title: Ranolazine promotes muscle differentiation and reduces oxidative stress in C2C12 skeletal muscle cells.
abstract: The purpose of this study is to investigate Ranolazine action on skeletal muscle differentiation and mitochondrial oxidative phenomena. Ranolazine, an antianginal drug, which acts blocking the late INaL current, was shown to lower hemoglobin A1c in patients with diabetes. In the present study, we hypothesized an action of Ranolazine on skeletal muscle cells regeneration and oxidative process, leading to a reduction of insulin resistance.
  
  
  
  10 μM Ranolazine was added to C2C12 murine myoblastic cells during proliferation, differentiation and newly formed myotubes.
  
  
  
  Ranolazine promoted the development of a specific myogenic phenotype: increasing the expression of myogenic regulator factors and inhibiting cell cycle progression factor (p21). Ranolazine stimulated calcium signaling (calmodulin-dependent kinases) and reduced reactive oxygen species levels. Furthermore, Ranolazine maintained mitochondrial homeostasis. During the differentiation phase, Ranolazine promoted myotubes formation. Ranolazine did not modify kinases involved in skeletal muscle differentiation and glucose uptake (extracellular signal-regulated kinases 1/2 and AKT pathways), but activated calcium signaling pathways. During proliferation, Ranolazine did not modify the number of mitochondria while decreasing osteopontin protein levels. Lastly, neo-formed myotubes treated with Ranolazine showed typical hypertrophic phenotype.
  
  
  
  In conclusion, our results indicate that Ranolazine stimulates myogenesis and reduces a pro-oxidant inflammation/oxidative condition, activating a calcium signaling pathway. These newly described mechanisms may partially explain the glucose lowering effect of the drug.
authors.affiliation: Diabetes Research Institute, Metabolism, Nutrigenomics and Cellular Differentiation Unit, San Raffaele Scientific Institute, 60 Olgettina street, 20132, Milan, Italy. terruzzi.ileana@hsr.it.
authors.forename: Ileana
authors.initials: I
authors.lastname: Terruzzi
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Montesano
authors.affiliation: Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Senesi
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Vacante
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.|Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Benedini
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.|Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Luzi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007333:Insulin Resistance; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D000069458:Ranolazine / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D000069458:Ranolazine
keywords: Muscle differentiation; Oxidative stress; Ranolazine