Modulation of melanocortin signaling ameliorates uremic cachexia.
Insulin-like growth factor (IGF)-I increases muscle mass while myostatin inhibits its development. Muscle wasting is common in patients with uremic cachexia and may be due to imbalance of this regulation. We had proposed a central mechanism involving leptin and melanocortin signaling in the pathogenesis of uremic cachexia since agouti-related peptide (AgRP), a melanocortin-4 receptor antagonist, reduced uremic cachexia. Here we found that injection of AgRP into the cerebral ventricles resulted in a gain of body mass and improved metabolic rate regulation in a mouse model of uremic cachexia. These salutary effects occurred independent of increased protein and calorie intake. Myostatin mRNA and protein concentrations were increased while those of IGF-I were decreased in the skeletal muscle of uremic mice. AgRP treatment partially corrected these uremia-induced changes. Suppressor of cytokine signaling-2 gene expression (SOCS2) was significantly increased in uremic animals and AgRP reduced this expression. We suggest that AgRP improves uremic cachexia and muscle wasting by a peripheral mechanism involving the balance between myostatin and IGF-I.
Cheung
Wai W
WW
Department of Pediatrics, Division of Pediatric Nephrology, University of California at San Diego, La Jolla, California 92093-0634, USA.
Rosengren
Sanna
S
Boyle
David L
DL
Mak
Robert H
RH
D054369:Agouti-Related Protein / Q000008:administration & dosage; D000818:Animals; D001069:Appetite Regulation; D002100:Cachexia / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002908:Chronic Disease; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D020738:Leptin / Q000378:metabolism; D008297:Male; D053486:Melanocortins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D055435:Myostatin; D009392:Nephrectomy; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D014511:Uremia / Q000150:complications / Q000378:metabolism*
D054369:Agouti-Related Protein; D020738:Leptin; C525911:MSTN protein, human; D053486:Melanocortins; C525912:Mstn protein, mouse; D055435:Myostatin; D012333:RNA, Messenger; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I