Muscle Xenografts Reproduce Key Molecular Features of Facioscapulohumeral Muscular Dystrophy

Overview

Journal Exp Neurol

Specialty Neurology

Date 2019 Jul 16

PMID 31306642

Citations 16

Authors

Amber L Mueller

Andrea ONeill

Takako I Jones

Anna Llach

Luis Alejandro Rojas

Paraskevi Sakellariou

Guido Stadler

Woodring E Wright

David Eyerman

Peter L Jones

Robert J Bloch

Affiliations

Soon will be listed here.

Abstract

Aberrant expression of DUX4, a gene unique to humans and primates, causes Facioscapulohumeral Muscular Dystrophy-1 (FSHD), yet the pathogenic mechanism is unknown. As transgenic overexpression models have largely failed to replicate the genetic changes seen in FSHD, many studies of endogenously expressed DUX4 have been limited to patient biopsies and myogenic cell cultures, which never fully differentiate into mature muscle fibers. We have developed a method to xenograft immortalized human muscle precursor cells from patients with FSHD and first-degree relative controls into the tibialis anterior muscle compartment of immunodeficient mice, generating human muscle xenografts. We report that FSHD cells mature into organized and innervated human muscle fibers with minimal contamination of murine myonuclei. They also reconstitute the satellite cell niche within the xenografts. FSHD xenografts express DUX4 and DUX4 downstream targets, retain the 4q35 epigenetic signature of their original donors, and express a novel protein biomarker of FSHD, SLC34A2. Ours is the first scalable, mature in vivo human model of FSHD. It should be useful for studies of the pathogenic mechanism of the disease as well as for testing therapeutic strategies targeting DUX4 expression.

Citing Articles

Human DUX4 and porcine DUXC activate similar early embryonic programs in pig muscle cells: implications for preclinical models of FSHD.

Nip Y, Bennett S, Smith A, Jones T, Jones P, Tapscott S Hum Mol Genet. 2023; 32(11):1864-1874.

PMID: 36728804 PMC: 10196675. DOI: 10.1093/hmg/ddad021.

FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?.

Himeda C, Jones P J Pers Med. 2022; 12(6).

PMID: 35743650 PMC: 9225474. DOI: 10.3390/jpm12060865.

Proximity ligation assay to detect DUX4 protein in FSHD1 muscle: a pilot study.

Beermann M, Homma S, Miller J BMC Res Notes. 2022; 15(1):163.

PMID: 35538497 PMC: 9092897. DOI: 10.1186/s13104-022-06054-8.

Meeting report: the 2021 FSHD International Research Congress.

Jagannathan S, de Greef J, Hayward L, Yokomori K, Gabellini D, Mul K Skelet Muscle. 2022; 12(1):1.

PMID: 35039091 PMC: 8762812. DOI: 10.1186/s13395-022-00287-8.

DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy.

Mocciaro E, Runfola V, Ghezzi P, Pannese M, Gabellini D Cells. 2021; 10(12).

PMID: 34943834 PMC: 8699294. DOI: 10.3390/cells10123322.

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