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

Abstract

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.

The effects of age and muscle contraction on AMPK activity and heterotrimer composition

“…This is consistent with previous findings in rodent (Ljubicic and Hood 2009; Thomson et al 2009) and human (Drummond et al 2008) muscle, and makes sense given the broad view of AMPK as part of a stress-sensing system.…”

Impaired AMPK Activity Drives Age-Associated Acute Lung Injury after Hemorrhage

“…For example, the capacity for AMPK activation in skeletal muscle in response to exercise was decreased in older rats. As in this study, AICAR administration only increased the activity of AMPK in younger rats (20). In contrast to studies involving LPS-induced lung injury (21), AICAR administration in this study did not affect NF-kB or TNF-a levels after hemorrhage-induced lung injury.…”

Diminished Autophagy Limits Cardiac Injury in Mouse Models of Type 1 Diabetes

“…For example, AMPK inhibits cellular processes that consume ATP and promotes ATP-generating pathways. It enhances mitochondrial oxidation of fatty acids (53) and promotes mitochondrial biogenesis (54). These autophagy-independent effects of AMPK may account for the ability of metformin to protect the diabetic heart.…”