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New insights intoexercise-inducedMitochondrial Adaptations

Mitochondria

Cristae Outer MembraneMatrix Inner MembraneLowell BB, and Shulman GI. Science 307: 384-387, 2005.Defects Parkinsons Alzheimerss Huntingtons Artherosclerosis Cardiomyopathies Diabetes

ADP + O2 ATP

Exercise-induced changes in mitochondrial content and mitochondrial respiration

Does antioxidant supplementation promote or impede skeletal muscle mitochondrial biogenesis?

Autophagy and exercise-induced mitochondrial biogenesis

Overview

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DefinitionsISEALMiller, K.L. (2012). Am J Physiol . 302: E496-499.Exercise: one-bout of exerciseTraining: a series of exercise boutsMitochondrial biogenesis: the making of new mitochondrial componentsit has been suggested that only measurements of the synthesis rates of mitochondrial proteins are indicative of mitochondrial biogenesis

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Mitochondrial adaptationsISEALGranata et al. 2016. FASEB J. 30(2): 959-970

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TerminologyISEALBishop, D.J., Skinner, T. (2014). Lactate Threshold. In: ESSA student manual for Health, Exercise and Sport Assessment.

Lactate inflection

Lactate threshold

8.51011.51314.51617.51920.5L1L2L3L4L5(HIT)

LILTL6(SIT)Wpeak

Terminology - LTISEALBishop, D.J., Skinner, T. (2014). Lactate Threshold. In: ESSA student manual for Health, Exercise and Sport Assessment.

L3L3L2L5

TerminologyISEALBishop, D.J., Skinner, T. (2014). Lactate Threshold. In: ESSA student manual for Health, Exercise and Sport Assessment.

TRTRUTUT

TerminologyISEALBaldwin et al. (2000). MSSE. 32:16481654.

Mitochondrial changes cross-sectionalISEALBishop et al. (2014). BBA. 140(4): 1266-1275.

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Changes in CS (rats) trainingISEAL

Bishop et al. (2014). BBA. 140(4): 1266-1275.

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Changes in CS trainingISEALTraining intensityTraining volumeBishop et al. (2014). BBA. 140(4): 1266-1275.

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Changes in CSISEAL

Granata et al. 2016. FASEB J. 30(2): 959-970

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Changes in CSISEALTraining intensity

Granata et al. 2016. FASEB J. 30(2): 959-970

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Changes in CSISEALTraining volume* Significantly different (P < 0.05) from NT, from RTGranata et al. (2016). FASEB J. In Press

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Changes in CSISEAL* Significantly different (P < 0.05) from pre-NT, # from post-NT

Training volumeGranata et al. (2016). FASEB J. In Press

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Changes in complexesISEAL

Granata et al. (2016). FASEB J. In Press

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Changes in CS (humans) trainingISEALTraining intensityTraining volume

Bishop et al. (2014). BBA. 140(4): 1266-1275.

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Changes in MR (mice) trainingISEALTraining intensityTraining volume

Bishop et al. (2014). BBA. 140(4): 1266-1275.

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ISEALGranata et al. (2015). FASEB J. in press

Changes in mitochondrial respiration

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ISEALIntensity & Mito RespirationDaussin, et al. (2008). Am J Physiol. 295: R264-272.

36%13%

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ISEAL

Changes in mitochondrial respirationGranata et al. (2015). In Review

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p160RIP140

v

PGC-1 mRNA

CREBMEF2PGC-1 AMPATP

AMPKPAMPKP

PGC-1

MEF2

Mito GenesNucleusPGC-1 PGC-1 p160

ROSp38 MAPKNRFp38PPP Thr ThrHDACPP Se SeNFATHDACRIP140p160PCaMK

PCalcineurinNFATP

T tubuleMuscle fibreAction potentialAxon terminalAchMotor end plateNa+K+Ca2+

Pp53

ISEALGranata et al. (2016) unpublished data

PGC-1 & p53 mRNA

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ISEALEdgett et al. (2013) PLOS ONE. 8(8): e71623

PGC-1 mRNA

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ISEALEdge et al. (2015) PLOS ONE. 10(12):e0141317

10 x 2 min intervals (90% VO2max, : 1 min rest).

Percival et al. (2015) JAP. 119(11): 1303-1312

PGC-1 mRNA

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Nuclear PGC-1ISEALGranata et al. (2016). Unpublished

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Effect of training statusISEALGranata et al. (2016). Unpublished

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ISEAL

p53

M

M

MDM2

PHF20

p53

M

Mnucleuscytosolstress

degradation

stability

MDM2

MDM2

PHF20 action on p53Cui et al. (2012). Nature Struct & Molec Biol 19, 916-924.

P53 and PHF20

30p53:The present study demonstrates that nuclear (and cytosolic) p53 protein content was increased immediately post-exercise, with no significant difference between the two exercise intensities.

A possible explanation for this concomitant increase may relate to an increase in p53 stability [39]. In this regard, p53 has been shown to have an extremely short half-life [47], and cellular stress has been reported to increase its half-life and stability [23, 28]. Consistent with these findings, p53 accumulation in both cellular pools may have been the result of an increased p53 stability in response to the increased physiological stress imparted to the cell by a single bout of exercise.

PHF20 (plant homeodomain finger-containing protein 20)

Given that our hypotheses is the exercise increases p53 stability, we investigated PHF20, a regulator of p53 that has been shown to increase p53 stability.How does this take place?In normal conditions p53 is bound to MDM2, which favours translocation outside the nucleus and its subsequent degradation by the proteasome.However, in condition of physiological stress (such as exercise) PHF20 moves inside the nucleus and binds to p53 reducing the p53-MDM2 interaction reducing p53 degradation and increasing p53 stability.

ISEAL

P53 and PHF20

Cui et al. (2012). Nature Struct & Molec Biol 19, 916-924.

31p53:The present study demonstrates that nuclear (and cytosolic) p53 protein content was increased immediately post-exercise, with no significant difference between the two exercise intensities.

A possible explanation for this concomitant increase may relate to an increase in p53 stability [39]. In this regard, p53 has been shown to have an extremely short half-life [47], and cellular stress has been reported to increase its half-life and stability [23, 28]. Consistent with these findings, p53 accumulation in both cellular pools may have been the result of an increased p53 stability in response to the increased physiological stress imparted to the cell by a single bout of exercise.

PHF20 (plant homeodomain finger-containing protein 20)

Given that our hypotheses is the exercise increases p53 stability, we investigated PHF20, a regulator of p53 that has been shown to increase p53 stability.How does this take place?In normal conditions p53 is bound to MDM2, which favours translocation outside the nucleus and its subsequent degradation by the proteasome.However, in condition of physiological stress (such as exercise) PHF20 moves inside the nucleus and binds to p53 reducing the p53-MDM2 interaction reducing p53 degradation and increasing p53 stability.

ISEAL

p53

Pnucleuscytosol

stabilityAMPKPp38P

P53 and PHF20Granata et al. (2016). Unpublished

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ConclusionsISEALExercise training volume key for mitochondrial content (citrate synthase)Exercise and training intensity key for mitochondrial respiration)May be related to exercise-dependent effects on nuclear PGC-1 and p53

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ISEALThanks

@BlueSpotScienceDavid.Bishop@vu.edu.au

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