Submitted on March 1, 2005
Accepted on June 29, 2005
TUMOR NECROSIS FACTOR-
AND MALNUTRITION-INDUCED INHIBITION OF DIAPHRAGM FIBER GROWTH IN YOUNG RATS
Michael I Lewis1*, Xiaoyu Da2, Hongmei Li2, and Mario Fournier1
1 Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
2 Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: michael.lewis{at}cshs.org.
Tumor necrosis factor (TNF)-
, has been implicated in several muscle wasting disorders with increased levels of the cytokine reported in malnourished children. The role of TNF- 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- antibody. DIA fiber cross-sectional areas (CSAs) were determined. Serum and muscle TNF- 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- had no effect on body weight or on DIA mass in ND animals. ND significantly reduced CSAs of all fiber types (33 to 46%). Anti-TNF- failed to attenuate ND-induced inhibition of DIA fiber growth. Serum TNF- levels increased 2.6 fold in ND animals, with levels suppressed to below CTL values with anti-TNF-. DIA TNF- mRNA and protein levels increased 2 to 3-fold in ND rats. Anti-TNF- antibodies suppressed muscle levels of the cytokine in ND animals to near CTL values. TNF- 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-) tracked those of TNF-. Muscle levels of IGF-I mRNA and phosphorylated Akt were markedly reduced in ND animals with no change following anti TNF- therapy. Thus, rat anti-TNF- at a dose known to neutralize the cytokine, failed to attenuate or reverse ND-induced inhibition of DIA fiber growth in our model.
