Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 297, Issue 2, Pages E392-E401Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.90529.2008
Keywords
muscle atrophy; creatinine kinase; nitric oxide synthase-2; Ref-1
Categories
Funding
- National Institute of Health [DK-38652, CA-96932, CA-128866]
- National Cancer Institute
- National Center for Research Resources
- United States Public Health Service [M01RR 000827]
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Ramamoorthy S, Donohue M, Buck M. Decreased Jun-D and myogenin expression in muscle wasting of human cachexia. Am J Physiol Endocrinol Metab 297: E392-E401, 2009. First published May 26, 2009; doi: 10.1152/ajpendo.90529.2008.-Muscle wasting is a critical feature of patients afflicted by acquired immune deficiency syndrome (AIDS), cancer, or chronic inflammatory diseases. In a mouse model of muscle wasting, TNF-alpha induces oxidative stress and nitric oxide synthase-2 (NOS2) and decreases myogenin, Jun-D, and creatinine kinase muscle isoform (CKM) expression. Here, we studied 12 patients with muscle wasting due to cancer (N = 10) or AIDS (N = 2) and 4 control subjects. We show that in skeletal muscle of cachectic patients there is 1) increased expression and activity of the TNF-alpha signaling, including TNF-alpha mRNA, activation of TNFR1, and TNF alpha- associated to TNFR1; 2) increased oxidative stress, as determined by the presence of malondialdehyde-lysine adducts; 3) increased NOS2 mRNA and protein; 4) decreased expression of Jun-D, myogenin, myosin, and CKM mRNA and protein; 5) impaired CKM-E box binding activities, associated with decreased Jun-D/myogenin activities; and 6) oxidative modification and ubiquitination of Jun-D. These studies show that these molecular pathways are modulated in association with muscle wasting in patients with cancer or AIDS, and whether or not they cause muscle wasting remains to be determined.
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