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. 2002 Dec 10;99(25):15983-7.
doi: 10.1073/pnas.252625599. Epub 2002 Nov 20.

AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation

Haihong Zong  1 , Jian Ming Ren, Lawrence H Young, Marc Pypaert, James Mu, Morris J Birnbaum, Gerald I Shulman
Affiliations

AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation

Haihong Zong et al. Proc Natl Acad Sci U S A. .

Abstract

Mitochondrial biogenesis is a critical adaptation to chronic energy deprivation, yet the signaling mechanisms responsible for this response are poorly understood. To examine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved fuel sensor, in mitochondrial biogenesis we studied transgenic mice expressing a dominant-negative mutant of AMPK in muscle (DN-AMPK). Both DN-AMPK and WT mice were treated with beta-guanidinopropionic acid (GPA), a creatine analog, which led to similar reductions in the intramuscular ATPAMP ratio and phosphocreatine concentrations. In WT mice, GPA treatment resulted in activation of muscle AMPK and mitochondrial biogenesis. However, the same GPA treatment in DN-AMPK mice had no effect on AMPK activity or mitochondrial content. Furthermore, AMPK inactivation abrogated GPA-induced increases in the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and calciumcalmodulin-dependent protein kinase IV (both master regulators of mitochondrial biogenesis). These data demonstrate that by sensing the energy status of the muscle cell, AMPK is a critical regulator involved in initiating mitochondrial biogenesis.

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Figures

Fig 1.
Fig 1.
Effect of GPA treatment on protein expression of CaMK IV and CaMK II in WT and DN-AMPK transgenic mice assessed by Western blot analysis (n = 5 in each group). *, P < 0.05 compared with other groups.
Fig 2.
Fig 2.
Effect of GPA treatment on PGC-1α mRNA expression, as assessed by Northern blot analysis, in WT and DN-AMPK transgenic mice (n = 5 in each group). *, P < 0.01 compared with other groups.
Fig 3.
Fig 3.
Effect of GPA treatment on mtDNA in WT and DN-AMPK transgenic mice, as assessed by Southern blot analysis (n = 5 in each group). *, P < 0.05 compared with other groups.
Fig 4.
Fig 4.
Effect of GPA treatment on mitochondrial content assessed by electron microscopy of the epitrochlearis (EPI) muscle of (a) WT mouse (saline treated), (b) WT mouse (GPA treated), (c) DN-AMPK transgenic mouse (saline treated), and (d) DN-AMPK transgenic mouse (GPA treated). Arrows point to mitochondria. (Bar, 1 μm.) (e) Mitochondria density (% of total volume) in the extensor digitorum longus (EDL; n = 10 in each group) and EPI muscles of each group mice (n = 5 in each group). *, P < 0.05 compared with other groups.
Fig 5.
Fig 5.
Effect of GPA treatment on protein expression of cytochrome c, as assessed by Western blot analysis, and ALAS mRNA, as assessed by Northern blot analysis (n = 5 in each group). *, P < 0.05 compared with other groups.
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