Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis

The underlying mechanism by which skeletal muscle adapts to exercise traini ng or chronic energy deprivation is largely unknown. To examine this questi on, rats were fed for 9 wk either with or without beta -guanadinopropionic acid (beta -GPA; 1% enriched diet), a creatine analog that is known to indu ce muscle adaptations similar to those induced by exercise training. Muscle phosphocreatine, ATP, and ATP/AMP ratios were all markedly decreased and l ed to the activation of AMP-activated protein kinase (AMPK) in the beta -GP A-fed rats compared with control rats. Under these conditions, nuclear resp iratory factor-1 (NRF-1) binding activity, measured using a cDNA probe cont aining a sequence encoding for the promoter of delta -aminolevulinate (ALA) synthase, was increased by about eightfold in the muscle of beta -GPA-fed rats compared with the control group. Concomitantly, muscle ALA synthase mR NA and cytochrome c content were also increased. Mitochondrial density in b oth extensor digitorum longus and epitrochlearis from beta -GPA-fed rats wa s also increased by more than twofold compared with the control group. In c onclusion, chronic phosphocreatine depletion during beta -GPA supplementati on led to the activation of muscle AMPK that was associated with increased NRF-1 binding activity, increased cytochrome c content, and increased muscl e mitochondrial density. Our data suggest that AMPK may play an important r ole in muscle adaptations to chronic energy stress and that it promotes mit ochondrial biogenesis and expression of respiratory proteins through activa tion of NRF-1.