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

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.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.Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.Duchenne muscular dystrophy (DMD) is a lethal progressive muscle-wasting disease with an incidence of 1 in 3500 live male births [1-3]. Duchenne muscular dystrophy is usually diagnosed by age 4 or 5 and results in the progressive loss of striated muscle function (including diaphragm function), cardiac malfunction, loss of mobility and muscle strength, such that DMD patients are typically wheelchair-bound by age 12, with death from respiratory and heart failure usually occuring by the late teens or early twenties [1-3]. DMD and the less severe, yet related, Becker muscular dystrophy (BMD) both result from mutation of the dystrophin gene [1-3]. The dystrophin gene is an X chromosome-linked gene that is one of the largest known, coding for a 427 kDa protein [1-3]. Dystrophin is a member of a multi