Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice

J Biol Chem. 2016 Jan 29;291(5):2181-95. doi: 10.1074/jbc.M115.676510. Epub 2015 Dec 8.


Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells.

Keywords: acetoacetate; cyclin D1; extracellular-signal-regulated kinase (ERK); muscle regeneration; muscular dystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetoacetates / pharmacology*
  • Animals
  • Cell Proliferation
  • Cyclin D1 / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Ketone Bodies / chemistry
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiology*
  • Muscular Dystrophy, Animal / drug therapy*
  • Regeneration / drug effects*
  • Satellite Cells, Skeletal Muscle / cytology
  • Signal Transduction


  • Acetoacetates
  • Ketone Bodies
  • Cyclin D1
  • acetoacetic acid
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse