Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy
X-linked myotubular myopathy (XLMTM, also known as XLCNM) is a severe congenital muscular disorder due to mutations in the myotubularin gene, MTM1. It is characterized by generalized hypotonia, leading to neonatal death of most patients. No specific treatment exists. Here, we show that tamoxifen, a well-known drug used against breast cancer, rescues the phenotype of Mtm1-deficient mice. Tamoxifen increases lifespan several-fold while improving overall motor function and preventing disease progression including lower limb paralysis. Tamoxifen corrects functional, histological and molecular hallmarks of XLMTM, with improved force output, myonuclei positioning, myofibrillar structure, triad number, and excitation-contraction coupling. Tamoxifen normalizes the expression level of the XLMTM disease modifiers DNM2 and PI3KC2B, likely contributing to the phenotypic rescue. Our findings demonstrate that tamoxifen is a promising candidate for clinical evaluation in XLMTM patients.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2018 |
|---|---|
| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
|---|---|
| Enthalten in: |
Nature communications - 9(2018), 1 vom: 19. Nov., Seite 4848 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Gayi, Elinam [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 18.12.2018 Date Revised 04.10.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41467-018-07058-4 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM29083905X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM29083905X | ||
| 003 | DE-627 | ||
| 005 | 20231225065602.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2018 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-018-07058-4 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0969.xml |
| 035 | |a (DE-627)NLM29083905X | ||
| 035 | |a (NLM)30451843 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Gayi, Elinam |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy |
| 264 | 1 | |c 2018 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.12.2018 | ||
| 500 | |a Date Revised 04.10.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a X-linked myotubular myopathy (XLMTM, also known as XLCNM) is a severe congenital muscular disorder due to mutations in the myotubularin gene, MTM1. It is characterized by generalized hypotonia, leading to neonatal death of most patients. No specific treatment exists. Here, we show that tamoxifen, a well-known drug used against breast cancer, rescues the phenotype of Mtm1-deficient mice. Tamoxifen increases lifespan several-fold while improving overall motor function and preventing disease progression including lower limb paralysis. Tamoxifen corrects functional, histological and molecular hallmarks of XLMTM, with improved force output, myonuclei positioning, myofibrillar structure, triad number, and excitation-contraction coupling. Tamoxifen normalizes the expression level of the XLMTM disease modifiers DNM2 and PI3KC2B, likely contributing to the phenotypic rescue. Our findings demonstrate that tamoxifen is a promising candidate for clinical evaluation in XLMTM patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Protective Agents |2 NLM | |
| 650 | 7 | |a Tamoxifen |2 NLM | |
| 650 | 7 | |a 094ZI81Y45 |2 NLM | |
| 650 | 7 | |a Class II Phosphatidylinositol 3-Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.1.137 |2 NLM | |
| 650 | 7 | |a Protein Tyrosine Phosphatases, Non-Receptor |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a myotubularin |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a DNM2 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 3.6.5.5 |2 NLM | |
| 650 | 7 | |a Dynamin II |2 NLM | |
| 650 | 7 | |a EC 3.6.5.5 |2 NLM | |
| 700 | 1 | |a Neff, Laurence A |e verfasserin |4 aut | |
| 700 | 1 | |a Massana Muñoz, Xènia |e verfasserin |4 aut | |
| 700 | 1 | |a Ismail, Hesham M |e verfasserin |4 aut | |
| 700 | 1 | |a Sierra, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Mercier, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Décosterd, Laurent A |e verfasserin |4 aut | |
| 700 | 1 | |a Laporte, Jocelyn |e verfasserin |4 aut | |
| 700 | 1 | |a Cowling, Belinda S |e verfasserin |4 aut | |
| 700 | 1 | |a Dorchies, Olivier M |e verfasserin |4 aut | |
| 700 | 1 | |a Scapozza, Leonardo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 9(2018), 1 vom: 19. Nov., Seite 4848 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
| 773 | 1 | 8 | |g volume:9 |g year:2018 |g number:1 |g day:19 |g month:11 |g pages:4848 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-018-07058-4 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 9 |j 2018 |e 1 |b 19 |c 11 |h 4848 | ||