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1 Departments of Internal Medicine, 3 Cell Biology, and 5 Cellular and Molecular Physiology, and the 6 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510; 2 Bristol-Myers Squibb, Princeton, New Jersey 08543; and 4 Departments of Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
The underlying mechanism by which
skeletal muscle adapts to exercise training or chronic energy
deprivation is largely unknown. To examine this question, rats were fed
for 9 wk either with or without 
-guanadinopropionic acid (-GPA;
1% enriched diet), a creatine analog that is known to induce muscle
adaptations similar to those induced by exercise training. Muscle
phosphocreatine, ATP, and ATP/AMP ratios were all markedly decreased
and led to the activation of AMP-activated protein kinase (AMPK) in the
-GPA-fed rats compared with control rats. Under these conditions,
nuclear respiratory factor-1 (NRF-1) binding activity, measured using a
cDNA probe containing a sequence encoding for the promoter of 
-aminolevulinate (ALA) synthase, was increased by about eightfold in
the muscle of -GPA-fed rats compared with the control group. Concomitantly, muscle ALA synthase mRNA and cytochrome c
content were also increased. Mitochondrial density in both extensor
digitorum longus and epitrochlearis from -GPA-fed rats was also
increased by more than twofold compared with the control group. In
conclusion, chronic phosphocreatine depletion during -GPA
supplementation led to the activation of muscle AMPK that was
associated with increased NRF-1 binding activity, increased cytochrome
c content, and increased muscle mitochondrial density. Our
data suggest that AMPK may play an important role in muscle adaptations
to chronic energy stress and that it promotes mitochondrial biogenesis
and expression of respiratory proteins through activation of NRF-1.
nuclear respiratory factor-1; muscle adaptation; -aminolevulinate synthase; cytochrome c; -guanadinopropionic acid
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