle contraction, p53 is phosphorylated on serine 15 and subsequently translocates to the mitochondria where it forms a complex with Tfam to modulate expression of mitochondrial-encoded subunits of the COX complex. In human skeletal muscle, the exercise-induced phosphorylation of p53 Ser15 is enhanced in conditions of reduced carbohydrate availability in association with enhanced upstream signalling through 5 0 adenosine monophosphateactivated protein kinase but not p38 mitogen-activated protein kinase. In this way, undertaking regular exercise in carbohydrate restricted states may therefore be a practical approach to achieve the physiological benefits of consistent p53 signalling. Although our knowledge of p53 in exercise metabolism has advanced considerably, much of our current understanding of p53 regulation and associated targets is derived from various non-muscle cells and tissues. As such, many fundamental questions remain unanswered in contracting skeletal muscle. Detailed studies concerning the time-course of p53 activation (including additional post-translational modifications and subsequent subcellular translocation), as well as the effects of exercise modality (endurance versus resistance), intensity, duration, fibre type, age, training status and nutrient availability, must now be performed so that we can optimise exercise prescription guideli...

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Section: Exercise Induces Post-translational Modification Of P53 and mentioning

confidence: 89%

Section: Perspectives and Future Directionsmentioning

confidence: 99%

The Emerging Role of p53 in Exercise Metabolism

Bartlett

Drust

et al. 2013

Sports Med

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“…Fast-twitch fibers can be further classified into types 2A and 2X in humans, while a sub-classification of type 2A, 2X and 2B exists in rodents (2,6,13,15). In addition to myosin heavy chain isoforms, many other components contribute to a fiber's physiological characteristics.…”

Section: Introduction To Skeletal Musclementioning

confidence: 99%

“…An abundance of intracellular signaling molecules have been shown to regulate skeletal muscle plasticity. For instance, stimulation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38) and the downstream, transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) promote a shift toward slower, more oxidative characteristics (2,3,4,5,6). In contrast, activation of receptor interacting protein 140 (RIP140) in skeletal muscle drives phenotypic remodelling in the opposite direction (7).…”

Section: Introductionmentioning

confidence: 99%

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Stouth

Manta

Ljubicic

2018

American Journal of Physiology-Cell Physiology

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Lay AbstractSkeletal muscle is a plastic tissue that is capable of adapting to various physiological demands. Previous work suggests that protein arginine methyltransferases (PRMTs) are important players in the regulation of skeletal muscle remodelling. However, their role in disuse-induced muscle plasticity is unknown. Therefore, the purpose of this study was to investigate the role of PRMTs within the context of early, upstream signaling pathways that mediate disuse-evoked muscle remodelling. We found differential responses of the PRMTs to muscle denervation, suggesting a unique sensitivity to, or regulation by, potential upstream signaling pathways. AMP-activated protein kinase (AMPK) was among the molecules that experienced a rapid change in activity following disuse. These alterations in AMPK predicted many of the modifications in PRMT biology during inactivity, suggesting that PRMTs factor into the molecular mechanisms that precede neurogenic muscle atrophy. This study expands our understanding of the role of PRMTs in regulating skeletal muscle plasticity.

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“…In contrast, C3(1)/SV40Tag mice express wild-type p53 which is inactivated by Tag binding. Therefore, given the role of p53 in the promotion of aerobic metabolism (vs. glycolytic), and the mitochondrial adaptive response to exercise, it is certainly plausible that these alterations in p53 may be linked to the divergent effects of exercise on tumorigenesis (28). Lastly, an interaction between the numerous physiological effects of physical activity and either C3(1) or SV40Tag expression could also have contributed to the increase in tumor number following exercise.…”

Section: Discussionmentioning

confidence: 99%

Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer

Steiner

Davis

McClellan

et al. 2013

International Journal of Oncology

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Abstract. Epidemiologic studies suggest an association between physical activity (PA) and breast cancer risk. We examined the relationship between voluntary wheel running and breast cancer in C3(1)/SV40Tag mice. Female FVB/N and C3(1)/SV40Tag mice were assigned to either PA [C3(1)-PA] (n=12) or sedentary (Sed) [C3(1)-Sed] (n=15) treatment and were placed in a cage with access to a running wheel (PA) or without (Sed) from 4 to 24 weeks of age (sacrifice). Physical activity data were analyzed for running distance, time and speed. Body composition was examined at 12 weeks of age. Tumors were counted twice weekly and at sacrifice to assess multiplicity. Tumor volume was calculated using external calipers [0.52 x (largest diameter) x (smallest diameter) 2 ]. Heart and body weight were also recorded at sacrifice. Results showed that voluntary wheel running reduced tumor volume per tumor [C3(1)-Sed, 422.3±89.9 mm 3 ; C3(1)-PA, 260.2±61.7 mm 3 ] (P<0.05), but was associated with increased tumor number (P<0.05). Body composition analysis showed no differences in body fat between the groups. Heart weight/body weight ratio was increased following physical activity (P<0.05) providing evidence of a training effect. In conclusion, voluntary wheel running activity was effective at slowing tumor growth in the C3(1)/SV40Tag mouse model of breast cancer, but did not inhibit tumor initiation. These data provide support for further development of the C3(1)/SV40Tag mouse model for use in understanding the role of physical activity on breast cancer progression and the mechanisms for its effects.

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Role of p53 Within the Regulatory Network Controlling Muscle Mitochondrial Biogenesis

Cited by 50 publications

References 33 publications

The Emerging Role of p53 in Exercise Metabolism

The Emerging Role of p53 in Exercise Metabolism

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer

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