Abstract
BackgroundDuchenne muscular dystrophy (DMD) is an incurable disease, caused by the mutations in the DMD gene, encoding dystrophin, an actin-binding cytoskeletal protein. Lack of functional dystrophin results in muscle weakness, degeneration, and as an outcome cardiac and respiratory failure. As there is still no cure for affected individuals, the pharmacological compounds with the potential to treat or at least attenuate the symptoms of the disease are under constant evaluation. The pleiotropic agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, have been suggested to exert beneficial effects in the mouse model of DMD. On the other hand, they were also reported to induce skeletal-muscle myopathy. Therefore, we decided to verify the hypothesis that simvastatin may be considered a potential therapeutic agent in DMD.MethodsSeveral methods including functional assessment of muscle function via grip strength measurement, treadmill test, and single-muscle force estimation, enzymatic assays, histological analysis of muscle damage, gene expression evaluation, and immunofluorescence staining were conducted to study simvastatin-related alterations in the mdx mouse model of DMD.ResultsIn our study, simvastatin treatment of mdx mice did not result in improved running performance, grip strength, or specific force of the single muscle. Creatine kinase and lactate dehydrogenase activity, markers of muscle injury, were also unaffected by simvastatin delivery in mdx mice. Furthermore, no significant changes in inflammation, fibrosis, and angiogenesis were noted. Despite the decreased percentage of centrally nucleated myofibers in gastrocnemius muscle after simvastatin delivery, no changes were noticed in other regeneration-related parameters. Of note, even an increased rate of necrosis was found in simvastatin-treated mdx mice.ConclusionIn conclusion, our study revealed that simvastatin does not ameliorate DMD pathology.
Highlights
Duchenne muscular dystrophy (DMD) is an incurable disease, caused by the mutations in the DMD gene, encoding dystrophin, an actin-binding cytoskeletal protein
We have found that simvastatin does not regulate important processes contributing to dystrophy progressions like fibrosis, inflammation, regeneration, angiogenesis, and does not improve muscle functionality
Simvastatin treatment does not influence Creatine kinase (CK) and Lactate dehydrogenase (LDH) activities in mdx mice Administration of simvastatin for 1 month in a dose of 10 mg/kg body weight (BW)/day by oral gavage did not result in the change in BW of the animals (Fig. 1A)
Summary
Duchenne muscular dystrophy (DMD) is an incurable disease, caused by the mutations in the DMD gene, encoding dystrophin, an actin-binding cytoskeletal protein. The pleiotropic agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, have been suggested to exert beneficial effects in the mouse model of DMD. Duchenne muscular dystrophy (DMD) is a progressive, severely debilitating, and lethal genetic disease caused by the mutations in the DMD gene, coding dystrophin, a 427 kDa actin-binding cytoskeletal protein, maintaining muscle fiber-extracellular matrix integrity and regulating several cellular pathways including nitric oxide (NO) production, Ca2+ entry, and the generation of reactive oxygen species (ROS) [1, 2]. In 2015, Whitehead et al for the first time showed that simvastatin improves muscle health, reduces inflammation and oxidative stress, and increases autophagy in mdx animals [12] and Kim et al reported beneficial effects on heart functions [13]. Other studies performed with simvastatin [15] and rosuvastatin [16] did not confirm such favorable properties in animal models of DMD
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