Research article

Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice

Richard T Hinkle¹ , Frank R Lefever¹ , Elizabeth T Dolan¹ , Deborah L Reichart¹ , Jefferey A Dietrich¹ , Kathryn E Gropp¹ , Robert I Thacker² , Jeffrey P Demuth¹ , Paula J Stevens¹ , Xiaoyan A Qu¹ , Alex R Varbanov¹ , Feng Wang¹ and Robert J Isfort¹

¹Research Division, Procter & Gamble Pharmaceuticals, Mason, OH, USA

²Department of Pathobiology and Molecular Medicine, University of Cincinnati, Cincinnati, OH, USA

author email corresponding author email

BMC Medicine 2007, 5:18doi:10.1186/1741-7015-5-18

Published:	12 July 2007

Abstract

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.

Conclusion

Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.