Mechanism of attenuation of skeletal muscle atrophy by zinc-alpha2-glycoprotein.
The mechanism by which the adipokine zinc-α2-glycoprotein (ZAG) increases the mass of gastrocnemius, but not soleus muscle of diabetic mice, has been evaluated both in vivo and in vitro. There was an increased phosphorylation of both double-stranded RNA-dependent protein kinase and its substrate, eukaryotic initiation factor-2α, which was attenuated by about two-thirds in gastrocnemius but not soleus muscle of ob/ob mice treated with ZAG (50 μg, iv daily) for 5 d. ZAG also reduced the expression of the phospho forms of p38MAPK and phospholipase A2, as well as expression of the ubiquitin ligases (E3) muscle atrophy F-box/atrogin-1 and muscle RING finger protein, and the increased activity of both caspase-3 and casapse-8 to values found in nonobese controls. ZAG also increased the levels of phospho serine-threonine kinase and mammalian target of rapamycin in gastrocnemius muscle and reduced the phosphorylation of insulin receptor substrate-1 (Ser307) associated with insulin resistance. Similar changes were seen with ZAG when murine myotubes were incubated with high glucose concentrations (10 and 25 mm), showing that the effect of ZAG was direct. ZAG produced an increase in cAMP in murine myotubes, and the effects of ZAG on protein synthesis and degradation in vitro could be replicated by dibutyryl cAMP. ZAG increased cAMP levels of gastrocnemius but not soleus muscle. These results suggest that protein accretion in skeletal muscle in response to ZAG may be due to changes in intracellular cAMP and also that ZAG may have a therapeutic application in the treatment of muscle wasting conditions.
Russell
Steven T
ST
Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, United Kingdom.
Tisdale
Michael J
MJ
D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D008820:Mice, Obese; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D029589:Seminal Plasma Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D000090203:Zn-Alpha-2-Glycoprotein; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D029589:Seminal Plasma Proteins; D000090203:Zn-Alpha-2-Glycoprotein; D048051:p38 Mitogen-Activated Protein Kinases