Title: Genes and exercise intolerance: Insights from McArdle disease

32 McArdle disease (glycogen storage disease type V) is caused by inherited deficiency of 33 a key enzyme in muscle metabolism, the skeletal-muscle specific isoform of glycogen 34 phosphorylase, ‘myophosphorylase’, which is encoded by the PYGM gene. Here we 35 review the main pathophysiological, genotypic and phenotypic features of McArdle 36 disease and their interactions. To date, moderate-intensity exercise (together with pre37 exercise carbohydrate ingestion) is the only treatment option that has proven useful for 38 these patients. Further, regular physical activity attenuates the clinical severity of 39 McArdle disease. This is quite remarkable for a monogenic disorder that consistently 40 leads to the same metabolic defect at the muscle tissue level, that is, complete inability 41 to use muscle glycogen stores. Further knowledge of this disorder would help patients 42 and enhance understanding of exercise metabolism as well as exercise genomics. 43 Indeed, McArdle disease is a paradigm of human exercise intolerance and PYGM 44 genotyping should be included in the genetic analyses that might be applied in the 45 coming personalized exercise medicine as well as in future research on genetics and 46 exercise-related phenotypes. 47