title: GH-Releasing Hormone Promotes Survival and Prevents TNF-α-Induced Apoptosis and Atrophy in C2C12 Myotubes.
abstract: Skeletal muscle atrophy is a consequence of different chronic diseases, including cancer, heart failure, and diabetes, and also occurs in aging and genetic myopathies. It results from an imbalance between anabolic and catabolic processes, and inflammatory cytokines, such as TNF-α, have been found elevated in muscle atrophy and implicated in its pathogenesis. GHRH, in addition to stimulating GH secretion from the pituitary, exerts survival and antiapoptotic effects in different cell types. Moreover, we and others have recently shown that GHRH displays antiapoptotic effects in isolated cardiac myocytes and protects the isolated heart from ischemia/reperfusion injury and myocardial infarction in vivo. On these bases, we investigated the effects of GHRH on survival and apoptosis of TNF-α-treated C2C12 myotubes along with the underlying mechanisms. GHRH increased myotube survival and prevented TNF-α-induced apoptosis through GHRH receptor-mediated mechanisms. These effects involved activation of phosphoinositide 3-kinase/Akt pathway and inactivation of glycogen synthase kinase-3β, whereas mammalian target of rapamycin was unaffected. GHRH also increased the expression of myosin heavy chain and the myogenic transcription factor myogenin, which were both reduced by the cytokine. Furthermore, GHRH inhibited TNF-α-induced expression of nuclear factor-κB, calpain, and muscle ring finger1, which are all involved in muscle protein degradation. In summary, these results indicate that GHRH exerts survival and antiapoptotic effects in skeletal muscle cells through the activation of anabolic pathways and the inhibition of proteolytic routes. Overall, our findings suggest a novel therapeutic role for GHRH in the treatment of muscle atrophy-associated diseases.
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Gesmundo
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Trovato
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pera
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gargantini
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Marco Alessandro
authors.initials: MA
authors.lastname: Minetto
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Ghigo
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology (D.G., I.G., L.T., G.P., E.Ga., R.G.), and Division of Endocrinology, Diabetes, and Metabolism (D.G., I.G., L.T., G.P., E.Ga., M.A.M., E.Gh., R.G.), Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Riccarda
authors.initials: R
authors.lastname: Granata
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D013007:Growth Hormone-Releasing Hormone / Q000502:physiology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000502:physiology*; D009124:Muscle Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D013007:Growth Hormone-Releasing Hormone; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; C546843:mTOR protein, mouse; C000605507:Gsk3b protein, mouse; C048250:somatotropin releasing hormone receptor