Simvastatin Influences Selected Aspects of Duchenne Muscular Dystrophy Pathology in a Mouse Model

Abstract

\n Background: Duchenne 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.Methods: Several methods including functional assessment of muscle function via grip strength measurement and treadmill test, enzymatic assays, histological analysis of muscle damage, gene expression evaluation, and immunofluorescence staining were conducted to study simvastatin-related alterations in mdx mice.Results: In our study, simvastatin treatment of mdx mice did not result in improved running performance; however, some beneficial effect was observed when grip strength was evaluated. Creatine kinase and lactate dehydrogenase activity, markers of muscle injury, were diminished after simvastatin delivery in mdx mice. Nevertheless, no significant changes in inflammation, fibrosis, and necrosis were noted. Interestingly, simvastatin treatment led to the decreased mRNA level of embryonic myosin heavy chain isoform, a declined percentage of centrally nucleated myofibers, and miR-1 upregulation, suggesting an alteration in the muscle regeneration. However, similarly to the changes noticed in the expression of some angiogenic factors, the obtained results are muscle-dependent, being prominent in gastrocnemius muscle but not in the diaphragm.Conclusion: In conclusion, we suggest that simvastatin has the potential to ameliorate selected aspects of DMD pathology; however, possible benefits still need to be thoroughly tested.