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

Abstract

We reported finding that apoptosis occurred in skeletal muscle in the early stage after implantation. In the present study, we investigated expression of the apoptosis-related proteins Bax and Bcl-2 to determine the mechanism of the apoptosis. In the early stage of tumor bearing, 20 days after implantation, lean body mass (LBM) was reduced by 5.06 ± ± ± ±1.10% in the tumor-bearing group, compared with an increase of 4.96 ± ± ± ±1.26% in the control group. The apoptotic index (AI) of the skeletal muscle in the tumor-bearing group increased to 40.5 ± ± ± ±3.20% but was 0% in the control group, and Bax expression was strongly positive in 5 of the 10 rabbits in the tumor-bearing group, and significantly stronger than in the control group (P = = = =0.0002). In the late stage of tumor bearing, 40 days after implantation, the AI had declined to 0.93 ± ± ± ±0.96% in the tumor-bearing group, but was still 0% in the control group. Bax expression was rarely detected in either the tumor-bearing group or the control group, and there was no significant difference between the two groups (P = = = =0.706). No significant changes in Bcl-2 were observed in either group. The above resultsshowed that apoptosis via Bax played a role in muscle wasting associated with progression of the malignant tumor. However, the apoptosis and expression of Bax were seen only in the early stage, within 20 days after implantation, not in the late stage. This suggested that the muscle wasting in the early stage might be caused by a different mechanism from that in the late stage.Key words: Apoptosis -Bax -Bcl-2 -Skeletal muscle -Cancer cachexia Cachexia is probably the most common complication in cancer patients. 1) Anorexia, weight loss, muscle loss, atrophy, and alterations in carbohydrate, lipid, and protein metabolism can occur early in the course of cancer cachexia. Although the etiology of cancer cachexia remains unclear, it appears to be associated with metabolic competition, malnutrition, or circulating humoral factors.2)It is well known that muscle protein wasting occurs in the cachectic state. Increasing muscle protein degradation and decreasing muscle protein synthesis cause muscle atrophy.3) We previously suggested that anemia-inducing substance (AIS) secreted by tumor tissue might cause cancer cachexia.4-7) Removing AIS by plasma perfusion has been found to inhibit the increased degradation of muscle proteins in rabbits at the late stage of cachexia induced by VX2 carcinoma.3) However, the mechanism of the muscle wasting that occurs in the early stage of tumor bearing is unknown. 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. By contrast, another member of the bcl-2 family...

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

“…Activation of PKR by PIF may be responsible for its ability to induce apoptosis in murine myotubes (Smith and Tisdale, 2003). Increased apoptosis has also been observed in the skeletal muscle of rats bearing the cachexia-inducing Yoshida AH-130 ascites hepatoma (van Royen et al, 2000) and in the early stage of weight loss in rabbits bearing the VX2 carcinoma (Yoshida et al, 2001). In addition, muscle biopsies from weight losing patients with upper gastro-intestinal cancer showed a threefold increase in DNA fragmentation compared with control subjects, together with an increased PARP cleavage and decrease in MyoD protein content (Busquets et al, 2007).…”

Activity level, apoptosis, and development of cachexia in ApcMin/+ mice

“…Both tumor-bearing animals and humans demonstrate activation of apoptotic pathways during cachexia (11,17,20,33). It has also been suggested that apoptosis is initiated early in the wasting process (6).…”

“…Apoptotic pathways are activated in the skeletal muscle of cachectic humans (11), in tumor-bearing animals (9,17,20,33), and in cell culture models of cachexia (14,31). In fact, B cell leukemia/lymphoma 2 (BCL2)-associated X protein (BAX) protein expression appears to be a key regulator during cachexia (20,33), and BCL2 is either not detected or weakly expressed (20). Conversely, aerobic exercise training is a potent stimulus that protects mitochondria from undergoing apoptosis in skeletal muscle (1).…”

Acute and chronic effects of alcohol exposure on skeletal muscle c-myc, p53, and Bcl-2 mRNA expression

“…17), we must conclude that, in general, p53 is not upregulated in this defined myopathic condition and is even downregulated in starvation. The situation for Bcl-2 is similarly contradictory, in that in myopathic conditions muscle Bcl-2 protein is unaffected in cancer cachexia (23,72); reduced in brachial plexus injury (25), cardiac cachexia (65,66), and muscle dystrophy (56); and increased in sporadic amyotrophic lateral sclerosis (58).…”