Phenotyping a new mitochondrial fatty acid oxidation deficient mouse model

Abstract

s ingediend voor het Amsterdam Kindersymposium 2013 33 Phenotyping a new mitochondrial fatty acid oxidation deficient mouse model E.F. Diekman (1,2), M.Weeghel (2), R.J. Wanders (2), G. Visser (1), S.M. Houten (2) (1) Department of Metabolic diseases, Wilhelmina Children’s Hospital, UMC Utrecht, the Netherlands (2) Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, the Netherlands INTRODUCTION Very long chain acyl-CoA dehydrogenase defi ciency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid (FAO) beta-oxidation. Patients present with hypoglycaemia, hepatomegaly, cardiomyopathy and myopathy. Although the phenotype of the LCAD KO mouse closely resembles the phenotype in humans, this mouse model does not have myopathy. As mice have two enzymes for degradation of long-chain fatty acids (LCAD and VLCAD), we hypothesised that a model in which one VLCAD allele is deleted in the LCAD KO mouse might have myopathy. LCAD/VLCAD double KO mice are not viable [Cox 2001]. Our objective was therefore to phenotype the LCAD-/-; VLCAD+/mouse model. METHODS We cross-bred LCAD+/-; VLCAD+/mice with LCAD-/-; VLCAD+/+ and characterized the resulting 4 genotypes using metabolic cages. RESULTS Enzymatic activity was signifi cantly decreased and C14:1/C2 acylcarnitine ratio was signifi cantly increased in the LCAD-/-; VLCAD+/mice opposed to all other genotypes. Heat production was decreased in LCAD-/-; VLCAD+/+ and LCAD-/-; VLCAD+/mice, but the RER was not signifi cantly changed. Locomotor activity was reduced in the LCAD-/-; VLCAD+/opposed to all other genotypes. Creatine kinase (CK) levels –a marker for rhabdomyolysiswere measured in plasma of mice of all genotypes after fasting. CK levels were within the normal range of 0-100 U/L. CONCLUSION Our preliminary data (n=4 per genotype) suggest that although LCAD-/-; VLCAD+/mice have lower FAO fl ux compared to LCAD-/-; VLCAD+/+ mice, they do not have myopathy.