IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.
Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.
Cai
Dongsheng
D
Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
Frantz
J Daniel
JD
Tawa
Nicholas E
NE
Melendez
Peter A
PA
Oh
Byung-Chul
BC
Lidov
Hart G W
HG
Hasselgren
Per-Olof
PO
Frontera
Walter R
WR
Lee
Jongsoon
J
Glass
David J
DJ
Shoelson
Steven E
SE
D000818:Animals; D001835:Body Weight; D002100:Cachexia / Q000378:metabolism* / Q000517:prevention & control; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D005260:Female; D006614:Hindlimb; D006801:Humans; D051550:I-kappa B Kinase; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009929:Organ Size; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012459:Salicylates / Q000008:administration & dosage / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D025801:Ubiquitin / Q000378:metabolism
D016207:Cytokines; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012459:Salicylates; D025801:Ubiquitin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse