Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice.
To address whether mdx mice with haploinsufficiency of utrophin (mdx/utrn+/-) develop more severe skeletal muscle inflammation and fibrosis than mdx mice, to represent a better model for Duchenne muscular dystrophy (DMD), we performed qualitative and quantitative analysis of skeletal muscle inflammation and fibrosis in mdx and mdx/utrn+/- littermates. Inflammation was significantly worse in mdx/utrn+/- quadriceps at age 3 and 6 months and in mdx/utrn+/- diaphragm at age 3 but not 6 months. Fibrosis was more severe in mdx/utrn+/- diaphragm at 6 months, and at this age, mild fibrosis was noted in quadriceps of mdx/utrn+/- but not mdx mice. The findings indicate that utrophin compensates, although insufficiently, for the effects of dystrophin loss with regard to inflammation and fibrosis of both quadriceps and diaphragm muscles in mdx mice. With more severe muscle dystrophy than mdx mice and a longer life span than utrophin-dystrophin-deficient (dko) mice, mdx/utrn+/- mice provide a better mouse model for testing potential therapies for muscle inflammation and fibrosis associated with DMD.
Zhou
Lan
L
Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA. ZHOUL2@CCF.ORG
Rafael-Fortney
Jill A
JA
Huang
Ping
P
Zhao
Xinyu S
XS
Cheng
Georgiana
G
Zhou
Xiaohua
X
Kaminski
Henry J
HJ
Liu
Liping
L
Ransohoff
Richard M
RM
D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003964:Diaphragm / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D016189:Dystrophin / Q000172:deficiency; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009220:Myositis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D052097:Quadriceps Muscle / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049411:Utrophin / Q000172:deficiency / Q000235:genetics*
D016189:Dystrophin; D049411:Utrophin