Lack of Glycogenin Causes Glycogen Accumulation and Muscle Function Impairment

Glycogenin is considered essential for glycogen synthesis, as it acts as a primer for the initiation of the polysaccharide chain. Against expectations, glycogenin-deficient mice (Gyg KO) accumulate high amounts of glycogen in striated muscle. Furthermore, this glycogen contains no covalently bound protein, thereby demonstrating that a protein primer is not strictly necessary for the synthesis of the polysaccharide in vivo. Strikingly, in spite of the higher glycogen content, Gyg KO mice showed lower resting energy expenditure and less resistance than control animals when subjected to endurance exercise. These observations can be attributed to a switch of oxidative myofibers toward glycolytic metabolism. Mice overexpressing glycogen synthase in the muscle showed similar alterations, thus indicating that this switch is caused by the excess of glycogen. These results may explain the muscular defects of GSD XV patients, who lack glycogenin-1 and show high glycogen accumulation in muscle. [Display omitted] •Glycogen synthesis does not require a protein primer•Glycogenin depletion causes high glycogen accumulation in striated muscles•Glycogenin depletion alters skeletal muscle functionality•Over-accumulation of skeletal muscle glycogen affects oxidative metabolism Although glycogenin is thought to be essential for glycogen synthesis, Testoni et al. show that glycogenin-deficient animals still make glycogen. Surprisingly, glycogen accumulates in striated muscle affecting functionality, including decreased exercise endurance. These findings impact our understanding of glycogen storage disease XV where patients lack glycogenin-1 and accumulate muscle glycogen.