Abstract
BackgroundDuchenne 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.MethodsUsing 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.ResultsWe 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.ConclusionTogether, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.
Highlights
Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function
Duchenne muscular dystrophy is usually diagnosed by age 4 or 5 and results in the progressive loss of striated muscle 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 [1,2,3]
Experimental design and goals For all experiments, mdx mice at 2–3 months of age were utilized. We chose this age for the mice because the major myofiber death/regeneration event is over, and the mice showed a steady progressive loss of diaphragm specific force with time
Summary
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. 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. 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 [1,2,3]. Other treatment modalities currently being evaluated include gene replacement therapy, stem cell transfer, protease inhibitors, exon skipping therapeutics and translation modulating agents, such as aminoglycosides [2,4,5,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
