Skeletal Muscle Gene Expression Profile in Type 1 Polysaccharide Storage Myopathy

Type 1 Polysaccharide Storage Myopathy (PSSM1) is caused by a gain of function in skeletal muscle glycogen synthase that leads to excessive glycogen and abnormal polysaccharide accumulation in muscle fibers. PSSM1 horses utilize glycogen, but develop exercise intolerance and rhabdomyolysis during sub-maximal exercise. The link between excessive glycogen, abnormal polysaccharide and rhabdomyolysis is unknown. Controlled regular exercise and a low starch/high fat diet improve PSSM1clinical signs. We hypothesized that 1) excess glycogen and/or improper regulation of glycogen synthase results in altered gene expression in skeletal muscle energy metabolism pathways leading to rhabdomyolysis in PSSM1; and 2) that clinical improvement with daily exercise is due to normalization of gene expression in PSSM1 horses. Gluteal muscle biopsies were collected from PSSM1 cases and controls receiving a high starch diet prior to training (t1), before (t2) and immediately after exercise (t3) following a standardized 3-week training protocol. RNA was isolated and sequenced at 40-million reads/sample; reads were mapped to EquCab2 (BOWTIE/TOPHAT) and transcripts assembled (CUFFLINKS). De novo assembly was performed to identify novel transcripts. Differential gene expression was measured by Edge-R. 195, 294 and 739 genes were differentially expressed between cases and controls at t1, t2 and t3, respectively. The largest differences in expression were in cases between t1-t3 (4822 genes) and t2-t3 (2474 genes). Genes involved in glycogen metabolism, glycolysis and mitochondrial electron transport were differentially expressed between cases and controls. Understanding altered energy regulation in PSSM1 should lead to new therapies and new insights in metabolic myopathies and muscle glycogen regulation.