Estrogens are essentially known for their actions on the female reproductive system. However, through their receptors and integration of many signaling pathways, they are able to coordinate and regulate many functions across multiple organs and systems in both males and females.

Estrogen signaling is complex, but that of estrogen-related compounds is even more so. For example, tamoxifen – a selective estrogen receptor modulator (SERM) – has been used for over 40 years to treat breast cancer. Its status as a SERM indicates that it is able to bind to estrogen receptors and, depending on the tissue in which it is found, have either pro- or anti-estrogenic effects. For example, in bone, tamoxifen mimics the action of estrogens (pro-estrogenic effects), while in breast tissue it blocks them and has anti-estrogenic effects.

The discovery of estrogen receptors in skeletal muscle and the various effects of tamoxifen mean that, in addition to breast cancer, tamoxifen could also be used to treat muscle diseases. This hypothesis has previously been tested in a mouse model of Duchenne muscular dystrophy; a neuromuscular disease characterised by progressive muscle loss due to the absence of the dystrophin protein. In this study, tamoxifen administration greatly improved muscle function and histology. Further molecular analysis also revealed that estrogen receptors were over-expressed in dystrophic muscle and that tamoxifen treatment normalized their ratio.

This thesis thus explores molecular insights into estrogen signaling in skeletal muscle obtained from preclinical animal models and discusses recent findings indicating that modulation of estrogen signaling – using estrogen-related compounds such as tamoxifen – is a viable therapeutic option for several serious muscle diseases, such as Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM), in which estrogen signaling appears to play a role in disease progression.

Title	Published in	Year	Views	Downloads

Estrogen signaling in skeletal muscle: Can it be modified to treat myopathies?		2024	224	46
Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy	Nature Communications	2018	514	362

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Gayi, Elinam

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