Michalis G. Nikolaidis_ECSS Vienna 2016

FUNDAMENTAL AND EMERGING CONCEPTS IN THE REDOX REGULATION OF EXERCISE RESPONSES AND ADAPTATIONS

Michalis G. NikolaidisDepartment of Physical Education and Sports Science (Serres)Aristotle University of ThessalonikiGreece

[email protected]

Trying to bring some order to chaos

Trying to bring some order to chaos

INVOLVEMENT of reactive species in exercise responses and adaptations

F

C

I

FUNDAMENTALITY of redox reactions in biology

COMPLEXITY of reactive species metabolism

I would argue for:

F C I

I would argue for:

INVOLVEMENT of reactive species in exercise responses and adaptations

F

C

I

FUNDAMENTALITY of redox reactions in biology

COMPLEXITY of reactive species metabolism

F C I

I would argue for:

INVOLVEMENT of reactive species in exercise responses and adaptations

F

C

I

FUNDAMENTALITY of redox reactions in biology

COMPLEXITY of reactive species metabolism

F C I

I would argue for:

INVOLVEMENT of reactive species in exercise responses and adaptations

F

C

I

FUNDAMENTALITY of redox reactions in biology

COMPLEXITY of reactive species metabolism

OH• H2O2

10-12 sO2

•-

10-6 s minROO•

2 sNO•

30 sHClO

s to min

F C I

Increasing half life

Heterogeneity of reactive species

Heterogeneity of antioxidantsF C I

Cell

SOD_3

SOD_1

SOD_1 SOD_2

VC

VC

VC

VC

Architectural and functional specificityof redox metabolism

H2O2 Prx-2red

STAT3redH2O Prx-2ox

STAT3ox Redox signaling

H2O2

Prx-2overox(inactive)

Target protein

Random oxidations

Redox signaling

Oxidative stress

F C I

Cell signaling via redox molecules

H2O2

H2O2

H2O

Plasma membrane

Sarcoplasmic reticulum

Ryanodine receptor

Place et al. PNAS 112:15492, 2015

MDA

Ca2+

F C I

Responses/adaptations to oxidative stress

CuZnSOD

Plasma membrane

Endothelium

ecSOD H2O2

nNOS

Sarcoplasmic reticulum

T-tubule

Mitochondrion

H2O2

MnSOD H2O2

NADPHoxidas

e

Phospholipase A2

XO

NADPHoxidas

e

NADPHoxidas

e

eNOSETC

Based on data from Sakellariou et al. Free Radic Res 48:12, 2014

O2−

O2−

O2−

F C I

Exercise produces reactive species

What is the role of reactive species and oxidative stress after exercise?

F C I

The conventional approach

Exercise

Rest

Reactive species

Cobley et al. Free Radic Biol Med 84:65, 2015

Reactive species

F C I

The conventional approach

Exercise

Rest

Antioxidant supplementation

Responses and adaptations

Cobley et al. Free Radic Biol Med 84:65, 2015

Gomez-Cabrera et al. Am J Clin Nutr 87:142, 2008Gomez-Cabrera et al. J Physiol 567:113, 2005

NF-κ

B (a

u)

12

6

3

0

9

Untrained Trained TrainedAllopurinol

Endu

ranc

e (%

)

Trained TrainedVitamin C

25

10

50

15

20

F C I

A milestone

Antioxidant supplementation eitherdoes not augment or hampers

exercise adaptations

“Too much of a good thing” *

* Bartlett et al. Eur J Sport Sci 15:3, 2015

TAPPI3-kinase

(active)

Azzi et al. Arch Biochem Biophys 595:100, 2016

Vit EOH

PI3-kinase(inactive)

Redox active

TAPVit E

OH

F C I

Non-antioxidant effects of antioxidants

TAPVit E

OH

Redox inactive

PI3-kinase(inactive)

Margaritelis et al. Redox Biol 2:520, 2014

0% 12% 100%

Oxidative stress

Reductive stress

F C I

Redox individuality

Paschalis et al. Eur J Nutr 55:45, 2016

F C I

Personalized antioxidant supplementation

High vitamin C

(n=10)

Low vitamin C (n=10)

60 daysWash out

30 days 30 days

Placebo

Vitamin C

Placebo

Vitamin C

Placebo

Vitamin C

Placebo

Vitamin C

n = 100

VO2m

ax (m

l/kg/

min

)

Paschalis et al. Eur J Nutr 55:45, 2016

Vita

min

C (μ

mol

/L)

20

40

60

80

0

F C I

Beneficial effects of Vit C on the ‘rancid’

F 2-is

opro

stan

es (p

g/m

g cr

.)

100

Presupplementation

Postsupplementation

200

400

600

0

800

Presupplementation

Postsupplementation

15

30

45

0

60

Presupplementation

Postsupplementation

High vitamin C group

Low vitamin C group

Margaritelis et al. under review

1st exercise trial

Low EIOSF2-Isop change

n=12

Moderate EIOS

F2-Isop changen=12

High EIOSF2-Isop change

n=12

2nd exercise trial

n=100

Stratification and regression to the mean

-40

-20

0

20

40

60

80

100

120

140

F 2-is

opro

stan

es (%

cha

nge)

1st trial 2nd trial 1st trial 2nd trialHigh EIOS Moderate EIOS

1st trial 2nd trialLow EIOS

Margaritelis et al. under review

Verification of regression to the mean

Margaritelis et al. under review

1st exercise trial

Low EIOSF2-Isop change

n=12

Moderate EIOS

F2-Isop changen=12

High EIOSF2-Isop change

n=12

2nd exercise trial

n=100

The role of oxidative stress in adaptations

Time (weeks)0

Cycling training3 6

Redox &Performanc

e

Redox &Performanc

e

VO2max (% change)

Low EIOS

Moderate EIOS

High EIOS

5 10 15 20

Time trial (% change)

10 20 30

Margaritelis et al. under review

00

F C I

Low oxidative stress leads to low adaptations

Low EIOS

Moderate EIOS

High EIOS

a ‘free radical’ supplement

Veskoukis et al. under review

F C I

Centrality of NADPH in redox regulation

Time to exhaustion (s)

Exercise

ExerciseNicotinamide riboside

40 80 120 160

Kourtzidis et al. under review

0

F C I

Nicotinamide riboside: an NADPH booster

Fundamentality Complexity Involvement

Conclusion

Acknowledgements

Antonios KyparosAristidis VeskoukisNikos MargaritelisAristotle University of Thessaloniki, Greece

Vassilis PaschalisUniversity of Thessaly, Greece

Anastasios TheodorouEuropean University, Cyprus