Decreased Jun-D and myogenin expression in muscle wasting of human cachexia

• Published in: American journal of physiology: endocrinology and metabolism Vol. 297; no. 2; pp. E392 - E401
• Main Authors: Ramamoorthy, Sonia, Donohue, Michael, Buck, Martina
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2009
• Subjects: Acquired immune deficiency syndrome; Adult; Aged; AIDS; Cachexia - complications; Cachexia - genetics; Cachexia - pathology; Cancer; Creatine Kinase, MM Form - genetics; Down-Regulation; Female; Gene expression; Humans; Male; Middle Aged; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Myogenin - genetics; Myogenin - metabolism; Nitric oxide; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Oxidative stress; Oxidative Stress - genetics; Oxidative Stress - physiology; Protein Binding; Proteins; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Response Elements; Rodents; Signal transduction; Studies; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Wasting Syndrome - etiology; Wasting Syndrome - genetics
• ISSN: 0193-1849; 1522-1555; 1522-1555
• DOI: 10.1152/ajpendo.90529.2008

1 Department of Surgery, 2 Department of Medicine, 3 Moores Cancer Center, 4 General Clinical Research Center, and 5 Biostatistics and Bioinformatics, University of California San Diego; and 6 Veterans Affairs Healthcare System, San Diego, California Submitted 22 June 2008 ; accepted in final form 17 May 2009 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- 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- signaling, including TNF- mRNA, activation of TNFR1, and TNF- -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. muscle atrophy; creatinine kinase; nitric oxide synthase-2; Ref-1 Address for reprint requests and other correspondence: M. Buck, VAMC, 9-111-D, 3350 La Jolla Village Dr., San Diego, CA 92161 (e-mail: mbuck{at}ucsd.edu )