AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle

AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle

One characteristic of ageing skeletal muscle is a decline in mitochondrial function. Activation of AMP-activated protein kinase (AMPK) occurs in response to an increased AMP/ATP ratio, which is one potential result of mitochondrial dysfunction. We have previously observed higher AMPK activity in old...

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Bibliographic Details
Published in:The Journal of physiology Vol. 587; no. 9; pp. 2077 - 2086
Main Authors: Thomson, D.M., Brown, J.D., Fillmore, N., Ellsworth, S.K., Jacobs, D. L., Winder, W.W., Fick, C.A., Gordon, S.E.
Format: Journal Article
Language:English
Published: Oxford, UK The Physiological Society 01-05-2009
Blackwell Publishing Ltd
Blackwell Science Inc
Subjects:
Aging - drug effects
Aging - physiology
Aminoimidazole Carboxamide - administration & dosage
Aminoimidazole Carboxamide - analogs & derivatives
AMP-Activated Protein Kinases - drug effects
AMP-Activated Protein Kinases - metabolism
Animals
Enzyme Activation - drug effects
Muscle Contraction - drug effects
Muscle Contraction - physiology
Rats
Rats, Inbred F344
Ribonucleotides - administration & dosage
Signal Transduction - drug effects
Signal Transduction - physiology
Skeletal Muscle and Exercise
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Summary:One characteristic of ageing skeletal muscle is a decline in mitochondrial function. Activation of AMP-activated protein kinase (AMPK) occurs in response to an increased AMP/ATP ratio, which is one potential result of mitochondrial dysfunction. We have previously observed higher AMPK activity in old (O; 30 months) vs young adult (YA; 8 months) fast-twitch muscle in response to chronic overload. Here we tested the hypothesis that AMPK would also be hyperactivated in O vs YA fast-twitch extensor digitorum longus muscles from Fischer 344 × Brown Norway (FBN) rats ( n = 8 per group) in response to high-frequency electrical stimulation of the sciatic nerve (HFES) or injection of AICAR, an activator of AMPK. Muscles were harvested immediately after HFES (10 sets of six 3-s contractions, 10 s rest between contractions, 1 min rest between sets) or 1 h after AICAR injection (1 mg (g body weight) −1 subcutaneously). The phosphorylations of AMPKα and acetyl-CoA carboxylase (ACC2; a downstream AMPK target) were both greatly increased ( P ≤ 0.05) in response to HFES in O muscles, but were either unresponsive (AMPK α) or much less responsive (ACC) in YA muscles. AMPK α2 activity was also greatly elevated in response to HFES in O muscles (but not YA muscles) despite a lower total AMPK α2 protein content in O vs YA muscles. In contrast, AMPK α2 activity was equally responsive to AICAR treatment in both age groups. Since mitochondrial content and/or efficiency could potentially underlie AMPK hyperactivation, we measured levels of mitochondrial proteins as well as citrate synthase (CS) activity. While CS activity was increased by 25% in O vs YA muscles, uncoupling protein-3 (UCP-3) protein level was upregulated with age by 353%. Thus, AMPK hyperactivation in response to contractile activity in aged fast-twitch muscle may be the result of compromised cellular energetics and not necessarily due to an inherent defect in responsiveness of the AMPK molecule per se.
ISSN:0022-3751
1469-7793
DOI:10.1113/jphysiol.2008.166512