Lack of estrogens aggravates the pathology in dystrophic mice

Duchenne muscular dystrophy (DMD) is a severe disorder that results in progressive muscle wasting and causes death in early adulthood. As part of our search for compounds to treat DMD, we have found that the inexpensive and safe anticancer drug tamoxifen (TAM) efficaciously counteracted dystrophic symptoms in the mdx5Cv mouse, a model of DMD. These effects were mimicked by several selective estrogen receptor modulators (SERMs) structurally related to TAM. We also found that TAM protection was abolished by fulvestrant, a pure anti-estrogenic compound. Moreover, female dystrophic mice were more resistant to muscle fatigue than males. Collectively, our findings point to a protective role of estrogen agonists in dystrophic muscle and suggest that enhancement of estrogenic signalling in muscle by SERMs might be a therapeutic approach to treat DMD. In order to investigate the roles of estrogen deficiency in dystrophic muscle, we have generated dystrophic (mdx5Cv) mice lacking aromatase, the rate-limiting enzyme in the biosynthesis of estrogens from androgens. Longitudinal analysis of mice from 2 months to 20 months of age revealed that lack of estrogens due to aromatase deficiency greatly decreased locomotor activity in both male and female dystrophic mice. At 2 years of age, aromatase deficiency aggravated muscle fatigue in dystrophic males and caused prominent fibrosis in the soleus muscle of dystrophic females. Other motor and structural features of aromatase deficient dystrophic mice are being analyzed. These findings highlight the important contribution of estrogens, not only in female but also in male dystrophic mice and warrant further investigation of SERMs as adjuvant therapy for DMD.