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

Published Article
The Journal of Physiology
Wiley Blackwell (Blackwell Publishing)
Publication Date
Pt 9
DOI: 10.1113/jphysiol.2008.166512
PMID: 19273578


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) x 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 AMPKalpha and acetyl-CoA carboxylase (ACC2; a downstream AMPK target) were both greatly increased (P <or= 0.05) in response to HFES in O muscles, but were either unresponsive (AMPK alpha) or much less responsive (ACC) in YA muscles. AMPK alpha2 activity was also greatly elevated in response to HFES in O muscles (but not YA muscles) despite a lower total AMPK alpha2 protein content in O vs YA muscles. In contrast, AMPK alpha2 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.


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