Cellular effects of Coenzyme Q10 and resveratrol in the SJL/J dysferlinopathy mouse model

Abstract

The muscular dystrophies (MDs) are genetic disorders of muscle degeneration due to mutations in genes that encode a wide variety of proteins. Dysferlinopathy encompasses a large variety of neuromuscular diseases characterized by the absence of dysferlin in skeletal muscle and an autosomal recessive mode of inheritance. Dysferlinopathy can manifest as limb girdle muscular dystrophy type 2B (LGMD 2B), Miyoshi myopathy (MM) or distal myopathy with anterior tibial onset (DMAT). The first symptoms usually appear during the second or third decade of life as clumsiness when running, fatigue when walking long distances and difficulty in climbing stairs. Progression of the disease eventually leads to a loss of ambulation. A deficit in membrane-repair machinery in dysferlinopathy suggested a direct role for dysferlin in the Ca2+-dependent membrane-repair process. Recently, dysferlin has also been implicated in the process of chemotaxis. Evidence exists that free radical mediated injury contributes to the pathogenesis of muscle necrosis in the muscular dystrophies. The imbalance of free radical synthesis and antioxidant capacity has been suggested to contribute to the necrotic process. It is therefore imperative to explore the effect of antioxidant supplementation in the MDs. The present study followed a novel approach in investigating the cellular effects afforded by the supplementation of the SJL/J mouse model for dysferlinopathy with the antioxidants, Coenzyme Q10 (CoQ10) and resveratrol. The study aimed to determine, at cellular level, the histopathology and ultrastructural changes in the SJL/J mouse model following a 90 day trial with antioxidant supplementation. In addition to studying the morphology, the study paid attention to nonspecific parameters. The study mainly focused on the histopathology and ultrastructural alterations in the SJLL/J mouse. In addition the oxidative stress index of the affected quadriceps muscle was determined. The outcome provides evidence that increased oxidative stress levels are present in the SJL/J mouse. Antioxidant supplementation with CoQ10 at 120mg/kg/day or a resveratrol/CoQ10 combination supplementation at 40 and 60mg/kg/day, decreased the levels of oxidative stress and dystrophic markers at a cellular level. In addition, increased physical strength was observed. This thesis provides evidence to create a new platform for combination therapeutic strategies.