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Nat Commun. 2018 Nov 19;9(1):4849. doi: 10.1038/s41467-018-07057-5.

Tamoxifen therapy in a murine model of myotubular myopathy.

Author information

1
Program for Genetics and Genome Biology, Hospital for Sick Children, 686 Bay Street, Toronto, ON, CAN M5G 0A4, Canada.
2
Department of Molecular Genetics, University of Toronto, Medical Science Building, Room 4386, 1 King's College Cir, Toronto, ON, CAN M5S 1A8, Canada.
3
Department of Paediatrics, University of Toronto, Room 1436D, 555 University Avenue, Toronto, ON, CAN M5G 1X8, Canada.
4
Department of Computer Science, University of Toronto, Pratt Building Room 286C, 6 King's College Rd, Toronto, ON, CAN M5S 3G4, Canada.
5
Centre for Computational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, CAN M5G 0A4, Canada.
6
Department of Pharmacology and Physiology, University of Rochester Medical Center School of Medicine and Dentistry, 601 Elmwood Ave, Box 711, Rochester, NY, 14642, USA.
7
Department of Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125, Berlin, Germany.
8
Program for Genetics and Genome Biology, Hospital for Sick Children, 686 Bay Street, Toronto, ON, CAN M5G 0A4, Canada. james.dowling@sickkids.ca.
9
Department of Molecular Genetics, University of Toronto, Medical Science Building, Room 4386, 1 King's College Cir, Toronto, ON, CAN M5S 1A8, Canada. james.dowling@sickkids.ca.
10
Department of Paediatrics, University of Toronto, Room 1436D, 555 University Avenue, Toronto, ON, CAN M5G 1X8, Canada. james.dowling@sickkids.ca.

Abstract

Myotubular myopathy (MTM) is a severe X-linked disease without existing therapies. Here, we show that tamoxifen ameliorates MTM-related histopathological and functional abnormalities in mice, and nearly doubles survival. The beneficial effects of tamoxifen are mediated primarily via estrogen receptor signaling, as demonstrated through in vitro studies and in vivo phenotypic rescue with estradiol. RNA sequencing and protein expression analyses revealed that rescue is mediated in part through post-transcriptional reduction of dynamin-2, a known MTM modifier. These findings demonstrate an unexpected ability of tamoxifen to improve the murine MTM phenotype, providing preclinical evidence to support clinical translation.

PMID:
30451841
PMCID:
PMC6242823
DOI:
10.1038/s41467-018-07057-5
[Indexed for MEDLINE]
Free PMC Article

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