Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration

Hum Mol Genet. 2016 Aug 1;25(15):3178-3191. doi: 10.1093/hmg/ddw167. Epub 2016 Jun 10.


Acute pharmacological activation of adenosine monophosphate (AMP)-kinase using 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) has been shown to improve muscle mitochondrial function by increasing mitochondrial biogenesis. We asked whether prolonged AICAR treatment is beneficial in a mouse model of slowly progressing mitochondrial myopathy (Cox10-Mef2c-Cre), and whether the compensatory mechanism is indeed an increase in mitochondrial biogenesis. We treated the animals for 3 months and found that sustained AMP-dependent kinase activation improved cytochrome c oxidase activity, rescued the motor phenotype and delayed the onset of the myopathy. This improvement was observed whether treatment started before or after the onset of the disease. We found that AICAR increased skeletal muscle regeneration thereby decreasing the levels of deleted Cox10-floxed alleles. We conclude that although increase in mitochondrial biogenesis and other pathways may contribute, the main mechanism by which AICAR improves the myopathy phenotype is by promoting muscle regeneration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Alkyl and Aryl Transferases / genetics
  • Alkyl and Aryl Transferases / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / genetics
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / pathology
  • Mitochondrial Myopathies / drug therapy*
  • Mitochondrial Myopathies / genetics
  • Mitochondrial Myopathies / metabolism*
  • Mitochondrial Myopathies / pathology
  • Muscle Fibers, Skeletal / physiology*
  • Regeneration / drug effects*
  • Ribonucleotides / pharmacology*


  • Membrane Proteins
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Alkyl and Aryl Transferases
  • COX10 protein, mouse
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide