Suppression of protein synthesis in brain during hibernation involves inhibition of protein initiation and elongation.
Protein synthesis (PS) has been considered essential to sustain mammalian life, yet was found to be virtually arrested for weeks in brain and other organs of the hibernating ground squirrel, Spermophilus tridecemlineatus. PS, in vivo, was below the limit of autoradiographic detection in brain sections and, in brain extracts, was determined to be 0.04% of the average rate from active squirrels. Further, it was reduced 3-fold in cell-free extracts from hibernating brain at 37 degreesC, eliminating hypothermia as the only cause for protein synthesis inhibition (active, 0.47 +/- 0.08 pmol/mg protein per min; hibernator, 0.16 +/- 0.05 pmol/mg protein per min, P < 0.001). PS suppression involved blocks of initiation and elongation, and its onset coincided with the early transition phase into hibernation. An increased monosome peak with moderate ribosomal disaggregation in polysome profiles and the greatly increased phosphorylation of eIF2alpha are both consistent with an initiation block in hibernators. The elongation block was demonstrated by a 3-fold increase in ribosomal mean transit times in cell-free extracts from hibernators (active, 2.4 +/- 0.7 min; hibernator, 7.1 +/- 1.4 min, P < 0.001). No abnormalities of ribosomal function or mRNA levels were detected. These findings implicate suppression of PS as a component of the regulated shutdown of cellular function that permits hibernating ground squirrels to tolerate "trickle" blood flow and reduced substrate and oxygen availability. Further study of the factors that control these phenomena may lead to identification of the molecular mechanisms that regulate this state.
Frerichs
K U
KU
Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Smith
C B
CB
Brenner
M
M
DeGracia
D J
DJ
Krause
G S
GS
Marrone
L
L
Dever
T E
TE
Hallenbeck
J M
JM
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006605:Hibernation / Q000502:physiology*; D007930:Leucine / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000302:isolation & purification; D010441:Peptide Chain Elongation, Translational; D010442:Peptide Chain Initiation, Translational; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D012589:Sciuridae; D012680:Sensitivity and Specificity; D014158:Transcription, Genetic
D002250:Carbon Radioisotopes; D015852:Eukaryotic Initiation Factor-2; D009419:Nerve Tissue Proteins; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D012333:RNA, Messenger; D000246:Adenosine Diphosphate Ribose; D007930:Leucine