Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats.
Peptide-chain initiation is inhibited in fast-twitch skeletal muscle, but not heart, of diabetic rats. We have investigated mechanisms that might maintain eukaryotic initiation factor (eIF)-2B activity, preventing loss of efficiency of protein synthesis in heart of diabetic rats but not in fast-twitch skeletal muscle. There was no change in the amount or phosphorylation state of eIF-2 in skeletal or cardiac muscle during diabetes. In contrast, eIF-2B activity was decreased in fast-twitch but not slow-twitch muscle from diabetic animals. NADP+ inhibited partially purified eIF-2B in vitro, but addition of equimolar NADPH reversed the inhibition. The NADPH-to-NADP+ ratio was unchanged in fast-twitch muscle after induction of diabetes but was increased in heart of diabetic rats, suggesting that NADPH also prevents inhibition of eIF-2B in vivo. The activity of casein kinase II, which can phosphorylate and activate eIF-2B in vitro, was significantly lower in extracts of fast-twitch, but not cardiac muscle, of diabetic rats compared with controls. The results presented here demonstrate that changes in eIF-2 alpha phosphorylation are not responsible for the effect of diabetes on eIF-2B activity in fast-twitch skeletal muscle. Modulation of casein kinase II activity may be a factor in the regulation of protein synthesis in muscle during acute diabetes. The activity of eIF-2B in heart might be maintained by the increased NADPH/NADP+.
Karinch
A M
AM
Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey 17033.
Kimball
S R
SR
Vary
T C
TC
Jefferson
L S
LS
D000818:Animals; D047388:Casein Kinases; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009132:Muscles / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009249:NADP / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D015852:Eukaryotic Initiation Factor-2; D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D011506:Proteins; D012333:RNA, Messenger; D009249:NADP; D011494:Protein Kinases; D047388:Casein Kinases