Final Accepted Version Jap-00238-2005.r2 Tumor Necrosis Factor-α and Malnutrition-induced Inhibition of Diaphragm Fiber Growth in Young Rats

Tumor necrosis factor (TNF)-α, has been implicated in several muscle wasting disorders with increased levels of the cytokine reported in malnourished children. The role of TNF-α 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-α antibody. DIA fiber cross-sectional areas (CSAs) were determined. Serum and muscle TNF-α 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-α 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-α failed to attenuate ND-induced inhibition of DIA fiber growth. Serum TNF-α levels increased 2.6 fold in ND animals, with levels suppressed to below CTL values with anti-TNF-α. DIA TNF-α mRNA and protein levels increased 2 to 3-fold in ND rats. Anti-TNF-α antibodies suppressed muscle levels of the cytokine in ND animals to near CTL values. TNF-α 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-α) tracked those of TNF-α. Muscle levels of IGF-I mRNA and phosphorylated Akt were markedly reduced in ND animals with no change following anti TNF-α therapy. Thus, rat anti-TNF-α at a dose known to neutralize the cytokine, failed to attenuate or reverse ND-induced inhibition of DIA fiber growth in our model.