Modified UCN2 peptide treatment improves skeletal muscle mass and function in mouse models of obesity‐induced insulin resistance

Abstract

Background Type 2 diabetes and obesity are often seen concurrently with skeletal muscle wasting, leading to further derangements in function and metabolism. Muscle wasting remains an unmet need for metabolic disease, and new approaches are warranted. The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin releasing factor receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance, glucose metabolism, and muscle mass. The aim of this study was to investigate the effects of modified UCN2 peptides as a pharmaceutical therapy to counteract the loss of skeletal muscle mass associated with obesity and casting immobilization. Methods High-fat-fed mice (C57Bl/6J; 26 weeks old) and ob/ob mice (11 weeks old) were injected daily with a PEGylated (Compound A) and non-PEGylated (Compound B) modified human UCN2 at 0.3 mg/kg subcutaneously for 14 days. A separate group of chow-fed C57Bl/6J mice (12 weeks old) was subjected to hindlimb cast immobilization and, after 1 week, received daily injections with Compound A. In vivo functional tests were performed to measure protein synthesis rates and skeletal muscle function. Ex vivo functional and molecular tests were performed to measure contractile force and signal transduction of catabolic and anabolic pathways in skeletal muscle. Results Skeletal muscles (extensor digitorum longus, soleus, and tibialis anterior) from high-fat-fed mice treated with Compound A were ~14% heavier than muscles from vehicle-treated mice. Chronic treatment with modified UCN2 peptides altered the expression of structural genes and transcription factors in skeletal muscle in high-fat diet-induced obesity including down-regulation of Trim63 and up-regulation of Nr4a2 and Igf1 (P < 0.05 vs. vehicle). Signal transduction via both catabolic and anabolic pathways was increased in tibialis anterior muscle, with increased phosphorylation of ribosomal protein S6 at Ser 235/236 , FOXO1 at Ser 256 , and ULK1 at Ser 317 , suggesting that UCN2 treatment modulates protein synthesis and degradation pathways (P < 0.05 vs. vehicle). Acutely, a single injection of Compound A in drug-naïve mice had no effect on the rate of protein synthesis in skeletal muscle, as measured via the surface sensing of translation method, while the expression of Nr4a3 and Ppargc1a4 was increased (P < 0.05 vs. vehicle). Compound A treatment prevented the loss of force production from disuse due to casting. Compound B treatment increased time to fatigue during ex vivo contractions of fast-twitch extensor digitorum longus muscle. Compound A and B treatment increased lean mass and rates of skeletal muscle protein synthesis in ob/ob mice. Conclusions Modified human UCN2 is a pharmacological candidate for the prevention of the loss of skeletal muscle mass associated with obesity and immobilization.

Urocortin 2 promotes hypertrophy and enhances skeletal muscle function through cAMP and insulin/IGF-1 signaling pathways

“…Indeed, in a recent study Borg et al. [ 16 ] have demonstrated that the treatment with a modified Ucn2 peptide analog of human Ucn2 increased lean mass and rates of skeletal muscle protein synthesis in ob/ob mice, even though cAMP intracellular signaling has not been investigated. The present finding that Ucn2 caused an upregulation of CREB phosphorylation, a well-established PKA target, and its target genes (i.e., PGC1 -α and SIK1 ) suggests that Ucn2 activated cAMP/PKA/CREB signaling pathway.…”

“…It has been demonstrated that acute treatment of Ucn2 increases muscle mass and strength [ 14 ], and prevents atrophy in rodent muscles submitted to models of sciatic motor denervation and treatment with dexamethasone [ 14 , 15 ]. A recent study demonstrated that modified Ucn2 peptide systemically administered enhances skeletal muscle mass and function in high-fat diet-induced obesity in mice [ 16 ]. Although the growth-promoting and anti-atrophy actions of Ucn2 are known, the underlying mechanisms and related intracellular mediators of these actions are not completely established.…”

Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss

“…Many of the same beneficial effects on body composition and metabolism observed for the ActRII inhibitors are seen in preclinical animal models following treatment with urocortin (Ucn) 2 and Ucn3, which are selective agonists of the corticotrophin-releasing hormone receptor 2 (CRHR2) (155). These urocortins have primarily been investigated for their beneficial effects on the cardiovascular system (156), but in addition, both Ucn2 and Ucn3 treatment or overexpression significantly increase muscle mass (157,158) while at the same time modulating food intake, fat mass, glucose tolerance, and insulin sensitivity (157,159,160). The effect of urocortins on muscle seems to be partially mediated through a direct effect on CRHR2 receptors on the muscle fibers resulting in both muscle growth and increased glucose uptake via increased glucose transporter type 4 (GLUT4) translocation and increased insulin signaling (159,160).…”

Musclin prevents depression-like behavior in male mice by activating urocortin 2 signaling in the hypothalamus

“…demonstrated that mice exposed to WI stress for 14 h a day for three consecutive days had impaired nesting behavior and proposed that this WI stress model is the apathy model ( 71 ). A recent study demonstrated that CRF type 2 receptors are present in skeletal muscles and Ucn 2 improves skeletal muscle quality and function in normal and obese mice ( 72 , 73 ). In the present study, administration of musclin to intact mice increased the swim distance, activation of Ucn 2; however, more musclin reversed the decrease in swim distance and Ucn 2 level induced by WI stress.…”