RESEARCH ARTICLE Metabolic Dysfunction and Altered Mitochondrial Dynamics in the Utrophin- Dystrophin Deficient Mouse Model of Duchenne Muscular Dystrophy

The utrophin-dystrophin deficient (DKO) mouse model has been widely used to under-stand the progression of Duchenne muscular dystrophy (DMD). However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was fo-cused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL) muscle and to determine changes in metabolic enzymes. Our re-sults show that the 8 week-old DKOmice consume higher oxygen relative to activity lev-els. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Ad-ditionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1) and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our stud-ies point out that the dystrophic disease has caused significant changes in muscle metab