Bente Klarlund Pedersen`s Group The Department of Infectious Diseases and The Copenhagen Muscle Research Centre Rigshospitalet University of Copenhagen www.bkpgroup.dk [e-mail]

1
Bente Klarlund Pedersens GroupThe Department of
Infectious Diseases and The Copenhagen Muscle
Research Centre Rigshospitalet University of
Copenhagen www.bkpgroup.dkbkp_at_rh.dk

• Muskelaktivitet,
• IL-6 og insulinfølsomhed
• ved mødet blev også præsenteret
• upublicerede data, som ikke
• kan lægges på nettet

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Muscle contraction
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?
Exercise factor
?
?
?
?
4
IL-6
Muscle contraction
IL-6
IL-6
IL-6
IL-6
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Cytokine response

Pro-inflammatory
TNF
6
Cytokine response

Pro-inflammatory
Anti-inflammatory
TNF
IL-1ra
TNF-R
IL-10
7
Cytokine response in Sepsis
IL-6

Pro-inflammatory
Anti-inflammatory
TNF
IL-1ra
TNF-R
IL-10
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Cytokine response in Exercise
IL-6

Anti-inflammatory
IL-1ra
TNF-R
IL-10
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Plasma IL-6 (G. Mean with 95 confidence
interval) Treadmill Marathon
Ostrowski et al J. Physiol 1999
Ostrowski et al J. Physiol, 1998
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Do muscles contribute?
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Muscle-IL-6mRNA
J. Physiol. 1999 J. Physiol. 2000 J. Physiol.
2001 J. Physiol. 2001 FASEB J. 2001
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IL-6 immunostainings of human muscle biopsies
AB Resting subjects
C-H 3 h of bicycling (0-3h) FASEB J 2003
3h
0
4.5h
6h
9h
24h
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Signal transduction - from muscle to IL-6 gene -
role of calcineurin and NFAT
Muscle contraction
Activation of IL-6 gene
Activation of other geners
pNFAT
Ca2
Calcineurin
active calcineurin
p
NFAT
Cytosol
NFAT
IL-6 gene
active
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Signal transduction - from muscle to IL-6 gene -
role of calcineurin and NFAT
Ionomycin
pNFAT
Ca2
Calcineurin
active calcineurin
p
NFAT
Cytosol
NFAT
IL-6 gene
active
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Role of calcineurin and NFAT
Ionomycin
Cyclosporin
pNFAT
Ca2
Calcineurin
active calcineurin
p
NFAT
Cytosol
NFAT
IL-6 gene
active
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Net-IL-6 release
Steensberg A. et al., Journal of Physiology
(2000), 529.1, pp237-242.
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Muscle contracktion
IL-6
Muscles produce and release IL-6 during
exercise
IL-6
IL-6
IL-6
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Does IL-6 induce a hormonal response?
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Arterial IL-6

• No changes
• Adrenaline
• Noradrenaline
• Glucagon

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rhIL-6 infusion enhancesCortisol levels
Steensberg et al Am J Physiol, 2003
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Antioxidants attenuate exercise-induced increase
in arterial IL-6


Exercise








Different from 0 h in aEC. Different from 0
h in ?EC. Different from 0 h in Control.
Difference between aEC and Control. Different
between ?EC and Control.
23
Fischer et al 2003
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Antioxidants inhibits exercise-induced leg
release of IL-6
Exercise





Different from 0 h in aEC. Different from 0
h in ?EC. Different from 0 h in Control.
Difference between aEC and Control. Different
between ?EC and Control.
23
23
Antioxidants inhibits exercise-induced increase
in cortisol



Exercise
Different from 0 h in aEC. Different from 0
h in ?EC. Different from 0 h in Control.
Difference between aEC and Control. Different
between ?EC and Control.
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Muscle-derived IL-6 induces cortisol production
during exercise
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Regulation of muscle-derived IL-6- role of
glycogenand CHO
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Glycogen Metabolism
Muscle Glycogen
Muscle Glycogen
Exercise
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Glycogen Metabolism
Muscle Glycogen
Muscle Glycogen
Exercise
Exercise
p38MAPK
GSK3
PP1
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Transcription rate for IL-6
DNA RNA
Exercise
Keller C et al, FASEB J, December, 2001
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Exercise with and withoutcarbohydrate
supplementation
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Exercise with and withoutcarbohydrate
supplementation
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Exercise with and withoutcarbohydrate
supplementation
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Exercise with and withoutcarbohydrate
supplementation
Febbraio M et al J.Physiol, 2003
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IL-6, glycogen and CHO

• Low muscle glycogen
• Carbohydrate

DNA mRNA
mRNA protein release
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Metabolic roles ofIL-6
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Does IL-6 influence blood supply of
carbohydrates and fat?
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Does IL-6 influence glucose production from the
liver?
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Arterial glucose
Ra glucose
Steensberg et al, J.Physiol 2003
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Does IL-6 induce Lipolysis ?

IL-6 induces lipolysis
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Arterial FA
Van Hall et al, J Clin Endocrinol Metab June 2003
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Rate of appearance of Fatty Acids
Van Hall et al, J Clin Endocrinol Metab June 2003
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Rate of disappearance of Fatty Acids
Van Hall et al, J Clin Endocrinol Metab June 2003
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IL-6 induces lipolysis in vitro of adipocyte cell
cultures
IL-6
Lipolysis
Reviewed in FASEB J 2002
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IL-6 KO mice develop obesity and insulin
resistance
Wallenius et al Nature Medicine 2002
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Muscle contraction
IL-6
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Muscle Contraction Low glycogen
IL-6
Keller, FASEB J December 2001 Steensberg, J
Physiol 2001
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Carbohydrate
Muscle Contraktion
IL-6
Febbraio et al 2003
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Relative changes
Ra Palmitate Rd Palmitate
IL-6
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Relative changes
Ra Palmitate Rd Palmitate
Ra Glucose Rd Glucose
IL-6
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Relative changes
Ra Palmitate Rd Palmitate
Ra Glucose Rd Glucose
IL-6 during exercise
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Relative changes
Ra Palmitate Rd Palmitate
Insulin
Ra Glucose Rd Glucose
IL-6
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Relative changes
Cortisol
Ra Palmitate Rd Palmitate
Insulin
Ra Glucose Rd Glucose
IL-6
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Relative changes
IL-10 IL-1ra
Cortisol
Ra Palmitate Rd Palmitate
Insulin
Ra Glucose Rd Glucose
IL-6
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Relative changes
IL-10 IL-1ra
Cortisol
Ra Palmitate Rd Palmitate
Insulin
TNF
Ra Glucose Rd Glucose
IL-6
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Relative changes
IL-10 IL-1ra
Cortisol
Ra Palmitate Rd Palmitate
Insulin
TNF
Ra Glucose Rd Glucose
IL-6 production
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Relative changes
IL-10 IL-1ra
Cortisol
Ra Palmitate Rd Palmitate
Insulin
TNF
Ra Glucose Rd Glucose
IL-6 production
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IL-6
IL-6?
IL-6
IL-6
IL-6
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IL-6
IL-6?
IL-6
IL-6
IL-6
Exercise factor?
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IL-6
IL-6?
IL-6
IL-6
IL-6
A myokine ?
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