The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Overall, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration.

Background: Satellite cell activation is orchestrated by several signals, which induce their differentiation into skeletal muscle fibers. Results: Obestatin and the GPR39 receptor exert an autocrine role on the control of myogenesis. Conclusion: Our data indicate that obestatin/GPR39 is an injury-regulated signal that functions as a myogenic regenerative system. Significance: Strategies to enhance obestatin-mediated signaling could be useful in treating trauma-induced muscle injuries and skeletal muscle myopathies.

Obestatin/GPR39 signaling stimulates skeletal muscle repair by inducing the expansion of satellite stem cells as well as myofiber hypertrophy. Here, we describe that the obestatin/GPR39 system acts as autocrine/paracrine factor on human myogenesis. Obestatin regulated multiple steps of myogenesis: myoblast proliferation, cell cycle exit, differentiation and recruitment to fuse and form multinucleated hypertrophic myotubes. Obestatin-induced mitogenic action was mediated by ERK1/2 and JunD activity, being orchestrated by a G-dependent mechanism. At a later stage of myogenesis, scaffolding proteins β-arrestin 1 and 2 were essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). Upon obestatin stimulus, β-arrestins are recruited to the membrane, where they functionally interact with GPR39 leading to Src activation and signalplex formation to EGFR transactivation by matrix metalloproteinases. This signalplex regulated the mitotic arrest by p21 and p57 expression and the mid- to late stages of differentiation through JNK/c-Jun, CAMKII, Akt and p38 pathways. This finding not only provides the first functional activity for β-arrestins in myogenesis but also identify potential targets for therapeutic approaches by triggering specific signaling arms of the GPR39 signaling involved in myogenesis.

The mal-positioning of total hip arthroplasty components can result in edge loading conditions. Purpose of this study was to determine if the wear rate of ceramic-on-ceramic and metal-on-polyethylene increases under edge loading conditions. The literature was reviewed to determine which of the commonly used hip bearings is the most forgiving to implant mal-orientation. Two 28-mm ceramic-on-ceramic articulations were tested in vitro: pure alumina (PAL) ceramic versus the new alumina-toughened zirconia (ATZ). Two 28-mm metal-on-polyethylene articulations were tested in vitro: conventional ultrahigh molecular weight polyethylene (UHMWPE) versus highly crosslinked polyethylene (HXLPE) stabilized with vitamin E. All bearings were tested at standard and at highest possible inclination angles. Hip simulator tests were run for five million cycles based on N = 3 tests per condition. The average wear rate of ATZ-on-ATZ is 0.024 mm(3) /Mcycles at 45° and 0.018 mm(3) /Mcycles at 65°. Wear rate of PAL-on-PAL is between 0.02 and 0.03 mm(3) /Mcycles at 45°, as well as 65°. The wear rate of UHMWPE was 31 ± 1 mm(3) /Mcycles at an inclination angle of 45° and 26 ± 1 mm(3) /Mcycles at 80°. The wear rate of vitamin E stabilized HXLPE was 5.9 ± 0.2 mm(3) /Mcycles at 45° and 5.8 ± 0.2 mm(3) /Mcycles at 80°. Edge loading does not increase the wear rate of ceramic-on-ceramic and metal-on-polyethylene articulations. The newest biomaterials showed markedly lower wear rates compared with their conventional counterparts. ATZ-on-ATZ showed the lowest wear rate of all tested pairings, but the vitamin E stabilized HXLPE seems to be the most forgiving material when it comes to implant mal-orientation.