Cellular Rescue in a Zebrafish Model of Congenital Muscular Dystrophy Type 1A

Overview

Journal NPJ Regen Med

Date 2019 Nov 23

PMID 31754462

Citations 12

Authors

T E Hall

A J Wood

O Ehrlich

M Li

C S Sonntag

N J Cole

I G Huttner

T E Sztal

P D Currie

Affiliations

Soon will be listed here.

Abstract

Laminins comprise structural components of basement membranes, critical in the regulation of differentiation, survival and migration of a diverse range of cell types, including skeletal muscle. Mutations in one muscle enriched Laminin isoform, , results in the most common form of congenital muscular dystrophy, congenital muscular dystrophy type 1A (MDC1A). However, the exact cellular mechanism by which Laminin loss results in the pathological spectrum associated with MDC1A remains elusive. Here we show, via live tracking of individual muscle fibres, that dystrophic myofibres in the zebrafish model of MDC1A maintain sarcolemmal integrity and undergo dynamic remodelling behaviours post detachment, including focal sarcolemmal reattachment, cell extension and hyper-fusion with surrounding myoblasts. These observations imply the existence of a window of therapeutic opportunity, where detached cells may be "re-functionalised" prior to their delayed entry into the cell death program, a process we show can be achieved by muscle specific or systemic Laminin delivery. We further reveal that Laminin also acts as a pro-regenerative factor that stimulates muscle stem cell-mediated repair in -deficient animals in vivo. The potential multi-mode of action of Laminin replacement therapy suggests it may provide a potent therapeutic axis for the treatment for MDC1A.

Citing Articles

Modeling Human Muscular Dystrophies in Zebrafish: Mutant Lines, Transgenic Fluorescent Biosensors, and Phenotyping Assays.

Tesoriero C, Greco F, Cannone E, Ghirotto F, Facchinello N, Schiavone M Int J Mol Sci. 2023; 24(9).

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and mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma.

Morgan K, Doggett K, Geng F, Mieruszynski S, Whitehead L, Smith K Elife. 2023; 12.

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Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy.

Smith S, Fabian L, Sheikh A, Noche R, Cui X, Moore S Hum Mol Genet. 2021; 31(5):733-747.

PMID: 34568901 PMC: 9989739. DOI: 10.1093/hmg/ddab278.

Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study.

Bouman K, Groothuis J, Doorduin J, van Alfen N, Udink Ten Cate F, van den Heuvel F BMC Neurol. 2021; 21(1):313.

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