Cancer cachexia in a mouse model of oxidative stress

Abstract

Background Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia. Methods Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data were analysed by two-way ANOVA with Tukey-Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM. Results Muscle mass and cross-sectional area were significantly reduced, in tumour-bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour-bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour-bearing mice compared with saline-injected wild-type mice. Mitochondrial protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.0204 ± 0.00159; wild-type LLC, 0.167 ± 0.00157) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2 ± 0.861; wild-type LLC, 28.8 ± 0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation. Conclusions Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.

Development and progression of cancer cachexia: Perspectives from bench to bedside

“…Moreover, muscle protein synthesis is one of the two major components when it comes to net protein balance while its role in CC has not been clearly understood. While our data 62 , 63 and other works 60 , 61 clearly demonstrate reduced protein anabolism in pre-clinical animal models of CC, understanding of the suppression of anabolic signaling remains incomplete. 60 , 75 The primary cellular signaling pathway of muscle growth known as Akt/mTOR signaling is an essential part of muscle protein synthesis.…”

“…Previous studies have reported that both in vivo and in vitro models of CC can lead to impaired mitochondrial function including reduced respiratory capacity, ATP production, and elevated reactive oxygen species (ROS) emission. 43 , 63 , 87 , 88 However, our recent findings reveal mitochondrial ROS generation and mitochondrial oxidative stress precedes the development of CC in LLC tumor-bearing mice. 84 Elevated ROS emission is associated with impaired mitochondrial quality control (MQC) mechanisms including mitochondrial dynamics (fusion and fission) and autophagy (mitophagy).…”

“… 59 Prior evidence shows pre-clinical models of CC have elevated protein degradation while protein synthesis is suppressed. 60 – 63 Two major protein degradation processes, the ubiquitin proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are often activated during muscle wasting conditions including CC. 64 In the UPS, ubiquitin is conjugated to target proteins that are tagged and recognized through E3-E2 ubiquitin ligases, which are then degraded via the ATP-dependent 26S proteasome.…”

Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

“…Evidence from preclinical models show that mitochondrial ROS emissions increase with cancer cachexia and are accompanied by increased markers of oxidative stress [35,138,139,150,151]. In contrast to these findings, some studies have reported decreased markers of muscle oxidative stress, and that exacerbated oxidative stress does not accentuate cancer cachexia [146,152]. Perhaps one explanation for this discrepancy between experimental findings can be explained by evidence of the time course of mitochondrial dysfunction.…”

Addressing the Need of a Translational Approach in Peripheral Neuropathy Research: Morphology Meets Function

“…The algorithm we proposed can be considered more comprehensive in respect to the others previously described. In the vast majority, only the motor system (most frequently one nerve) [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ] or only the sensory or mixed nerves [ 12 , 44 , 45 , 46 , 47 ] were tested. A few groups tested both the motor and sensory systems, but none of the tests were performed at the same time as EMG recordings [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”