Adeno-Associated Virus–Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I

Charles H. Vannoy, Haowen Zhou, Chunping Qiao, Xiao Xiao, Anne G. Bang, Qi L. Lu

Research output: Research - peer-reviewArticle

Abstract

Agrin is a basement membrane-specific proteoglycan that can regulate orientation of cytoskeleton proteins and improve function of dystrophic skeletal muscle. In skeletal muscle, agrin binds with high affinity to laminin(s) and α-dystroglycan (α-DG), an integral part of the dystrophin-glycoprotein complex. Miniaturized forms of agrin (mAgrin) have been shown to ameliorate disease pathology in a laminin-α2 knockout mouse model of muscular dystrophy, acting as a link between α-DG and laminin(s). Here, we test whether mAgrin might also improve pathologies associated with FKRP-related dystroglycanopathies, another form of muscular dystrophy characterized by weak interactions between muscle and basement membranes. We demonstrate in vitro that mAgrin enhances laminin binding to primary myoblasts and fibroblasts from an FKRP mutant mouse model and that this enhancement is abrogated when mAgrin is in molar excess relative to laminin. However, in vivo delivery of mAgrin via adeno-associated virus (AAV) into FKRP mutant mice was unable to improve dystrophic phenotypes, both histologically and functionally. These results likely reflect insufficient binding of mAgrin to hypoglycosylated α-DG on muscle fibers and possibly abrogation of binding from molar excess of overexpressed AAV-delivered mAgrin. Further exploration of mAgrin modification is necessary to strengthen its binding to other membrane components, including hypoglycosylated α-DG, for potential therapeutic applications.

LanguageEnglish (US)
Pages431-440
Number of pages10
JournalAmerican Journal of Pathology
Volume187
Issue number2
DOIs
StatePublished - Feb 1 2017

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Agrin
Dependovirus
Phenotype
Muscular Dystrophy, Limb-Girdle, Type 2I
Laminin
Dystroglycans
Muscular Dystrophies
Basement Membrane
Skeletal Muscle
Pathology
Muscles
Dystrophin
Myoblasts
Proteoglycans
Cytoskeleton
Knockout Mice
Glycoproteins
Fibroblasts
Membranes
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Adeno-Associated Virus–Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I. / Vannoy, Charles H.; Zhou, Haowen; Qiao, Chunping; Xiao, Xiao; Bang, Anne G.; Lu, Qi L.

In: American Journal of Pathology, Vol. 187, No. 2, 01.02.2017, p. 431-440.

Research output: Research - peer-reviewArticle

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