caa a22 4500 606237089 CHVBK 20210128101251.0 cr unu---uuuuu 210128e20150301xx s 000 0 eng 10.1007/s11010-014-2305-y doi (NATIONALLICENCE)springer-10.1007/s11010-014-2305-y Nitrite circumvents canonical cGMP signaling to enhance proliferation of myocyte precursor cells [Elektronische Daten] [Matthias Totzeck, Andreas Schicho, Pia Stock, Malte Kelm, Tienush Rassaf, Ulrike Hendgen-Cotta] Skeletal muscle tissue has a remarkable high regenerative capacity. The underlying cellular events are governed by complex signaling processes, and the proliferation of skeletal myoblasts is a key initial event. The role of nitric oxide (NO) in cell cycle regulation is well-appreciated. Nitrite, an NO oxidation product, is a stable source for NO-like bioactivity particularly in cases when oxygen shortage compromises NO-synthases activity. Although numerous studies suggest that nitrite effects are largely related to NO-dependent signaling, emerging evidence also implicates that nitrite itself can activate protein pathways albeit under physiological, normoxic conditions. This includes a recently demonstrated cyclic guanosine monophosphate-(cGMP)-independent enhancement of endothelial cell proliferation. Whether nitrite itself has the potential to affect myoblast proliferation and metabolism with or without activation of the canonical NO/cGMP pathway to subsequently support muscle cell regeneration is not known. Here we show that nitrite increases proliferation and metabolic activity of murine cultured myoblasts dose-dependently. This effect is not abolished by the NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5-tetramethylimida-zoline-1-oxyl-3 oxide and does not affect intracellular cGMP levels, implicating a cGMP-independent mechanism. Nitrite circumvents the rapamycin induced attenuation of myoblast proliferation and enhances mTOR activity. Our results provide evidence for a novel potential physiological and therapeutic approach of nitrite in skeletal muscle regeneration processes under normoxia independent of NO and cGMP. Springer Science+Business Media New York, 2014 Nitrite nationallicence Nitric oxide nationallicence Myoblast nationallicence Cyclic GMP nationallicence Totzeck Matthias Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut Schicho Andreas Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut Stock Pia Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut Kelm Malte Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut Rassaf Tienush Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut Hendgen-Cotta Ulrike Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 401/1-2(2015-03-01), 175-183 0300-8177 401:1-2<175 2015 401 11010 https://doi.org/10.1007/s11010-014-2305-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-014-2305-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Totzeck Matthias Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut NATIONALLICENCE 700 1- Schicho Andreas Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut NATIONALLICENCE 700 1- Stock Pia Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut NATIONALLICENCE 700 1- Kelm Malte Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut NATIONALLICENCE 700 1- Rassaf Tienush Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut NATIONALLICENCE 700 1- Hendgen-Cotta Ulrike Division of Cardiology, Pulmonology and Vascular Medicine, Department of Medicine, Medical Faculty, University Hospital Duesseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 401/1-2(2015-03-01), 175-183 0300-8177 401:1-2<175 2015 401 11010