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.

We wish to thank the following members of IRB Barcelona: Anna Adrover, Emma Veza, Natalia Plana, and Vanessa Hernandez for technical assistance; and Dr. Antonio Zorzano for essential reagents and advice, the histopathology, the mouse mutant, and the biostatistics/bioinformatics core facilities. Thanks also to Dr. Marina Gay for mass spectrometry advice and data analysis and Dr. Mireia Díaz-Lobo for mass spectrometry experiments. Mass spectrometry was performed at the IRB Barcelona Mass Spectrometry and Proteomics Core Facility, which actively participates in the BMBS European COST Action BM 1403 and is a member of Proteored, PRB2-ISCIII, supported by grant PRB2 (IPT13/0001 - ISCIII-SGEFI / FEDER). Thanks also to Dr. Carmen Lopez-Iglesias (University of Barcelona) for assistance with the electron microscope. G.T. is supported by the “La Caixa” PhD Fellowship Program. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). This study was supported by grants from the Spanish MINECO (BFU2011-30554-C02-00 and SAF2014-54525-P). M.A.S. was supported by an NHMRC CJ Martin Fellowship (GNT1092451). NIH grants to Velocigene at Regeneron (U01HG004085) and the CSD Consortium (U01HG004080) funded the generation of gene-targeted ES cells in the KOMP Program. None of the supporting agencies had any role in establishing the work or in writing the manuscript.