Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

Abstract

It is established that cancer cachexia causes limb muscle atrophy and is strongly associated with morbidity and mortality; less is known about how the development of cachexia impacts the diaphragm. The purpose of this study was to investigate cellular signaling mechanisms related to mitochondrial function, reactive oxygen species (ROS) production, and protein synthesis during the development of cancer cachexia. C57BL/J6 mice developed Lewis Lung Carcinoma for either 0 weeks (Control), 1 week, 2 weeks, 3 weeks, or 4 weeks. At designated time points, diaphragms were harvested and analyzed. Mitochondrial respiratory control ratio was ~50% lower in experimental groups, which was significant by 2 weeks of cancer development, with no difference in mitochondrial content markers COXIV or VDAC. Compared to the controls, ROS was 4-fold elevated in 2-week animals but then was not different at later time points. Only one antioxidant protein, GPX3, was altered by cancer development (~70% lower in experimental groups). Protein synthesis, measured by a fractional synthesis rate, appeared to become progressively lower with the cancer duration, but the mean difference was not significant. The development and progression of cancer cachexia induces marked alterations to mitochondrial function and ROS production in the diaphragm and may contribute to increased cachexia-associated morbidity and mortality.

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

“…Findings from both preclinical and clinical studies confirm that the hallmarks of cancer cachexia are decreased myofiber cross-sectional area, disrupted muscle ultrastructure, and increased fibrosis [ 35 , 135 , 136 , 137 , 138 ]. Both depressed protein synthesis and accelerated proteolysis have been observed with muscle wasting due to cancer cachexia [ 139 , 140 , 141 , 142 ]. While the factors that contribute to cancer-induced muscle wasting are believed to be multifactorial, recent evidence has implicated mitochondrial dysfunction as a key contributor to cancer cachexia.…”

“…As discussed previously, chronic elevation in mitochondrial ROS emissions can elicit muscle wasting. 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. For instance, it appears that mitochondrial ROS emissions are elevated within the first three weeks of cancer induction before returning to baseline in rodent models of cancer cachexia [ 138 , 139 ]. Hence, it is plausible that muscle atrophy is first initiated by early elevations in mitochondrial ROS emissions.…”

Cancer cachexia as a multiorgan failure: Reconstruction of the crime scene

“…Indeed, a marked depletion in hepatic glycogen content has been reported in different preclinical models of cancer cachexia ( Narsale et al, 2015 ; Rosa-Caldwell et al, 2019 ), suggesting a conserved mechanism for alterations in hepatic metabolism across different cancer types. Cachectic liver also shows mitochondrial alterations in mouse models ( Rosa-Caldwell et al, 2020 ), which precede a fibrotic phenotype during the progression of cancer-cachexia also observed in patients ( Pinter et al, 2016 ; Judge et al, 2019 ). Similarly, it has been reported that liver mitochondria from tumor-bearing rats request a higher amount of nutrients to sustain the ATP production ( Dumas et al, 2011 ).…”

Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy

“…Oral administration of coenzyme Q 10 (CoQ 10 ), a vitamin-like substance, improves mitochondrial biogenesis and function in skeletal muscle of Goto-Kakizaki rats [66]. Mitochondria biogenesis play a critical role in the metabolic and physiological adaptation of skeletal muscle [67]. Similarly, Liu et al reported that CoQ 10 administration ameliorates disuse-induced skeletal muscle atrophy via the activation of mitochondrial biogenesis and the amelioration of oxidative stress in SD rats.…”