Dissociation of AMP-activated protein kinase activation and glucose transport in contracting slow-twitch muscle.

Abstract

5AMP-activated protein kinase (AMPK) has been suggested to be a key regulatory protein in exercise signaling of muscle glucose transport. To test this hypothesis, we investigated whether muscle glycogen levels affect AMPK activation and glucose transport stimulation similarly during contractions. Rats were preconditioned by a combination of swimming exercise and diet to obtain a glycogen-supercompensated group (high muscle glycogen content [HG]) with ~3-fold higher muscle glycogen levels than a glycogen-depleted group (low muscle glycogen content [LG]). In perfused fast-twitch muscles, contractions induced significant increases in AMPK activity and glucose transport and decreases in acetyl-CoA carboxylase (ACC) activity in both HG and LG groups. Contraction-induced glucose transport was nearly 2-fold (P < 0.05) and AMPK activation was 3-fold (P < 0.05) higher in the LG group compared with the HG group, whereas ACC deactivation was not different between groups. Thus, there was a significant positive correlation between AMPK activity and glucose transport in contracting fast-twitch muscles (r = 0.80, P < 0.01). However, in slow-twitch muscles with HG, glucose transport was increased 6-fold (P < 0.05) during contractions, whereas AMPK activity did not increase. In contracting slow-twitch muscles with LG, the increase in AMPK activity (315%) and the decrease in ACC activity (54 vs. 34% at 0.2 mmol/l citrate, LG vs. HG) was higher (P < 0.05) compared with HG muscles, whereas the increase in glucose transport was identical in HG and LG. In conclusion, in slow-twitch muscles, high glycogen levels inhibit contraction-induced AMPK activation without affecting glucose transport. This observation suggests that AMPK activation is not an essential signaling step in glucose transport stimulation in skeletal muscle.

Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle during exercise

“…Altogether, the present study suggests that during exercise, covalent regulation of ␣ 2 -AMPK on Thr 172 is glycogen dependent, but that ACC␤ Ser 221 phosphorylation does not parallel ␣ 2 -AMPK activity when circulating glucose and epinephrine levels are standardized. This is supported by findings in isolated contracting rodent skeletal muscle with high and low muscle glycogen levels, where differences in ␣ 2 -AMPK activity did not translate into differences in ACC activity (8).…”

“…In the present study, circulating epinephrine did not differ significantly between conditions, and, still, ␣ 2 -AMPK activity during exercise was markedly higher in L-CHO than in H-CHO (Table 1). This suggests that altered muscle glycogen alone can influence ␣ 2 -AMPK activity in human skeletal muscle during exercise independently of adrenergic stimulation, in agreement with studies in rodent muscle (8). On this basis, AMPK could be a likely candidate mediating the effect of muscle glycogen on fat oxidation through regulation of ACC activity and malonylCoA formation, as suggested earlier (34,41).…”

“…It was previously suggested that low preexercise muscle glycogen content might be associated with high AMPK activity in rodents during muscle contraction in vitro (8) and in humans during exercise (44). However, in the latter study, circulating epinephrine was also dependent on muscle glycogen content (44), wherefore the possible effect of muscle glycogen on ␣ 2 -AMPK activity may have been confounded by adrenergic stimulation of ␣ 2 -AMPK.…”

AICAR Administration Causes an Apparent Enhancement of Muscle and Liver Insulin Action in Insulin-Resistant High-Fat-Fed Rats

“…Insulin action was assessed 24 h after AICAR administration, long after its acute effects on plasma glucose and glycerol levels had dissipated. Also, ACC activity, which is considered a good indicator of AMPK activation (48), was similar in liver of HF-Con and HF-AIC groups during the clamp, suggesting that the effect of AICAR on AMPK activation had worn off by 24 h. Finally, in a separate study, we found no residual increase in AMPK or reduction in ACC activity in muscle or liver of control rats 24 h after injection of a similar dose of AICAR (A.S. and N.B.R., unpublished observations). Whether by activating AMPK a single dose of AICAR induced chronic changes (e.g., at the level of transcription [49]) that inhibited hepatic glucose output or enhanced glucose utilization was not studied.…”

Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity

“…A number of studies have shown that AMPK activity in skeletal muscle is increased following exercise in both humans and rodents [4][5][6][7][8]. Furthermore, activation of AMPK in resting skeletal muscle increases both glucose uptake and fatty acid oxidation [9] as well as gene expression [10; 11], leading to speculation that AMPK could mediate the increase in these pathways in response to exercise {Winder, 1999 3011 /id format ref}.…”