Abstract
Tamoxifen and raloxifene are selective estrogen receptor modulators (SERM) used to treat or reduce the risk of breast cancer as well as for osteoporosis. These drugs act to block estrogen in various tissues while having a pro-estrogen activity in others. Furthermore, they have been shown to have anti-fibrotic and anti-inflammatory properties making them a potential therapeutic option for muscular dystrophy. Previous studies by our lab and others have examined tamoxifen and raloxifene treatments in muscular dystrophy mouse models with success. These include numerous studies in the mdx mouse resulting in improved muscle function and pathology. Studies in our lab demonstrated long-term, dose dependent improvements in muscle function and pathology with daily treatment of up to 50 mg/kg tamoxifen and up to 100 mg/kg raloxifene. Additionally, ribitol has been shown to be effective in mitigating the dystrophic pathology in the FKRP-P448Lneo- mutant mouse, thus providing a potential supplement option for improving the effectiveness of current drugs. Here we examined the effectiveness of low-dose tamoxifen and raloxifene with and without ribitol supplement. FKRP-P448Lneo- mutant mice were treated with 1 mg/kg tamoxifen or 10 mg/kg raloxifene with and without 2 g/kg ribitol daily for 12 months. Muscle function was examined using grip force, treadmill, whole body plethysmography and echocardiogram at 6 and 12 months. Muscle histology and pathology was examined at 12 months. Muscle function improvements, specifically in treadmill distance and grip force, were seen after 6 months of treatment with combined treatment showing further improvement over each drug alone. Improvements were also noted in respiratory and cardiac parameters. Although there was a reduction in improvements after 12 months of treatment the treated animals retained higher function over untreated controls. Furthermore, an increase in alpha-dystroglycan glycosylation was noted in the combination treated groups as well as improvements in fibrosis and central nucleation in all treated groups but more prominent with the combined treatment. Taken together these data suggest the combinatorial treatment is effective over drug alone. These results demonstrate the potential benefit of low dose tamoxifen and raloxifene for the treatment of FKRP-related muscular dystrophies and other muscular dystrophies.