The Interplay of Genetics, Exercise, and Nutrition in Polysaccharide Storage Myopathy

Polysaccharide storage myopathy (PSSM), identified in 1992 in a subset of horses with exertional rhabdomyolysis, is a glycogenosis characterized by amylase-resistant polysaccharide in a small number of skeletal muscle fibers along with 1.5 to 4 times normal muscle glycogen. Extensive biochemical and physiological analyses failed to identify defects in glycogenolysis and glycolysis. In 2008, a genome-wide association analysis detected a locus on equine chromosome 10 that was strongly associated with the PSSM in Quarter Horses. Glycogen synthase 1 (GYS1), which encodes the skeletal muscle isoform of glycogen synthase (GS), was a strong candidate gene for PSSM based on its location on equine chromosome 10. Sequencing of the GYS1 gene in PSSM and control Quarter Horses identified only one single base-pair change that resulted in an amino acid substitution in the GS enzyme. Mean GS activity was higher in PSSM than control muscle homogenates in both the presence and absence of the allosteric activator glucose 6-phosphate, suggesting that the GS enzyme in horses with PSSM is constitutively active. High-grain diets increase serum insulin concentrations which further act to stimulate GS activity. An restriction fragment length polymorphism assay for the GYS1 mutation showed that 10% of the Quarter Horse breed and a minimum of 20 other breeds have the GYS1 mutation. Muscle biopsies obtained after 20 minutes of aerobic exercise revealed much higher inosine monophosphate concentrations and lower adenosine monophosphate in whole muscle and single fibers from PSSM as compared with control horse muscle. Thus, the GYS1 mutation responsible for PSSM seems to cause an energy imbalance exacerbated by high-grain diets, which results in adenine nucleotide degradation in individual muscle fibers of horses with PSSM during submaximal exercise.