Muscle-specific overexpression of NCOATGK, splice variant of O-GlcNAcase, induces skeletal muscle atrophy

Am J Physiol Cell Physiol. 2011 Mar;300(3):C456-65. doi: 10.1152/ajpcell.00124.2010. Epub 2010 Dec 22.


The protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification plays an important role in skeletal muscle development and physiological function. In this study, bitransgenic mice were generated that overexpressed NCOAT(GK), an O-GlcNAcase-inactive spliced variant of the O-GlcNAcase gene, specifically in skeletal muscle using the muscle creatine kinase promoter. Expression of the chimeric enhanced green fluorescent protein-NCOAT(GK) transgene caused an increase of cellular O-GlcNAc levels, along with the accumulation and activation of proapoptotic factors in muscles of bitransgenic mice. The consequence of overexpressing the transgene for a 2-wk period was muscle atrophy and, in some cases, resulted in the death of male mice. Muscle atrophy is a common complication of many diseases, some of which correlate markedly with high cellular O-GlcNAc levels, such as diabetes. Our study provides direct evidence linking muscle atrophy and the disruption of O-GlcNAcase activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation, Enzymologic / physiology
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology*
  • Muscle, Skeletal / enzymology*
  • Muscle, Skeletal / pathology*
  • Muscular Atrophy / enzymology*
  • Muscular Atrophy / pathology*
  • Promoter Regions, Genetic / genetics
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Transgenes / genetics
  • Up-Regulation / genetics
  • beta-N-Acetylhexosaminidases / chemistry
  • beta-N-Acetylhexosaminidases / genetics
  • beta-N-Acetylhexosaminidases / metabolism*


  • Apoptosis Regulatory Proteins
  • Protein Isoforms
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases