Apoptosis of Muscle Cells Causes Weight Loss Prior to Impairment of DNA Synthesis in Tumor‐bearing Rabbits

Abstract

The mechanism of weight loss induced by the growth of malignant tumors is still unknown. We investigated it by focusing on apoptosis of skeletal muscle. VX2-tumor was implanted into rabbits and the apoptotic index (AI) of skeletal muscle was measured by in situ end-labeling assay. Plasma of the tumor-bearing rabbits was perfused repeatedly through non-coated charcoal resin. The AI reached 54.6% early after tumor implantation, when weight loss amounted to an 18% decrease in lean body mass (LBM) without change in muscle DNA synthesis or urinary 3-methylhistidine/ creatinine ratio (3-MH/Cr). When the decrease of LBM reached 30%, DNA synthesis was decreased by 48% and 3-MH/Cr was increased by 104%, whereas AI was only 4.7%. The plasma perfusion did not prevent apoptosis in muscle, but improved LBM, DNA synthesis, and 3-MH/Cr. There may be two mechanisms of muscle depletion during the tumor growth: apoptosis in the early stage and metabolic abnormalities in muscle in the late stage.Key words: Muscle cell -Apoptosis -DNA synthesis -Weightloss -Plasma perfusion The weight loss induced by the progression of malignant tumors is the symptom that has attracted the greatest attention among investigators attempting to identify the etiology of cancer cachexia, a condition that gives rise to a variety of symptoms. Cancer cachexia is generally considered to be characterized metabolically by proteolysis and lipolysis rates that exceed protein synthesis and lipogenesis, but no conclusion has been reached concerning how these metabolic abnormalities occur. Todorov et al. succeeded in purifying a cancer cachectic factor that induces skeletal muscle catabolism from mice transplanted with MAC16 tumors. 1) Other humoral factors such as cachectin, tumor-necrosis factor, interleukin (IL)-1, IL-6, interferon (IFN)-γ, leukemia-inhibitory factor (LIF), and lipid-mobilizing factor have also been reported to act as mediators inducing cancer cachexia.2-4) We purified an anemiainducing substance (AIS) that depresses erythrocyte and immunocompetent cell functions, as reported in our previous papers, 5,6) and AIS has been recently shown to have another biological action, i.e., lipolytic activity. As stated above, many substances have been reported to be causative agents of cancer cachexia, and at present it is difficult to discuss the etiology of this condition in a coherent fashion.In the present study using tumor-bearing rabbits, we examined the relationship between weight loss induced during the progression of malignant tumors and the morphological and energy metabolism changes in muscle tissue. MATERIALS AND METHODSExperimental animals Male Japanese White rabbits implanted with VX2-carcinoma 7) in the muscles of their right thigh were supplied by Tsukuba Animal Research Laboratories Co. (Tsukuba) and fed essential CR-3 (Clea, Tokyo) and water. When the VX2-carcinoma in the right thigh of the rabbits grew to more than 5 cm in diameter, it was resected, and cell suspensions (1×10 5 cells in 1 ml of 0.15 M NaCl) were injected intramuscularly in...

Pathophysiology of peripheral muscle wasting in cardiac cachexia

“…A decrease in the apoptotic index has also been reported in the late stages of cancer cachexia. In rabbits with cancer cachexia, there is an increase in the apoptotic index in the early stages of cachexia but a decrease at higher losses [63]. The expression of Bax, which promotes apoptosis, is also increased in the early stage of weight loss, but thereafter declines.…”

Mechanisms of Cancer Cachexia

“…Fragmentation of poly(ADP-ribose) polymerase (PARP) was also observed, which is cleaved during apoptosis by caspases -3 and -7, although there was no evidence for DNA fragmentation into a nucleosomal ladder typical of apoptosis. However, enhanced laddering of DNA was observed in the skeletal muscle of rats bearing the Yoshida AH-130 ascites hepatoma, mice bearing the Lewis lung carcinoma (266), and rabbits bearing the UX2 tumor (113), indicative of apoptosis. The expression of Bax, which promotes apoptosis, was also increased in the early stages of weight loss.…”

“…Ishiko et al (113) proposed two mechanisms for muscle depletion during tumor growth: apoptosis in the early stages and metabolic abnormalities in the late stage. An increased activity of caspases-1, -3, -6, -8, and -9 was observed in gastrocnemius muscle of mice bearing the cachexia-inducing MAC16 tumor (17).…”

Expression of Apoptosis Regulatory Proteins in the Skeletal Muscle of Tumorbearing Rabbits

“…The results showed that LBM and body fat began to decrease in the early stage after implantation, when the pathological manifestations of cachexia were still not marked. We have also reported the occurrence of apoptosis of normal skeletal muscle in the early stage of tumor bearing, 8) and in the present study we investigated its pathogenetic mechanism.…”

“…We previously reported observing that apoptosis occurs in normal skeletal muscle cell of VX2-bearing rabbits in the early stage after tumor implantation. 8) Apoptosis plays a key role in various biological processes and functions and is observed in many different tumor and normal tissues. Various genes related to apoptosis have already been identified, and one of them, bcl-2, is known to be a suppressor of apoptosis.…”