Mechanism of attenuation of protein loss in murine C2C12 myotubes by D-myo-inositol 1,2,6-triphosphate.
D-myo-inositol 1,2,6-triphosphate (alpha trinositol, AT) has been shown to attenuate muscle atrophy in a murine cachexia model through an increase in protein synthesis and a decrease in degradation. The mechanism of this effect has been investigated in murine myotubes using a range of catabolic stimuli, including proteolysis-inducing factor (PIF), angiotensin II (Ang II), lipopolysaccharide, and tumor necrosis factor-alpha/interferon-gamma. At a concentration of 100 muM AT was found to attenuate both the induction of protein degradation and depression of protein synthesis in response to all stimuli. The effect on protein degradation was accompanied by attenuation of the increased expression and activity of the ubiquitin-proteasome pathway. This suggests that AT inhibits a signalling step common to all four agents. This target has been shown to be activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) and the subsequent phosphorylation of eukaryotic initiation factor 2 on the alpha-subunit, together with downstream signalling pathways leading to protein degradation. AT also inhibited activation of caspase-3/-8, which is thought to lead to activation of PKR. The mechanism of this effect may be related to the ability of AT to chelate divalent metal ions, since the attenuation of the increased activity of the ubiquitin-proteasome pathway by PIF and Ang II, as well as the depression of protein synthesis by PIF, were reversed by increasing concentrations of Zn(2+). The ability of AT to attenuate muscle atrophy by a range of stimuli suggests that it may be effective in several catabolic conditions.
Russell
Steven T
ST
Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
Siren
Pontus M A
PM
Siren
Matti J
MJ
Tisdale
Michael J
MJ
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001284:Atrophy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007295:Inositol Phosphates / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011509:Proteoglycans / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D057149:Ubiquitinated Proteins / Q000378:metabolism; D019287:Zinc Sulfate / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015852:Eukaryotic Initiation Factor-2; D007295:Inositol Phosphates; D008070:Lipopolysaccharides; D016328:NF-kappa B; D021122:Protein Subunits; D011506:Proteins; D011509:Proteoglycans; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D057149:Ubiquitinated Proteins; C042057:proteolysis-inducing peptide; D000804:Angiotensin II; D019287:Zinc Sulfate; D007371:Interferon-gamma; D019892:eIF-2 Kinase; D011493:Protein Kinase C; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C059368:atrinositol