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Expressing a Z-disk Nebulin Fragment in Nebulin-deficient Mouse Muscle: Effects on Muscle Structure and Function

Overview
Journal Skelet Muscle
Specialty Physiology
Date 2020 Jan 30
PMID 31992366
Citations 5
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Abstract

Background: Nebulin is a critical thin filament-binding protein that spans from the Z-disk of the skeletal muscle sarcomere to near the pointed end of the thin filament. Its massive size and actin-binding property allows it to provide the thin filaments with structural and regulatory support. When this protein is lost, nemaline myopathy occurs. Nemaline myopathy causes severe muscle weakness as well as structural defects on a sarcomeric level. There is no known cure for this disease.

Methods: We studied whether sarcomeric structure and function can be improved by introducing nebulin's Z-disk region into a nebulin-deficient mouse model (Neb cKO) through adeno-associated viral (AAV) vector therapy. Following this treatment, the structural and functional characteristics of both vehicle-treated and AAV-treated Neb cKO and control muscles were studied.

Results: Intramuscular injection of this AAV construct resulted in a successful expression of the Z-disk fragment within the target muscles. This expression was significantly higher in Neb cKO mice than control mice. Analysis of protein expression revealed that the nebulin fragment was localized exclusively to the Z-disks and that Neb cKO expressed the nebulin fragment at levels comparable to the level of full-length nebulin in control mice. Additionally, the Z-disk fragment displaced full-length nebulin in control mice, resulting in nemaline rod body formation and a worsening of muscle function. Neb cKO mice experienced a slight functional benefit from the AAV treatment, with a small increase in force and fatigue resistance. Disease progression was also slowed as indicated by improved muscle structure and myosin isoform expression.

Conclusions: This study reveals that nebulin fragments are well-received by nebulin-deficient mouse muscles and that limited functional benefits are achievable.

Citing Articles

Role of Actin-Binding Proteins in Skeletal Myogenesis.

Nguyen M, Dash R, Jeong K, Lee W Cells. 2023; 12(21).

PMID: 37947600 PMC: 10650911. DOI: 10.3390/cells12212523.


NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.

Casey J, Kim E, Joseph R, Li F, Granzier H, Gupta V Hum Mol Genet. 2023; 32(10):1711-1721.

PMID: 36661122 PMC: 10162428. DOI: 10.1093/hmg/ddad011.


Mature Myotubes Generated From Human-Induced Pluripotent Stem Cells Without Forced Gene Expression.

Fujiwara K, Yamamoto R, Kubota T, Tazumi A, Sabuta T, Takahashi M Front Cell Dev Biol. 2022; 10:886879.

PMID: 35706901 PMC: 9189389. DOI: 10.3389/fcell.2022.886879.


Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle.

Kiss B, Gohlke J, Tonino P, Hourani Z, Kolb J, Strom J Sci Adv. 2020; 6(46).

PMID: 33177085 PMC: 7673738. DOI: 10.1126/sciadv.abc1992.


Correction to: Expressing a Z-disk nebulin fragment innebulin-deficient mouse muscle: effects on muscle structure and function.

Li F, Kolb J, Crudele J, Tonino P, Hourani Z, Smith 3rd J Skelet Muscle. 2020; 10(1):9.

PMID: 32312330 PMC: 7168831. DOI: 10.1186/s13395-020-00223-8.

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