Regulation of Mitochondrial Biogenesis and GLUT4 Expression by Exercise

Holloszy, John O.

doi:10.1002/cphy.c100052

Cited by 78 publications

(88 citation statements)

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“…Although the changes to existing PGC-1a activity co-ordinate the initial signalling pathways required to stimulate mitochondrial biogenesis, it is the subsequent increase in PGC-1a protein content that occurs with repeated exercise sessions that is therefore considered a necessary requirement to stimulate further mitochondrial adaptations during the course of an endurance training program [35]. For this reason, an understanding of the control of PGC-1a transcription is also important and, with this in mind, the reader is directed to several contemporary and excellent reviews [10,39,40].…”

Section: Regular Exercise Training Promotes Skeletal Muscle Mitochondmentioning

confidence: 99%

“…Although the phenomenon of training-induced increases in skeletal muscle mitochondria was first recognised over 40 years ago, the precise molecular mechanisms underpinning mitochondrial biogenesis are only beginning to be understood [10]. It is now generally recognised that acute muscle contraction induces homeostatic perturbations to cellular energy status to activate a number of cell signalling kinases such as the calcium/calmodulin-dependent protein kinase II (CaMKII), the p38 mitogen-activated protein kinase (p38MAPK) and the AMP-dependent protein kinase (AMPK).…”

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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: Regular Exercise Training Promotes Skeletal Muscle Mitochondmentioning

confidence: 99%

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confidence: 99%

The Emerging Role of p53 in Exercise Metabolism

Bartlett

Drust

et al. 2013

Sports Med

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“…Endurance exercise, such as running or swimming, induces an adaptive increase in skeletal muscle mitochondria with a shift in fiber type to red/high oxidative (20). There is evidence that the increase in cytosolic Ca 2ϩ that mediates excitationcontraction coupling and the increase in AMP resulting from ATP breakdown during muscle contraction are involved in mediating the increase in mitochondrial biogenesis induced by exercise (20).…”

Section: Discussionmentioning

confidence: 99%

“…It has been known for many years that endurance exercise results in an increase in mitochondria in skeletal muscle (21,22). This increase in mitochondria, which is limited to the muscles performing the exercise, can be as great as two-or threefold if the exercise is sufficiently intense and prolonged (20,23). It plays a key role in the training-mediated increase in exercise capacity (9,20).…”

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confidence: 99%

“…This increase in mitochondria, which is limited to the muscles performing the exercise, can be as great as two-or threefold if the exercise is sufficiently intense and prolonged (20,23). It plays a key role in the training-mediated increase in exercise capacity (9,20). For a long time, nothing was known regarding the mechanism by which the increase in mitochondria is mediated.…”

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β-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1α in skeletal muscle

Kim

Asaka

Higashida

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1␣ in skeletal muscle. Am J Physiol Endocrinol Metab 304: E844 -E852, 2013. First published March 5, 2013 doi:10.1152/ajpendo.00581.2012.-There are reports that the ␤-adrenergic agonist clenbuterol induces a large increase in peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣) in skeletal muscle. This has led to the hypothesis that the increases in PGC-1␣ and mitochondrial biogenesis induced in muscle by endurance exercise are mediated by catecholamines. In the present study, we evaluated this possibility and found that injecting rats with clenbuterol or norepinephrine induced large increases in PGC-1␣ and mitochondrial proteins in brown adipose tissue but had no effect on PGC-1␣ expression or mitochondrial biogenesis in skeletal muscle. In brown adipocytes, the increase in PGC-1␣ expression induced by ␤-adrenergic stimulation is mediated by activation of p38 mitogenactivated protein kinase (p38 MAPK), which phosphorylates and activates the cAMP response element binding protein (CREB) family member activating transcription factor 2 (ATF2), which binds to a cyclic AMP response element (CRE) in the PGC-1␣ promoter and mediates the increase in PGC-1␣ transcription. Phospho-CREB does not have this effect. Our results show that the reason for the lack of effect of ␤-adrenergic stimulation on PGC-1␣ expression in muscle is that catecholamines do not activate p38 or increase ATF2 phosphorylation in muscle.phospho-ATF2; clenbuterol; norepinephrine; mitochondria; brown fat PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␥ coactivator 1␣ (PGC-1␣) was discovered during a study of the regulation of uncoupling protein-1 (UCP1) expression by the nuclear receptor PPAR␥ during induction of adaptive thermogenesis in brown fat (34) PGC-1␣ expression is powerfully induced in brown fat cells of mice exposed to cold (34). This effect is mediated by the cold-induced increase in catecholamine secretion and is mimicked by treatment with ␤ 2

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How Animals Move: Comparative Lessons on Animal Locomotion

Schaeffer

Lindstedt

2013

Comprehensive Physiology

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Comparative physiology often provides unique insights in animal structure and function. It is specifically through this lens that we discuss the fundamental properties of skeletal muscle and animal locomotion, incorporating variation in body size and evolved difference among species. For example, muscle frequencies in vivo are highly constrained by body size, which apparently tunes muscle use to maximize recovery of elastic recoil potential energy. Secondary to this constraint, there is an expected linking of skeletal muscle structural and functional properties. Muscle is relatively simple structurally, but by changing proportions of the few muscle components, a diverse range of functional outputs is possible. Thus, there is a consistent and predictable relation between muscle function and myocyte composition that illuminates animal locomotion. When animals move, the mechanical properties of muscle diverge from the static textbook force-velocity relations described by A. V. Hill, as recovery of elastic potential energy together with force and power enhancement with activation during stretch combine to modulate performance. These relations are best understood through the tool of work loops. Also, when animals move, locomotion is often conveniently categorized energetically. Burst locomotion is typified by high-power outputs and short durations while sustained, cyclic, locomotion engages a smaller fraction of the muscle tissue, yielding lower force and power. However, closer examination reveals that rather than a dichotomy, energetics of locomotion is a continuum. There is a remarkably predictable relationship between duration of activity and peak sustainable performance.

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Regulation of Mitochondrial Biogenesis and GLUT4 Expression by Exercise

Cited by 78 publications

References 235 publications

The Emerging Role of p53 in Exercise Metabolism

The Emerging Role of p53 in Exercise Metabolism

β-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1α in skeletal muscle

How Animals Move: Comparative Lessons on Animal Locomotion

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