Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype.
Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency. A fundamental question in DMD pathogenesis and dystrophin gene therapy is whether muscle health depends on continuous dystrophin expression throughout the life. Published data suggest that transient dystrophin expression in early life might offer permanent protection. To study the consequences of adulthood dystrophin loss, we generated two strains of floxed mini-dystrophin transgenic mice on the dystrophin-null background. Muscle diseases were prevented in skeletal muscle of the YL238 strain and the heart of the SJ13 strain by selective expression of a therapeutic mini-dystrophin gene in skeletal muscle and heart, respectively. The mini-dystrophin gene was removed from the tibialis anterior (TA) muscle of 8-month-old YL238 mice and the heart of 7-month-old SJ13 mice using an adeno-associated virus serotype-9 Cre recombinase vector (AAV.CBA.Cre). At 12 and 15 months after AAV.CBA.Cre injection, mini-dystrophin expression was reduced by ∼87% in the TA muscle of YL238 mice and ∼64% in the heart of SJ13 mice. Mini-dystrophin reduction caused muscle atrophy, degeneration and force loss in the TA muscle of YL238 mice and significantly compromised left ventricular hemodynamics in SJ13 mice. Our results suggest that persistent dystrophin expression is essential for continuous muscle and heart protection.
Department of Molecular Microbiology and Immunology, School of Medicine duand@missouri.edu.
Nalinda B
NB
Wasala
Department of Molecular Microbiology and Immunology, School of Medicine duand@missouri.edu.
Yi
Y
Lai
Department of Molecular Microbiology and Immunology, School of Medicine.
Jin-Hong
JH
Shin
Department of Molecular Microbiology and Immunology, School of Medicine.
Junling
J
Zhao
Department of Molecular Microbiology and Immunology, School of Medicine.
Yongping
Y
Yue
Department of Molecular Microbiology and Immunology, School of Medicine duand@missouri.edu.|Department of Neurology, School of Medicine.|Department of Bioengineering, The University of Missouri, Columbia, MO 65212, USA.
Dongsheng
D
Duan
D000818:Animals; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D023281:Genomics; D051379:Mice; D008808:Mice, Inbred CBA; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism
D016189:Dystrophin