Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation.
BACKGROUND
Mechanical unloading of the heart results in atrophic remodeling. In skeletal muscle, atrophy is associated with inactivation of the mammalian target of rapamycin (mTOR) pathway and upregulation of critical components of the ubiquitin proteosome proteolytic (UPP) pathway. The hypothesis is that mechanical unloading of the mammalian heart has differential effects on pathways of protein synthesis and degradation.


RESULTS
In a model of atrophic remodeling induced by heterotopic transplantation of the rat heart, we measured gene transcription, protein expression, polyubiquitin content, and regulators of the mTOR pathway at 2, 4, 7, and 28 days. In atrophic hearts, there was an increase in polyubiquitin content that peaked at 7 days and decreased by 28 days. Furthermore, gene and protein expression of UbcH2, a ubiquitin conjugating enzyme, was also increased early in the course of unloading. Transcript levels of TNF-alpha, a known regulator of UbcH2-dependent ubiquitin conjugating activity, were upregulated early and transiently in the atrophying rat heart. Unexpectedly, p70S6K and 4EBP1, downstream components of mTOR, were activated in atrophic rat heart. This activation was independent of Akt, a known upstream regulator of mTOR. Rapamycin treatment of the unloaded rat hearts inhibited the activation of p70S6K and 4EBP1 and subsequently augmented atrophy in these hearts compared with vehicle-treated, unloaded hearts.


CONCLUSIONS
Atrophy of the heart, secondary to mechanical unloading, is associated with early activation of the UPP. The simultaneous activation of the mTOR pathway suggests active remodeling, involving both protein synthesis and degradation.
Razeghi
Peter
P
Division of Cardiology, University of Texas Houston-Medical School, Houston, Tex 77030, USA.
Sharma
Saumya
S
Ying
Jun
J
Li
Yi-Ping
YP
Stepkowski
Stanislaw
S
Reid
Michael B
MB
Taegtmeyer
Heinrich
H
D000818:Animals; D001284:Atrophy / Q000209:etiology / Q000378:metabolism*; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D016042:Transplantation, Heterotopic / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D044763:Ubiquitin-Conjugating Enzymes; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus