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

Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15983-7. doi: 10.1073/pnas.252625599. Epub 2002 Nov 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine Nucleotides / metabolism
  • Adenylate Kinase / deficiency
  • Adenylate Kinase / genetics
  • Adenylate Kinase / physiology*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Energy Metabolism / drug effects
  • Enzyme Induction / drug effects
  • Gene Expression Regulation / drug effects
  • Genes, Dominant
  • Guanidines / pharmacology
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / physiology*
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology*
  • Muscle, Skeletal / ultrastructure
  • Phosphocreatine / metabolism
  • Propionates / pharmacology
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics

Substances

  • Adenine Nucleotides
  • Guanidines
  • Muscle Proteins
  • Propionates
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Phosphocreatine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Camk4 protein, mouse
  • Adenylate Kinase
  • guanidinopropionic acid