Angela C. Smith

AMP kinase activation with AICAR simultaneously increases fatty acid and glucose oxidation in resting rat soleus muscle

5‐Amino‐4‐imidazolecarboxamide riboside (AICAR), a pharmacological activator of AMP‐activated protein kinase (AMPK), acutely stimulates glucose uptake and fatty acid (FA) oxidation in skeletal muscle. However, it is not fully understood whether AICAR‐induced changes in glucose oxidation are secondary to changes in FA oxidation (i.e. glucose fatty acid cycle), or what role AMPK may be playing in the regulation of intramuscular triacylglycerol (TAG) esterification and hydrolysis. We examined the acute (60 min) effects of AICAR (2 mm) on FA metabolism, glucose oxidation and pyruvate dehydrogenase (PDH) activation in isolated resting rat soleus muscle strips exposed to two different FA concentrations (low fatty acid, LFA, 0.2 mm; high fatty acid, HFA, 1 mm). AICAR significantly increased AMPK α2 activity (+192%; P < 0.05) over 60 min, and simultaneously increased both FA (LFA: +33%, P < 0.05; HFA: +36%, P < 0.05) and glucose (LFA: +105%, P < 0.05; HFA: +170, P < 0.001) oxidation regardless of FA availability. While there were no changes in TAG esterification, AICAR did increase the ratio of FA partitioned to oxidation relative to TAG esterification (LFA: +15%, P < 0.05; HFA: +49%, P < 0.05). AICAR had no effect on endogenous TAG hydrolysis and oxidation in resting soleus. The stimulation of glucose oxidation with AICAR was associated with an increase in PDH activation (+126%; P < 0.05) but was without effect on pyruvate, an allosteric activator of the PDH complex, suggesting that AMPK may stimulate PDH directly. In conclusion, AMPK appears to be an important regulator of both FA metabolism and glucose oxidation in resting skeletal muscle.

AMP kinase activation with AICAR further increases fatty acid oxidation and blunts triacylglycerol hydrolysis in contracting rat soleus muscle

Muscle contraction increases glucose uptake and fatty acid (FA) metabolism in isolated rat skeletal muscle, due at least in part to an increase in AMP‐activated kinase activity (AMPK). However, the extent to which AMPK plays a role in the regulation of substrate utilization during contraction is not fully understood. We examined the acute effects of 5‐aminoimidazole‐4‐carboxamide riboside (AICAR; 2 mm), a pharmacological activator of AMPK, on FA metabolism and glucose oxidation during high intensity tetanic contraction in isolated rat soleus muscle strips. Muscle strips were exposed to two different FA concentrations (low fatty acid, LFA, 0.2 mm; high fatty acid, HFA, 1 mm) to examine the role that FA availability may play in both exogenous and endogenous FA metabolism with contraction and AICAR. Synergistic increases in AMPK α2 activity (+45%; P < 0.05) were observed after 30 min of contraction with AICAR, which further increased exogenous FA oxidation (LFA: +71%, P < 0.05; HFA: +46%, P < 0.05) regardless of FA availability. While there were no changes in triacylglycerol (TAG) esterification, AICAR did increase the ratio of FA partitioned to oxidation relative to TAG esterification (LFA: +65%, P < 0.05). AICAR significantly blunted endogenous TAG hydrolysis (LFA: −294%, P < 0.001; HFA: −117%, P < 0.05), but had no effect on endogenous oxidation rates, suggesting a better matching between TAG hydrolysis and subsequent oxidative needs of the muscle. There was no effect of AICAR on the already elevated rates of glucose oxidation during contraction. These results suggest that FA metabolism is very sensitive to AMPK α2 stimulation during contraction.