Effects of a CRF2R agonist and exercise on mdx and wildtype skeletal muscle

Abstract

Corticotrophin-releasing factor 2 receptor (CRF2R) agonists prevent muscle atrophy due to immobilization, denervation, and corticosteroid-induced muscle atrophy in wildtype mice. We hypothesized that a CRF2R agonist will increase skeletal muscle mass in mdx mice. Mdx (C57BL/10ScSn-Dmd(mdx)) and wildtype (C57BL/6) mice were divided into four groups: sedentary placebo, sedentary CRF2R agonist, exercised placebo, and exercised CRF2R agonist. Mice exercised on a treadmill twice weekly for 30 min (8-12 m/min, 8 weeks). Muscle and heart weights, serum creatine kinase, and gamma-glutamyltransferase activities were measured. The CRF2R agonist increased extensor digitorum longus and soleus muscle weights (P < 0.05) in wildtype and mdx mice. Sedentary mdx CRF2R and exercised mdx placebo mice had lower serum creatine kinase activity than sedentary mdx placebo mice. CRF2R-treated mice had decreased heart weights compared to placebo-treated mice. We conclude that CRF2R agonists should be further evaluated as a potential therapy for dystrophinopathies.

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

“…Adaptive functions of sustained GPCR signaling have been identified using chronic treatment with agonists and antagonists in humans and model organisms (9,18,43,57,63,86,91,101,115,121,154,155,197) as well as by targeted genetic approaches in mice (42,163,164). These and other studies have revealed striking myofiber hypertrophy and fiber-type transitions to faster fiber types with prolonged activation of ␤-AR signaling in particular.…”

“…␤ 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.…”

“…Many studies have shown, however, that cAMP-inducing agents or genetic modification of proteins involved in cAMP signaling can also have adaptive effects on skeletal muscle by increasing myofiber size and promoting fiber-type transitions to glycolytic fibers (9,18,42,43,57,63,86,91,101,121,128,154,155,163,190,193,194,215). 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).…”

“…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).…”