TAMYOCAL · Tamoxifen mediated protection on X-linked centronuclear myopathy: a mechanistic and pre-clinical study

Tamoxifen mediated protection on X-linked centronuclear myopathy: a mechanistic and pre-clinical study

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy caused by the absence of lipid phosphatase myotubularin. XLMTM affects 1/50.000 male births, there is no treatment and many cases lead to premature death. Thus, treatments are needed. Tamoxifen (TAM) is a selective estrogen receptor modulator that mimics estrogen signalling in skeletal muscle. Pilot study and previous results from the hosting group, have shown that TAM improve muscle symptoms and survival rate in Mtm1-/y mice, a validate model of XLMTM. Results strongly support the idea that TAM protects skeletal muscle via enhancement of estrogenic signalling positively modulating multiple pathways linked to muscle function. However, the exact mechanism(s) is not yet understood. This project aims at elucidating the mechanism(s) of action of TAM and evaluate further its efficacy in Mtm1-/y mice. Two specific aims are proposed. First, to determine how TAM acts on pathways and key players involved in XLCNM. Estrogen signalling, phosphoinositide balance, autophagy and mTORC1 signalling were targeted in Mtm1+/y (WT from now on) and Mtm1-/y (KO from now on) mice treated and non-treated by TAM. Second, to investigate the pre-clinical efficacy of TAM combined with other compounds in XLMTM mice. TAM extends the lifespan of XLMTM mice according to the pilot study but it prevents only partly leg muscle atrophy, restricting complete functional rescue. Thus, TAM is combined with other approved drugs that target muscle atrophy (L-Citrullin and IGF). These parallel approaches will provide knowledge about not-yet explained events related to XLMTM and TAM effects, from molecular to in-vivo level, and instrumental information for other myopathies and rare diseases where lipid phosphatases are missing and phosphoinositide are unbalanced. This knowledge might provide the rationale for new therapeutic options for these dramatic conditions, being highly relevant to patients and families. The overarching objective of the project was to understand the mechanisms of action of tamoxifen and to evaluate further its efficacy in XLMTM. Two specific aims were determined to accomplish this main objective. First aim was the determination of the mechanisms underlying tamoxifen protection on XLMTM muscles. Second aim was the pre-clinical study of the combination of tamoxifen with other compounds in order to achieve a complete rescue of the XLMTM phenotype, targeting the observed muscle atrophy.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз