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Review
. 2023 May 5;24(9):8314.
doi: 10.3390/ijms24098314.

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

Chiara Tesoriero  1 , Francesca Greco  1 , Elena Cannone  2 , Francesco Ghirotto  1 , Nicola Facchinello  3 , Marco Schiavone  2 , Andrea Vettori  1
Affiliations
Review

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

Chiara Tesoriero et al. Int J Mol Sci. .

Abstract

Muscular dystrophies (MDs) are a heterogeneous group of myopathies characterized by progressive muscle weakness leading to death from heart or respiratory failure. MDs are caused by mutations in genes involved in both the development and organization of muscle fibers. Several animal models harboring mutations in MD-associated genes have been developed so far. Together with rodents, the zebrafish is one of the most popular animal models used to reproduce MDs because of the high level of sequence homology with the human genome and its genetic manipulability. This review describes the most important zebrafish mutant models of MD and the most advanced tools used to generate and characterize all these valuable transgenic lines. Zebrafish models of MDs have been generated by introducing mutations to muscle-specific genes with different genetic techniques, such as (i) N-ethyl-N-nitrosourea (ENU) treatment, (ii) the injection of specific morpholino, (iii) tol2-based transgenesis, (iv) TALEN, (v) and CRISPR/Cas9 technology. All these models are extensively used either to study muscle development and function or understand the pathogenetic mechanisms of MDs. Several tools have also been developed to characterize these zebrafish models by checking (i) motor behavior, (ii) muscle fiber structure, (iii) oxidative stress, and (iv) mitochondrial function and dynamics. Further, living biosensor models, based on the expression of fluorescent reporter proteins under the control of muscle-specific promoters or responsive elements, have been revealed to be powerful tools to follow molecular dynamics at the level of a single muscle fiber. Thus, zebrafish models of MDs can also be a powerful tool to search for new drugs or gene therapies able to block or slow down disease progression.

Keywords: disease phenotype; in vivo analysis; muscular dystrophies; transgenic biosensors; zebrafish.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Zebrafish muscle organization. As teleost fish, zebrafish are characterized by two distinct types of muscle fibers: slow-red (in red) and fast-white muscle (in gray) (panel C). Regardless of the type, zebrafish skeletal muscle fibers are organized into myofibrils, which are long protein bundles surrounded by the so-called sarcoplasm and held together by the sarcolemma (panel B). Several proteins are involved in the functioning and maintenance of myofibril integrity. The (panel A) shows a model of the spatial configuration of the Dystrophin-associated glycoprotein complex (DGC) and related proteins that provide the connection of the sarcolemma to the basal lamina. In this panel is shown the dystrophin core complex (dystrophin, dystroglycans, sarcoglycans, sarcospan, syntrophins and dystrobrevins) as well as other DCG-associated proteins that forms a network with the extracellular matrix, the cytoskeleton, the sarcolemma, and the sarcomere. Because of graphical limitations, the physiological proportions of both cytoskeletal filaments and single proteins are not represented here. MD-associated genes encoding the (i) basal membrane and extracellular matrix proteins (ii) cytosolic proteins, (iii) dystroglycan and α-DG glycosylation-related proteins, (iv) nuclear envelope and cytoskeleton proteins, and (v) membrane proteins are listed in Tables reported below in the Chapter 2 of this review. Abbreviation: IFs, intermediate filaments. Image was partially created with BioRender (www.biorender.com), accessed on 2 March 2023.
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