title: Effect of testosterone on the regulation of p53 and p66Shc during oxidative stress damage in C2C12 cells.
abstract: Accumulating evidence indicates that apoptosis is activated in the aged skeletal muscle, contributing to sarcopenia. We have previously demonstrated that testosterone protects against hydrogen peroxide (H2O2)-induced apoptosis in C2C12 muscle cells, at different levels: morphological, physiological, biochemical and molecular. In the present study we observed that H2O2 induces the mitochondrial permeability transition pore (mPTP) opening and exerts p53 activation in a time-dependent way, with a maximum response after 1-2h of treatment. Testosterone treatment, prior to H2O2, reduces not only p53 phosphorylation but also p66Shc expression, activation and its mitochondrial localization, at the same time that it prevents the mPTP opening. Furthermore, testosterone diminishes JNK and PKCβI phosphorylation induced by H2O2 and probably contributing thus, to reduce the activation of p66Shc. Thus, the mPTP opening, p53, JNK and PKCβI activation, as well as p66Shc mRNA increase, induced by oxidative stress, were reduced by testosterone pretreatment. The data presented in this work show some of the components upstream of the classical apoptotic pathway, that are activated during oxidative stress and that are points where testosterone exerts its protective action against apoptosis, exposing some of the puzzle pieces of the intricate network that aged skeletal muscle apoptosis represents.
authors.affiliation: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET), 8000 Bahía Blanca, Argentina.
authors.forename: Lucía
authors.initials: L
authors.lastname: Pronsato
authors.affiliation: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET), 8000 Bahía Blanca, Argentina. Electronic address: milanesi@criba.edu.ar.
authors.forename: Lorena
authors.initials: L
authors.lastname: Milanesi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects*; D011487:Protein Conformation / Q000187:drug effects; D064546:Protein Kinase C beta / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016159:Tumor Suppressor Protein p53; D013739:Testosterone; D006861:Hydrogen Peroxide; D064546:Protein Kinase C beta; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Apoptosis; Skeletal muscle; Testosterone; p53; p66Shc