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

Huang P, Ho SR, Wang K, Roessler BC, Zhang F, Hu Y, Bowe DB, Kudlow JE, Paterson AJ. Muscle-specific overexpression of NCOAT(GK), splice variant of O-GlcNAcase, induces skeletal muscle atrophy. Am J Physiol Cell Physiol 300: C456-C465, 2011. First published December 22, 2010; doi:10.1152/ajpcell.00124.2010.-The protein O-linked beta-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.