Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice.
The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:beta1,4-N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcbeta1,4[NeuAc(orGc)alpha2, 3]Galbeta1,4GlcNAcbeta-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.
Martin
Paul T
PT
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State Univ. College of Medicine, 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210-1218, USA.
Xu
Rui
R
Rodino-Klapac
Louise R
LR
Oglesbay
Elaine
E
Camboni
Marybeth
M
Montgomery
Chrystal L
CL
Shontz
Kim
K
Chicoine
Louis G
LG
Clark
K Reed
KR
Sahenk
Zarife
Z
Mendell
Jerry R
JR
Janssen
Paul M L
PM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005552:Forelimb; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb; D007537:Isometric Contraction; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000201:enzymology; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D015854:Up-Regulation
D016695:Glycosyltransferases; C505903:Galgt2 protein, mouse