Decreasing muscle phosphagen content through dietary administration of the
creatine analog
beta-guanidinopropionic acid (beta-GPA) improves skeletal muscle oxidative capacity and resistance to
fatigue during aerobic exercise in rodents, similar to that observed with
endurance training. Surprisingly, the effect of beta-GPA on muscle substrate metabolism has been relatively unexamined, with only a few reports of increased muscle GLUT4 content and
insulin-stimulated
glucose uptake/clearance in rodent muscle. The effect of chronically decreasing muscle phophagen content on muscle
fatty acid (FA) metabolism (transport, oxidation, esterification) is virtually unknown. The purpose of the present study was to examine changes in muscle substrate metabolism in response to 8 wk feeding of beta-GPA. Consistent with other reports, beta-GPA feeding decreased muscle
ATP and total
creatine content by approximately 50 and 90%, respectively. This decline in energy charge was associated with simultaneous increases in both
glucose (GLUT4; +33 to 45%, P < 0.01) and FA (FAT/CD36; +28 to 33%, P < 0.05) transporters in the sarcolemma of red and white muscle. Accordingly, we also observed significant increases in
insulin-stimulated
glucose transport (+47%, P < 0.05) and
AICAR-stimulated
palmitate oxidation (+77%, P < 0.01) in the soleus muscle of beta-GPA-fed animals. Phosphorylation of AMPK (+20%, P < 0.05), but not total
protein, was significantly increased in both fiber types in response to muscle phosphagen reduction. Thus the content of sarcolemmal transporters for both of the major energy substrates for muscle increased in response to a reduced energy charge. Increased phosphorylation of AMPK may be one of the triggers for this response.