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Abstract
Duchenne muscular dystrophy (DMD) is characterized by striated muscle weakness, cardiomyopathy, and respiratory failure. Since oxidative stress is recognized as a secondary pathology in DMD, the efficacy of antioxidant intervention, using the superoxide scavenger tempol, was examined on functional and biochemical status of dystrophin-deficient diaphragm muscle. Diaphragm muscle function was assessed, ex vivo, in adult male wild-type and dystrophin-deficient mdx mice, with and without a 14-day antioxidant intervention. The enzymatic activities of muscle citrate synthase, phosphofructokinase, and lactate dehydrogenase were assessed using spectrophotometric assays. Dystrophic diaphragm displayed mechanical dysfunction and altered biochemical status. Chronic tempol supplementation in the drinking water increased diaphragm functional capacity and citrate synthase and lactate dehydrogenase enzymatic activities, restoring all values to wild-type levels. Chronic supplementation with tempol recovers force-generating capacity and metabolic enzyme activity in mdx diaphragm. These findings may have relevance in the search for therapeutic strategies in neuromuscular disease.
Highlights
Duchenne muscular dystrophy (DMD) is the most common form of inherited muscle disease in childhood, with an estimated incidence of 1:3500 male births [1]
The main findings of this study are (1) diaphragm muscle weakness in mdx mice is evidenced by reduced specific force, work and power output; (2) dystrophin-deficiency in mdx diaphragm is associated with reduced citrate synthase and lactate dehydrogenase enzyme activities, whereas phosphofructokinase activity is equivalent to wild-type; (3) chronic tempol supplementation in mdx mice completely restored diaphragm force- and power-generating capacity; (4) chronic tempol supplementation significantly increased mdx diaphragm citrate synthase and lactate dehydrogenase enzyme activities to wild-type levels; (5) acute bath application of tempol had limited effects on dystrophic diaphragm function ex vivo
B-dystroglycan expression was increased in mdx diaphragm following α-lipoic acid/L-carnitine
Summary
Duchenne muscular dystrophy (DMD) is the most common form of inherited muscle disease in childhood, with an estimated incidence of 1:3500 male births [1]. DMD is caused by a deficiency in the protein dystrophin, which is a component of the dystrophin associated protein complex (DAPC) [2]. Dystrophin deficiency results in destabilization of the DAPC, leading to muscle weakness and fragility, resulting in muscle damage, fibrosis, and necrosis [4]. Inflammation is secondary to muscle damage in DMD, with attendant disruption to Ca2+ homeostasis, oxidative stress, and mitochondrial dysfunction [5]. DMD patients suffer severe limb and respiratory muscle weakness [6]. Patients have compromised lung function due to diaphragm muscle weakness, altered chest wall compliance, and scoliosis [7]. Cardio-respiratory failure is the leading cause of death in DMD
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