Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis - PubMed (original) (raw)

doi: 10.1016/j.cmet.2007.01.008.

Haihong Zong, Ji Li, Katsutaro Morino, Irene K Moore, Hannah J Yu, Zhen-Xiang Liu, Jianying Dong, Kirsty J Mustard, Simon A Hawley, Douglas Befroy, Marc Pypaert, D Grahame Hardie, Lawrence H Young, Gerald I Shulman

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Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis

Richard M Reznick et al. Cell Metab. 2007 Feb.

Abstract

Recent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-alpha(2) activity by 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats. Furthermore, mitochondrial biogenesis in response to chronic activation of AMPK with beta-guanidinopropionic acid (beta-GPA) feeding was also diminished in old rats. These results suggest that aging-associated reductions in AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with aging.

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Figures

Figure 1

Figure 1

The Effect of AICAR Infusions on AMPK and LKB1 in Young and Old Rats (A) AMPK-α2 activity in the EDL muscle of young and old rats infused with either AICAR or saline (control). AMPK-α2 activity was increased by 44% in the young AICAR-treated rats compared to the young saline-treated rats. In contrast, there was no difference between the old AICAR-treated and saline-treated rats. (n = 7–10 in each group.) ∗p = 0.01. In this and all other figures, values are presented as means ± SEM. (B) p-ACC (Ser79) in the EDL muscle of young and old rats infused with either AICAR or saline (control). AICAR infusion resulted in a 120% increase in p-ACC (Ser79) in the young rats. In contrast, there was no effect of AICAR infusion on p-ACC (Ser79) in the old rats. (n = 4–6 in each group.) ∗p < 0.05. (C) p-AMPK (Thr172) in the EDL muscle of young and old rats infused with either AICAR or saline (control). AICAR infusion resulted in a 162% increase in p-AMPK (Thr172) in the young rats. In contrast, there was no effect of AICAR infusion on p-AMPK (Thr172) in the old rats. (n = 4–6 in each group.) ∗p < 0.05. (D) LKB1 protein expression in the EDL muscle of young and old rats infused with either AICAR or saline (control). LKB1 protein expression in EDL muscle of young and old rats did not differ significantly during aging or in response to AICAR infusion. (n = 4 in each group.) (E) LKB1 activity in the EDL muscle of young and old rats infused with either AICAR or saline (control). LKB1 activity in the EDL muscle of young and old rats did not differ significantly during aging or in response to AICAR infusion. (n = 4 in each group.)

Figure 2

Figure 2

The Effect of Exercise on AMPK in Young and Old Rats (A) AMPK-α2 activity in the EDL muscle of exercising or sedentary young and old rats. AMPK-α2 activity was increased by 110% in the young exercising rats compared to the young sedentary rats. In contrast, there was no difference between the old exercising rats and old sedentary rats. (n = 8 in each group.) ∗p = 0.01. (B) p-ACC (Ser79) in the EDL muscle of exercising or sedentary young and old rats. Exercise resulted in a 127% increase in p-ACC (Ser79) in the young rats. In contrast, there was no effect of exercise on p-ACC (Ser79) in the old rats. (n = 4 in each group.) ∗p < 0.05. (C) p-AMPK (Thr172) in the EDL muscle of exercising or sedentary young and old rats. Exercise resulted in a 55% increase in p-AMPK (Thr172) in the young rats. In contrast, there was no effect of exercise on p-AMPK (Thr172) in the old rats. (n = 4 in each group.) ∗p < 0.05.

Figure 3

Figure 3

The Effect of β-GPA Feeding on AMPK and Mitochondrial Biogenesis in Young and Old Rats (A) AMPK-α2 activity in the EDL muscle of young and old rats fed either a β-GPA-supplemented diet or a control diet. The β-GPA-supplemented diet resulted in a 146% increase in AMPK-α2 activity in the young rats. In contrast, the β-GPA-supplemented diet had no effect on AMPK-α2 activity in the old rats. (n = 3–4 in each group.) ∗p < 0.01. (B) Pgc-1_α mRNA expression in the EDL muscle of young and old rats fed either a β-GPA-supplemented diet or a control diet. Pgc-1_α mRNA expression increased by 86% in the young β-GPA-fed rats. In contrast, there was no difference in Pgc-1_α mRNA expression in the old rats. (n = 5–8 in each group.) ∗p < 0.05. (C) Percent increase in mitochondrial density in the EDL muscle of young and old rats fed a β-GPA-supplemented diet compared to control rats. Mitochondrial density increased by 38% in the young β-GPA-fed rats. In contrast, the β-GPA-supplemented diet resulted in no difference in mitochondrial density in the old rats. (n = 4–5 in each group.) ∗p < 0.05. (D) δ_-Alas mRNA expression in the EDL muscle of young and old rats fed either a β-GPA-supplemented diet or a control diet. δ_-Alas mRNA expression increased by 289% in the young β-GPA-fed rats. In contrast, there was no difference in δ_-Alas mRNA expression in the old rats. (n = 3–8 in each group.) ∗p = 0.05. (E) Cytochrome c protein expression in the EDL muscle of young and old rats fed either a β-GPA-supplemented diet or a control diet. Cytochrome c protein expression increased by 76% in the young β-GPA-fed rats. In contrast, there was no difference in cytochrome c protein expression in the old rats. (n = 4–8 in each group.) ∗p < 0.05 .

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