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J Appl Physiol 99: 1649-1657, 2005. First published July 7, 2005; doi:10.1152/japplphysiol.00238.2005
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Tumor necrosis factor-{alpha} and malnutrition-induced inhibition of diaphragm fiber growth in young rats

Michael I. Lewis,1,2 Xiaoyu Da,1 Hongmei Li,1 and Mario Fournier1,2

1Division of Pulmonary/Critical Care Medicine, The Burns & Allen Research Institute, Cedars-Sinai Medical Center; and 2The David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California

Submitted 1 March 2005 ; accepted in final form 29 June 2005

Tumor necrosis factor (TNF)-{alpha} has been implicated in several muscle-wasting disorders, with increased levels of the cytokine reported in malnourished children. The role of TNF-{alpha} in mediating malnutrition-induced inhibition of diaphragm (DIA) muscle growth in young growing rats was evaluated. Three groups of rats were studied: 1) control (CTL); 2) nutritional deprivation (ND; 50% of normal food intake for 7 days); and 3) ND + rat specific anti-TNF-{alpha} antibody. DIA fiber cross-sectional areas were determined. Serum and muscle TNF-{alpha} levels were measured by real-time PCR, ELISA, and immunohistochemistry. Body weights decreased 20% in ND rats and increased 46% in CTL animals. Anti-TNF-{alpha} had no effect on body weight or on DIA mass in ND animals. ND significantly reduced cross-sectional areas of all fiber types (33–46%). Anti-TNF-{alpha} failed to attenuate ND-induced inhibition of DIA fiber growth. Serum TNF-{alpha} levels increased 2.6-fold in ND animals, with levels suppressed to below CTL values with anti-TNF-{alpha}. DIA TNF-{alpha} mRNA and protein levels increased two- to threefold in ND rats. Anti-TNF-{alpha} antibodies suppressed muscle levels of the cytokine in ND animals to near CTL values. TNF-{alpha} immunoreactivity in all DIA fibers revealed similar directions of change in both ND groups. Direction and magnitude of change in DIA phosphorylated p38 MAPK (a likely second messenger of TNF-{alpha}) tracked those of TNF-{alpha}. Muscle levels of IGF-I mRNA and phosphorylated Akt were markedly reduced in ND animals with no change following anti-TNF-{alpha} therapy. Thus rat anti-TNF-{alpha} at a dose known to neutralize the cytokine failed to attenuate or reverse ND-induced inhibition of DIA fiber growth in our model.

cytokines; respiratory muscles; muscle wasting; nutritional depletion; p38


Address for reprint requests and other correspondence: M. I. Lewis, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Rm. 6732, Los Angeles, CA 90048 (e-mail: michael.lewis{at}cshs.org)






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