Polysaccharide Storage Myopathy (PSSM), Type 1
Polysaccharide Storage Myopathy (PSSM) is an inherited muscle disease that affects many and diverse breeds of horses. The clinical characteristics of PSSM vary between breeds, from muscle pain, cramping and cell damage with exercise, to progressive muscle atrophy. Our previous work lead to the discovery of a dominant genetic mutation in the GYS1 gene that is responsible for PSSM in many horses (McCue et al 2008). This mutation results in the accumulation of abnormal complex sugars within skeletal muscle of horses. This form of PSSM is termed Type 1 PSSM. More information about the breeds affected with Type 1 PSSM can be found here: Equine Neuromuscular Lab. Subsequent work in our laboratory has also demonstrated that a mutation in a second gene important in muscle function RYR1, can make the clinical signs of PSSM worse in certain individuals (McCue et al 2009).
To test a horse for PSSM type1, please visit the Minnesota Veterinary Diagnostic Lab for more details.
In addition to the identification of the mutation responsible for Type 1 PSSM, we have three ongoing projects in our laboratory that focus on Type 1 PSSM:
Evidence for positive selection for the GYS1 mutation in Polysaccharide Storage Myopathy.
The mutation in GYS1 resulting in PSSM has been recognized in many different breeds and is quite common (up to 35% prevalence) in some of them. It is surprising that a mutation linked to moderate-to-severe clinical disease has persisted at such high frequencies in several different breeds. We believe that under historical management conditions (daily work with limited feed), excess sugar accumulation in the muscles was advantageous for horses and as a result this “thrifty” genotype was positively selected for through breeding. Under modern management conditions (limited work and excess feed) however, the mutation leads to disease. We are using molecular genetics techniques to provide evidence for previous positive selection at the GYS1 locus, which is the first example of such selection reported in this species. “Thrifty” genotypes have also been proposed as the underlying cause for susceptibility to common diseases in humans, such as Type II diabetes and hypertension, therefore horses with the GYS1 mutation may be a good model in which to study this theory.
This work is funded by the American Quarter Horse Foundation “Genetic Analysis of Glycogen Storage Disorders in Quarter Horses” and NIH-NIAMS “Regulation of glycogen metabolism: Insights from novel genetic models” and University of Minnesota Summer Scholars research program
Determine the functional basis of the GYS1 mutation.
GYS1 codes for the skeletal muscle isoform of glycogen synthase, the enzyme responsible for the formation of glycogen in skeletal muscle. The PSSM mutation occurs in a region of the glycogen synthase enzyme whose amino acid sequence is conserved throughout mammalian and yeast species. We believe that the likely gain of function in the PSSM horse glycogen synthase is due to altered kinetic properties or altered regulation of the enzyme. In this project we are expressing the mutant and normal forms of glycogen synthase in vitro using an insect cell system, so we can study the effect of the PSSM mutation on enzyme function.
This work is funded by NIH-NIAMS “Regulation of glycogen metabolism: Insights from novel genetic models”
Skeletal muscle energy dysregulation in Polysaccharide Storage Myopathy.
The clinical manifestation of skeletal muscle glycogen storage diseases is typically either rhabdomyolysis (damage of muscle cells) and/or fixed, progressive weakness due to an inability to maintain adequate ATP levels. PSSM horses can metabolize glycogen and have a normal flux of metabolites through glycolysis during maximal exercise, yet these horses demonstrate exercise intolerance, painful muscle cramping, and rhabdomyolysis during sub-maximal (aerobic) exercise. During submaximal exercise, muscle in PSSM horses demonstrates a marked energy deficiency when compared to normal controls. During submaximal exercise, muscle is largely dependant on fat metabolism for energy generation, suggesting that the skeletal muscle cellular energy deficit and rhabdomyolysis in PSSM cannot be explained solely by the altered glycogen metabolism secondary to the GYS1 mutation. We believe that the skeletal muscle energy deficit and rhabdomyolysis in PSSM horses is due to altered regulation of gene expression in energy producing metabolic pathways induced by excessive glycogen levels and\or improperly regulated glycogen synthase activity. In this project, we will investigate the genes and gene pathways that are altered in PSSM horses during rhabdomyolysis, and the alteration of gene expression patterns after exercise training. Expression will be quatified using next-generation sequencing of the skeletal muscle transcriptome (RNA-seq) in PSSM cases and controls both before and after a controlled exercise regimen.
This work is funded by Office of the VP of Research University of Minnesota Grant in Aid “Skeletal muscle energy dysregulation in PSSM”
McCue, ME, Valberg, SJ, Miller, M, Wade, C, Mickelson , JR. Glycogen synthase 1 mutation causes a novel myopathy in horses. Genomics 91 (5): 458-466, 2008. PMC2430182
McCue, ME, Valberg, SJ and Mickelson JR. Glycogen synthase (GYS1) mutation in diverse breeds with Polysaccharide Storage Myopathy. Journal of Veterinary Internal Medicine, 2008, 22(5): 1228-1233. PMID: 18822097.
McCue ME, Valberg SJ, Jackson M, Borgia L, Lucio M, Mickelson JR. Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation. Neuromuscul Disord. 2009 Jan;19(1):37-43. PMID: 19056269.