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

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.

cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration

“…Interestingly, elevated PDE activity is observed in skeletal muscle of dystrophic mice (20,21,143). Although these findings do not imply that reduced cAMP abundance in dystrophic muscle causes the dystrophic phenotype, it would be interesting to test whether chronic PDE inhibition can improve muscle regeneration or function in dystrophic muscle in a manner analogous to ␤ 2 -AR and CRFR2 agonists (90,103,185,254,256). Studies with prolonged PDE inhibitor treatment should be evaluated with caution, as mice lacking Pde4d display exercise intolerance and evidence of myofiber damage after downhill running (17).…”

“…␤ 2 -AR agonists have also been shown to reduce muscle atrophy in animals with cancer cachexia (31,33,46). In addition, agonists for ␤ 2 -AR or CRF receptors improve muscle function in dystrophin-deficient mdx (86,90,103,185,192,254,256) and laminin-deficient dy/dy (94) mice. However, efficacy of ␤ 2 -AR agonists on muscle size and force generation vary with the type and dose of agonist, as well as the muscle studied.…”

“…Several proteins involved in cAMP signaling, including receptors, G proteins, and cAMP-activated transcription factors, have been found to promote muscle regeneration (80,163,216) and functional recovery after injury (15,196). Ligands for these GPCRs also improve muscle function and slow disease progression in dystrophic mdx mice (86,90,103,185,192,254,256). In conjunction with the anti-atrophy effects described in the preceding section (see Hypertrophy), GPCR signaling in muscle precursor cells is a potential area for development of novel therapeutic agents that could promote regeneration and limit atrophy in patients with muscular dystrophy, denervation atrophy, age-related sarcopenia, or muscle wasting due to cancer.…”

“…All of these cellular events are required for efficient regeneration of adult skeletal muscle (93). In adult muscle, stimulation of cAMP production can slow degeneration or promote regeneration in rodent models of necrotic muscle injury (15,80,196) and Duchenne's muscular dystrophy (86,90,103,254).…”

“…The prohypertrophic actions of ␤-adrenergic receptor (␤-AR) agonists and corticotropin-releasing factor receptor 2 (CRFR2) agonists have recently been harnessed to improve muscle function and ameliorate atrophy in several rodent models, including disuse (99, 101, 245), denervation (98, 100 -102, 127, 154, 253), aging (195, 254), and muscular dystrophy (90,103,185,254,256). ␤-AR agonists have also shown some promise in promoting muscle function in patients with muscular dystrophy (64,125,126,211, 235).…”