Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

Abstract

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C(6)H(12)CIN(3)O(4)S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower (P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (-38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (~-54 to -69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (-80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients

“…Six weeks after surgical resection of the primary tumor, muscle protein synthetic responses to feeding and leg proteolysis had returned to normal with additional decreases in lean leg mass, which was a disparity that we believe to be attributable to the now spent surgical insult (43). With a greater understanding of the processes at work in the skeletal muscle of cancer patients (in different cancers and at different stages), it may be possible to better tailor future therapies to both stimulate MPS, under fasted and fed conditions, and reduce MPB to combat the serious problem of cancer cachexia.…”

Clinical Classification of Cancer Cachexia: Phenotypic Correlates in Human Skeletal Muscle

“…In mice bearing the MAC-16 adenocarcinoma, muscle loss is due to the combination of reduced synthesis and increased degradation [37]. Similarly Samuels et al demonstrated reduced protein synthesis and increased degradation in skeletal muscle co-incident with the onset of cachexia in mice implanted with the C26 murine model [38].…”

Mechanisms of skeletal muscle depletion in wasting syndromes: role of ATP-ubiquitin-dependent proteolysis

“…It has been recently reported that mice administered cystemustine experience a transient reduction of muscle protein synthesis rates [37]. In contrast, novel findings have shown that chemotherapeutic regimens decrease muscle protein breakdown rates in both controls and tumor-bearing animals.…”