Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways.
Progression of skeletal muscle atrophy is one of the characteristic features in cancer patients. Interleukin-6 (IL-6) has been reported to be responsible for the loss of lean body mass during cancer cachexia in colon-26 adenocarcinoma (C-26)-bearing mice. This study was carried out to elucidate the intracellular proteolytic pathways operating in skeletal muscle in C-26-bearing mice, and to examine the effect of anti IL-6 receptor antibody on muscle atrophy. On day 17 after tumor inoculation, the gastrocnemius muscle weight of C-26-bearing mice had significantly decreased to 69% of that of the pair-fed control mice. This weight loss occurred in association with increases in the mRNA levels of cathepsins B and L, poly-ubiquitin (Ub) and the subunits of proteasomes in the muscles. Furthermore, enzymatic activity of cathepsin B+L in the muscles also increased to 119% of the control. The administration of anti-murine IL-6 receptor antibody to C-26-bearing mice reduced the weight loss of the gastrocnemius muscles to 84% of that of the control mice, whose enzymatic activity of cathepsin B+L and mRNA levels of cathepsin L and poly-Ub were significantly suppressed compared with those of the C-26-bearing mice. Our data indicate that both the lysosomal cathepsin pathway and the ATP-dependent proteolytic pathway might be involved in the muscle atrophy of C-26-bearing mice. The results also suggest that anti IL-6 receptor antibody could be a potential therapeutic agent against muscle atrophy in cancer cachexia by inhibiting these proteolytic systems.
Fujita
J
J
Department of Surgery II, Osaka University Medical School, Japan.
Tsujinaka
T
T
Yano
M
M
Ebisui
C
C
Saito
H
H
Katsume
A
A
Akamatsu
K
K
Ohsugi
Y
Y
Shiozaki
H
H
Monden
M
M
D000230:Adenocarcinoma / Q000503:physiopathology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D003110:Colonic Neoplasms / Q000503:physiopathology*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009133:Muscular Atrophy / Q000378:metabolism / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects*; D014452:Ubiquitins / Q000378:metabolism*
D000906:Antibodies; D015850:Interleukin-6; D014452:Ubiquitins; D000255:Adenosine Triphosphate