AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle
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Date
2009-05-01
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Authors
Thomson, D. M.
Brown, J. D.
Fillmore, N.
Ellworth, S. K.
Jacobs, D. L.
Winder, W. W.
Fick, C. A.
Gordon, Scott Edward
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East Carolina University
Abstract
One characteristic of aging 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; 8months) 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 Fischer344 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, 1min rest between sets) or 1 h after AICAR injection (1mg (g body weight)-1 subcutaneously). The phosphorylations of AMPKalpha and acetyl-CoA carboxylase (ACC2; a downstream AMPK target) were both greatly increased (P less than or equal to 0.05) in response to HFES inOmuscles, but were either unresponsive (AMPKalpha) or much less responsive (ACC) in YA muscles. AMPKalpha2 activity was also greatly elevated in response to HFES in O muscles (but not YA muscles) despite a lower total AMPKalpha2 protein content in O vs YA muscles. In contrast, AMPKalpha2 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. Originally published Journal of Physiology, Vol. 589, Pt. 9, May 2009
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Citation
Journal of Physiology; 587:9 p. 2077-2086
DOI
10.1113/jphysiol.2008.166512