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

Abstract

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.

• Authors: Ping Huang, Shiuh-Rong Ho, Kai Wang, Bryan C Roessler, Fengxue Zhang, Yong Hu, Damon B Bowe, Jeffrey E Kudlow, Andrew J Paterson
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 300 Issue 3 Pg. C456-65 (Mar 2011) ISSN: 1522-1563 [Electronic] United States
• PMID: 21178104 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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