Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice.
BACKGROUND
Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy.


METHODS
Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R) agonist treatment has on diaphragm function, morphology and gene expression.


RESULTS
We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression.


CONCLUSIONS
Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.
Hinkle
Richard T
RT
Research Division, Procter & Gamble Pharmaceuticals, Mason, OH, USA. hinkle.rt.2@pg.com
Lefever
Frank R
FR
Dolan
Elizabeth T
ET
Reichart
Deborah L
DL
Dietrich
Jefferey A
JA
Gropp
Kathryn E
KE
Thacker
Robert I
RI
Demuth
Jeffrey P
JP
Stevens
Paula J
PJ
Qu
Xiaoyan A
XA
Varbanov
Alex R
AR
Wang
Feng
F
Isfort
Robert J
RJ
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D016189:Dystrophin / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists*; D013997:Time Factors
C101531:CRF receptor type 2; D016189:Dystrophin; D018019:Receptors, Corticotropin-Releasing Hormone