Enzyme inducing antiepileptic drugs are associated with mitochondrial proliferation and increased cytochrome c oxidase activity in muscle of children with epilepsy

Abstract

To evaluate the effects of epilepsy-related factors associated with mitochondrial pathology and function in skeletal muscle of children with suspected mitochondrial disorders. This case-control study evaluated patients and age-matched controls with muscle biopsies at Cincinnati Children's Hospital Medical Center obtained between January, 2000 and December, 2008. A total of 65 epilepsy patients and 65 age-matched controls met the inclusion criteria. No significant clinical, pathological, or biochemical differences were found between the epilepsy and control groups. Treatment resistance was associated with decreased electron transport chain (ETC) complex II+III activity compared to treatment-responsive patients. Only patients receiving enzyme inducer antiepileptic drugs (AEDs) had ETC complex activities equivalent to or greater than other study groups. Robust regression modeling found a significant effect between percentage of myofibers with subsarcolemmal mitochondrial aggregates (SSMA) and ETC complex IV activity for the enzyme inducer AED group. Least squares regression showed that only complex IV/citrate synthase ratio was strongly correlated with SSMA percentage for the enzyme inducer AED group. As far as we can determine this is the first study to show an association between enzyme inducer AED treatment and enhanced ETC complex IV activity. In skeletal muscle mitochondrial density, assessed by SSMA percentage, and ETC complex IV activity are positively correlated in patients receiving enzyme inducer AED treatment.