Total Polyunsaturated Fatty Acid Level in Abdominal Adipose Tissue as an Independent Predictor of Recurrence-Free Survival in Women with Ovarian Cancer.

Prognostic factors for epithelial ovarian cancers (EOCs) are in particular clinical factors such as pathology staging at diagnosis (FIGO stages), genetic mutation, or histological phenotypes. In the present study, FIGO stage, tumor residue after surgery, and body mass index were clinical predictors of recurrence-free survival (RFS). Nonetheless, a number of studies support a lipid metabolism disorder in ovarian cancer patients. The objective of this pilot study was to explore whether fatty acid composition of adipose reflecting the qualitative dietary intake and fatty acids metabolism may be associated with RFS. Forty-six women with EOCs and six with borderline ovarian tumors between March 2017 and January 2020 were included in this prospective study at Tours university teaching hospital (central France). The patients involved in the present study are part of the METERMUS trial (clinicaltrials.gov NCT03027479). Adipose tissue specimens from four abdominal locations (superficial and deep subcutaneous, visceral (pericolic), and omental) were collected during surgery or exploratory laparoscopy. A fatty acid profile of adipose tissue triglycerides was established by gas chromatography. Fatty acids composition was compared among the four locations using nonparametric Friedman's ANOVA test for repeated measures. Median follow-up of EOC patients was 15 months and patients' RFS was analyzed using Kaplan−Meier survival curves and log-rank test by separating patients into two groups according to median fatty acid levels. The content of long-chain saturated fatty acids (SFAs) was increased and that of long-chain polyunsaturated fatty acids (PUFAs) decreased in deep versus superficial subcutaneous adipose tissue in EOC patients. Nevertheless, the content of total SFAs was ~28%, monounsaturated fatty acids (MUFAs) ~55%, PUFAs n-6 ~11.5%, and PUFAs n-3 about 1.3%, whatever the adipose tissue. When EOC patients were separated into two groups by median fatty acid content, total PUFAs (n-6+n-3) levels, whatever the adipose tissue, were positively and independently associated with RFS. RFS was about two times longer in EOC patients with high versus low total PUFA content (median survival: 12 vs. 27 months, p = 0.01 to <0.0001 according to the tissue). Content of total PUFAs (n-6+n-3) in abdominal adipose tissue (visceral and subcutaneous) are new prognostic factors in EOC.

Autophagy and mitophagy in cancer metabolic remodelling.

Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global metabolic adaptations allowing them to survive in the low oxygen and nutrient tumour microenvironment. Among these metabolic adaptations, cancer cells use glycolysis but also mitochondrial oxidations to produce ATP and building blocks needed for their high proliferation rate. Another particular adaptation of cancer cell metabolism is the use of autophagy and specific forms of autophagy like mitophagy to recycle intracellular components in condition of metabolic stress or during anticancer treatments. The plasticity of cancer cell metabolism is a major limitation of anticancer treatments and could participate to therapy resistances. The aim of this review is to report recent advances in the understanding of the relationship between tumour metabolism and autophagy/mitophagy in order to propose new therapeutic strategies.

Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer.

Cardiolipins (CLs) are specific phospholipids of the mitochondria composing about 20% of the inner mitochondria membrane (IMM) phospholipid mass. Dysregulation of CL metabolism has been observed in several types of cancer. In most cases, the evidence for a role for CL in cancer is merely correlative, suggestive, ambiguous, and cancer-type dependent. In addition, CLs could play a pivotal role in several mitochondrial functions/parameters such as bioenergetics, dynamics, mitophagy, and apoptosis, which are involved in key steps of cancer aggressiveness (i.e., migration/invasion and resistance to treatment). Therefore, this review focuses on studies suggesting that changes in CL content and/or composition, as well as CL metabolism enzyme levels, may be linked with the progression and the aggressiveness of some types of cancer. Finally, we also introduce the main mitochondrial function in which CL could play a pivotal role with a special focus on its implication in cancer development and therapy.

Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma.

The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse.

Reduced cardiolipin content decreases respiratory chain capacities and increases ATP synthesis yield in the human HepaRG cells.

Cardiolipin (CL) is a unique mitochondrial phospholipid potentially affecting many aspects of mitochondrial function/processes, i.e. energy production through oxidative phosphorylation. Most data focusing on implication of CL content and mitochondrial bioenergetics were performed in yeast or in cellular models of Barth syndrome. Previous work reported that increase in CL content leads to decrease in liver mitochondrial ATP synthesis yield. Therefore the aim of this study was to determine the effects of moderate decrease in CL content on mitochondrial bioenergetics in human hepatocytes. For this purpose, we generated a cardiolipin synthase knockdown (shCLS) in HepaRG hepatoma cells showing bioenergetics features similar to primary human hepatocytes. shCLS cells exhibited a 55% reduction in CLS gene and a 40% decrease in protein expression resulting in a 45% lower content in CL compared to control (shCTL) cells. Oxygen consumption was significantly reduced in shCLS cells compared to shCTL regardless of substrate used and energy state analyzed. Mitochondrial low molecular weight supercomplex content was higher in shCLS cells (+60%) compared to shCTL. Significant fragmentation of the mitochondrial network was observed in shCLS cells compared to shCTL cells. Surprisingly, mitochondrial ATP synthesis was unchanged in shCLS compared to shCTL cells but exhibited a higher ATP:O ratio (+46%) in shCLS cells. Our results suggest that lowered respiratory chain activity induced by moderate reduction in CL content may be due to both destabilization of supercomplexes and mitochondrial network fragmentation. In addition, CL content may regulate mitochondrial ATP synthesis yield.

Pharmacological inhibition of carnitine palmitoyltransferase 1 restores mitochondrial oxidative phosphorylation in human trifunctional protein deficient fibroblasts.

BACKGROUND: Mitochondrial Trifunctional Protein deficiency (TFPD) is a severe genetic disease characterized by altered energy metabolism and accumulation of long-chain (LC) acylcarnitines in blood and tissues. This accumulation could impair the mitochondrial oxidative phosphorylation (OxPhos), contributing to the non-optimal outcome despite conventional diet therapy with medium-chain triglycerides (MCT). METHOD: Acylcarnitine and OxPhos parameters were measured in TFPD-fibroblasts obtained from 8 children and cultured in medium mimicking fasting (LCFA) or conventional treatment (MCT), with or without Etomoxir (ETX) an inhibitor of carnitine palmitoyltransferase 1 (CPT1) activity, and were compared to results obtained with fibroblasts from 5 healthy-control children. The effects of various acylcarnitines were also tested on control fibroblasts. RESULTS: In the LCFA-condition, TFPD-fibroblasts demonstrated a large accumulation of LC-acylcarnitines associated with decreased O2-consumption (63±3% of control, P<0.001) and ATP production (67±5%, P<0.001) without modification of coupling efficiency. A dose-dependent decrease in O2-consumption was reproduced in control fibroblasts by addition of increasing dose of LC-acylcarnitines, while it was almost preserved with MC-acylcarnitines. The MCT-condition reduced LC-acylcarnitine accumulation and partially improved O2-consumption (80±3%, P<0.01) in TFPD-fibroblasts. The addition of ETX in both LCFA- and MCT-conditions normalized acylcarnitine profiles and restored O2-consumption and ATP production at the same levels than control. CONCLUSION: Accumulation of LC-acylcarnitines plays a major role in the pathophysiology of TFPD, reducing OxPhos capacities. These deleterious effects could be partially prevented by MCT-therapy and totally corrected by ETX. Inhibition of CPT1 may be view as a new therapeutic target for patients with a severe form of TFPD.

ATP-dependent activity and mitochondrial localization of drug efflux pumps in doxorubicin-resistant breast cancer cells.

BACKGROUND: We hypothesized that, among the mechanisms of drug-resistance acquired by doxorubicin (DOX)-resistant breast cancer cells to maintain cell survival, ATP-dependent drug efflux pumps could be expressed in their mitochondrial membranes and this might limit the accumulation of DOX in this subcellular compartment in relation to mitochondrial ATP production. METHODS/RESULTS: Mitochondrial DOX accumulation: the presence and the activity of mitochondrial efflux pumps and their relationship with mitochondrial ATP synthesis were analyzed in DOX-resistant (MCF-7doxR) and -sensitive (MCF-7S) breast cancer cells. Mitochondrial accumulation of DOX (autofluorescence) was decreased when ATP was produced, but only in MCF-7doxR. In these DOX-resistant cells, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) were expressed and localized in mitochondria (confocal microscopy and confocal spectral imaging studies). In addition, mitochondrial accumulation of DOX was increased by BCRP and MRP1 inhibitors and, to a lower extent, by the mitochondrial ATP synthase inhibitor, oligomycin, in MCF-7doxR. CONCLUSIONS: Both BCRP and MRP1 were localized in mitochondria and participated to the reduction of mitochondrial accumulation of DOX in MCF-7doxR. This process was partly dependent of mitochondrial ATP synthesis. GENERAL SIGNIFICANCE: The present study provides novel insights in the involvement of mitochondria in the underlying mechanisms of DOX-resistance in breast cancer cells.

Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia.

Cardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p<0.02) and cardiolipin synthase (CLS) activity decreased 44% (p<0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p<0.01) and 50% (p<0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p<0.05), mitochondrial oxygen consumption 33% (p<0.05), PGPS gene expression 44% (p<0.05) and MLCL AT-1 activity 20% (p<0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression.

Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase.

Cancer-induced cachexia describes the progressive skeletal muscle wasting associated with many cancers leading to shortened survival time in cancer patients. We previously reported that cardiolipin content and energy-wasting processes were both increased in liver mitochondria in a rat model of peritoneal carcinosis (PC)-induced cachexia. To increase the understanding of the cellular biology of cancer cachexia, we investigated the involvement of adenine nucleotide translocator (ANT) in mitochondrial energy-wasting processes in liver mitochondria of PC and pair-fed control rats and its interactions with cardiolipin in isolated liver mitochondria from healthy rats exposed to cardiolipin-enriched liposomes. We showed in this study that functional ANT content was decreased in liver mitochondria from PC rats but without any effects on the efficiency of ATP synthesis. Moreover, non-phosphorylating energy wasting was not affected by saturating concentrations of carboxyatractylate (CAT), a potent inhibitor of ANT, in liver mitochondria from PC rats. Decreased efficiency of ATP synthesis was found in normal liver mitochondria exposed to cardiolipin-enriched liposomes, with increased non-phosphorylating energy wasting, thus mimicking mitochondria from PC rats. However, the functional ANT content in these cardiolipin-enriched mitochondria was unchanged, although non-phosphorylating energy wasting was reduced by CAT-induced inhibition of ANT. Finally, non-phosphorylating energy wasting was increased in cardiolipin-enriched mitochondria with substrates for complexes 1 and 2, but not for complex 4. In conclusion, increased energy wasting measured in liver mitochondria from rats with cancer cachexia is dependent on cardiolipin but independent of ANT. Interactions between ANT and cardiolipin are modified when cancer cachexia occurs.

Call for standardization in assessment and reporting of muscle and adipose change using computed tomography analysis in oncology: A scoping review.

Investigators are increasingly measuring skeletal muscle (SM) and adipose tissue (AT) change during cancer treatment to understand impact on patient outcomes. Recent meta-analyses have reported high heterogeneity in this literature, representing uncertainty in the resulting estimates. Using the setting of palliative-intent chemotherapy as an exemplar, we aimed to systematically summarize the sources of variability among studies evaluating SM and AT change during cancer treatment and propose standards for future studies to enable reliable meta-analysis. Studies that measured computed tomography-defined SM and/or AT change in adult patients during palliative-intent chemotherapy for solid tumours were included, with no date or geographical limiters. Of 2496 publications screened by abstract/title, 83 were reviewed in full text and 38 included for extraction, representing 34 unique cohorts across 8 tumour sites. The timing of baseline measurement was frequently defined as prior to treatment, while endpoint timing ranged from 6 weeks after treatment start to time of progression. Fewer than 50% specified the actual time interval between measurements. Measurement error was infrequently discussed (8/34). A single metric (cm2 /m2 , cm2 or %) was used to describe SM change in 18/34 cohorts, while multiple metrics were presented for 10/34 and no descriptive metrics for 6/34. AT change metrics and sex-specific reporting were available for 10/34 cohorts. Associations between SM loss and overall survival were evaluated in 24 publications, with classification of SM loss ranging from any loss to >14% loss over variable time intervals. Age and sex were the most common covariates, with disease response in 50% of models. Despite a wealth of data and effort, heterogeneity in study design, reporting and statistical analysis hinders evidence synthesis regarding the severity and outcomes of SM and AT change during cancer treatment. Proposed standards for study design include selection of homogenous cohorts, clear definition of baseline/endpoint timing and attention to measurement error. Standard reporting should include baseline SM and AT by sex, actual scan interval, SM and AT change using multiple metrics and visualization of the range of change observed. Reporting by sex would advance understanding of sexual dimorphism in SM and AT change. Evaluating the impact of tissue change on outcomes requires adjustment for relevant covariates and concurrent disease response. Adoption of these standards by researchers and publishers would alter the current paradigm to enable meta-analysis of future studies and move the field towards meaningful application of SM and AT change to clinical care.

Pectoralis major muscle atrophy is associated with mitochondrial energy wasting in cachectic patients with gastrointestinal cancer.

BACKGROUND: Cancer cachexia is a multifactorial syndrome characterized by involuntary and pathological weight loss, mainly due to skeletal muscle wasting, resulting in a decrease in patients' quality of life, response to cancer treatments, and survival. Our objective was to investigate skeletal muscle alterations in cachectic cancer patients. METHODS: This is a prospective study of patients managed for pancreatic or colorectal cancer with an indication for systemic chemotherapy (METERMUCADIG - NCT02573974). One lumbar CT image was used to determine body composition. Patients were divided into three groups [8 noncachectic (NC), 18 with mild cachexia (MC), and 19 with severe cachexia (SC)] based on the severity of weight loss and muscle mass. For each patient, a pectoralis major muscle biopsy was collected at the time of implantable chamber placement. We used high-resolution oxygraphy to measure mitochondrial muscle oxygen consumption on permeabilized muscle fibres. We also performed optical and electron microscopy analyses, as well as gene and protein expression analyses. RESULTS: Forty-five patients were included. Patients were 67% male, aged 67 years (interquartile range, 59-77). Twenty-three (51%) and 22 (49%) patients were managed for pancreatic and colorectal cancer, respectively. Our results show a positive correlation between median myofibres area and skeletal muscle index (P = 0.0007). Cancer cachexia was associated with a decrease in MAFbx protein expression (P < 0.01), a marker of proteolysis through the ubiquitin-proteasome pathway. Mitochondrial oxygen consumption related to energy wasting was significantly increased (SC vs. NC, P = 0.028) and mitochondrial area tended to increase (SC vs. MC, P = 0.056) in SC patients. On the contrary, mitochondria content and networks remain unaltered in cachectic cancer patients. Finally, our results show no dysfunction in lipid storage and endoplasmic reticulum homeostasis. CONCLUSIONS: This clinical protocol brings unique data that provide new insight to mechanisms underlying muscle wasting in cancer cachexia. We report for the first time an increase in mitochondrial energy wasting in the skeletal muscle of severe cachectic cancer patients. Additional clinical studies are essential to further the exploring and understanding of these alterations.

Efficiency of oxidative phosphorylation in liver mitochondria is decreased in a rat model of peritoneal carcinosis.

BACKGROUND & AIMS: Cancer cachexia is a dynamic process characterized by a negative energy balance induced by anorexia and hypermetabolism. The mechanisms leading to hypermetabolism are not totally elucidated. This study examines the efficiency of oxidative phosphorylation and energy wasting in liver mitochondria isolated from rats with cancer cachexia induced by peritoneal carcinosis (PC). METHODS: PC was generated by an intraperitoneal injection of cancer cells (PROb) in BDIX rats. The efficiency of oxidative phosphorylation and energy wasting as well as the role played by reactive oxygen species (ROS) and cardiolipin (mitochondrial inner membrane phospholipid) in these processes were assessed in liver mitochondria of PC and pair-fed control rats. RESULTS: The efficiency of oxidative phosphorylation decreased (-26%) while energy wasting increased (+22%) in liver mitochondria from PC compared to control rats. The increased energy wasting was associated with a higher cardiolipin content (+55%, p<0.05; R(2)=0.64, p<0.05) and with a lower n-6/n-3 polyunsaturated fatty acid ratio in cardiolipin (-45%, p<0.05; R(2)=0.21, p<0.05) in PC rats. ROS production was increased by 12-fold in liver mitochondria from PC rats. CONCLUSIONS: The efficiency of ATP synthesis was reduced and energy wasting processes were increased in liver mitochondria of PC rats. This suggests that liver mitochondria from PC rats request more nutrients than liver mitochondria from control rats to maintain the same ATP production. These alterations were associated to the content and fatty acid composition of cardiolipin.

n-3 PUFA-enriched diet delays the occurrence of cancer cachexia in rat with peritoneal carcinosis.

The aim of this study was to evaluate the effects of a fish oil (FO) diet (rich in long chain, n-3, polyunsaturated fatty acid) on cancer cachexia symptoms in rats. To this end, peritoneal carcinosis (PC) was generated by an intraperitoneal injection of cancer cells in BDIX rats fed FO or standard (Std) diets. Food intake and body weight were recorded throughout the study until sacrifice. PC rats were sacrificed when food intake was significantly and severely reduced. Fat and skeletal muscles masses were weighed and serum inflammatory cytokines concentration measured at sacrifice. Occurrence of anorexia in PC rats was delayed in the FO diet group (median time was multiplied by 2.5) in comparison with Std diet. At the time of sacrifice, PC rats displayed a lower body weight gain as well as lower muscle and fat masses than pair-fed rats, suggesting the presence of a hypermetabolism state. Serum TNF-alpha was significantly increased in PC rats compared with controls rats. There was no effect of FO diet on tissue mass (skeletal muscle and fat) or on TNF-alpha concentration. In conclusion, FO diet delays the appearance of anorexia induced by PC in rats.

Up-regulation of avian uncoupling protein in cold-acclimated and hyperthyroid ducklings prevents reactive oxygen species production by skeletal muscle mitochondria.

BACKGROUND: Although identified in several bird species, the biological role of the avian homolog of mammalian uncoupling proteins (avUCP) remains extensively debated. In the present study, the functional properties of isolated mitochondria were examined in physiological or pharmacological situations that induce large changes in avUCP expression in duckling skeletal muscle. RESULTS: The abundance of avUCP mRNA, as detected by RT-PCR in gastrocnemius muscle but not in the liver, was markedly increased by cold acclimation (CA) or pharmacological hyperthyroidism but was down-regulated by hypothyroidism. Activators of UCPs, such as superoxide with low doses of fatty acids, stimulated a GDP-sensitive proton conductance across the inner membrane of muscle mitochondria from CA or hyperthyroid ducklings. The stimulation was much weaker in controls and not observed in hypothyroid ducklings or in any liver mitochondrial preparations. The production of endogenous mitochondrial reactive oxygen species (ROS) was much lower in muscle mitochondria from CA and hyperthyroid ducklings than in the control or hypothyroid groups. The addition of GDP markedly increased the mitochondrial ROS production of CA or hyperthyroid birds up to, or above, the level of control or hypothyroid ducklings. Differences in ROS production among groups could not be attributed to changes in antioxidant enzyme activities (superoxide dismutase or glutathione peroxidase). CONCLUSION: This work provides the first functional in vitro evidence that avian UCP regulates mitochondrial ROS production in situations of enhanced metabolic activity.

Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know?

Research investigators have shown a growing interest in investigating alterations underlying skeletal muscle wasting in patients with cancer. However, skeletal muscle dysfunctions associated with cancer cachexia have mainly been studied in preclinical models. In the present review, we summarize the results of clinical studies in which skeletal muscle biopsies were collected from cachectic vs. non-cachectic cancer patients. Most of these studies suggest the presence of significant physiological alterations in skeletal muscle from cachectic cancer patients. We suggest a hypothesis, which connects structural and metabolic parameters that may, at least in part, be responsible for the skeletal muscle atrophy characteristic of cancer cachexia. Finally, we discuss the importance of a better standardization of the diagnostic criteria for cancer cachexia, as well as the requirement for additional clinical studies to improve the robustness of these conclusions.

Concurrent losses of skeletal muscle mass, adipose tissue and bone mineral density during bevacizumab / cytotoxic chemotherapy treatment for metastatic colorectal cancer.

BACKGROUND: Changes in skeletal muscle mass (SMM), total adipose tissue mass (TAT) or bone mineral density (BMD) have been described in patients with cancer undergoing various treatments; simultaneous variations of all 3 tissues has not been reported. METHODS: Data were prospectively collected in a clinical study (NCT00489697) including patients with liver metastases of colorectal cancer who received 4 cycles of bevacizumab in combination with cytotoxic chemotherapy. Computerized tomography (CT) at baseline and after chemotherapy was used to quantify skeletal muscle and adipose tissue cross-sectional areas, and mean lumbar spine BMD using validated approaches. RESULTS: After exclusion of patients lacking adequate CT images or missing data, 72 subjects were included. Patients were 63% male, aged 63.2 ± 10.3 years, 100% had liver metastases and 54%, 24% and 22% respectively has 0, 1 and ≥2 extrahepatic metastases. 100% tolerated 4 cycles of treatment and none showed progressive disease at the end of treatment. The scan interval was 70 days (95% CI, 62.3 to 80.5). Thresholds for loss of tissue were defined as loss ≥ measurement error. 10% of patients showed no loss of any tissue and a further 43% lost one tissue (SMM, TAT or BMD); 47% of patients lost 2 tissues (16.5% lost SMM + TAT, 8% lost SMM + BMD, 10% lost TAT + BMD) or all 3 tissues (12.5%). Catabolic behavior (2 or 3 tissue loss vs 0 or 1 tissue loss) associated with disease burden, including unresectable primary tumor (p = 0.010), presence of extrahepatic (EH) metastases (p = 0.039) and number of EH metastases (p = 0.004). No association was found between the number of tissues lost and treatment response, which was uniformly high, or treatment toxicity, which was uniformly low. CONCLUSION: Multiple tissues can be measured in routine CT images and these show considerable inter-individual variation. Substantial losses in some individuals appear to associate with disease burden.

Prevention of unloading-induced atrophy by vitamin E supplementation: links between oxidative stress and soleus muscle proteolysis?

Exposure to reduced activity induces skeletal muscle atrophy. Oxidative stress might contribute to muscle wasting via proteolysis activation. This study aimed to test two hypotheses in rats. First, supplementation of the antioxidant vitamin E, prior and during the phase of unloading, would partly counteract unloading-induced soleus muscle atrophy. Secondly, vitamin E supplementation would decrease the rate of muscle proteolysis by reducing expression of calpains, caspases-3, -9, and -12, and E3 ubiquitin ligases (MuRF1 and MAFbx). Soleus muscle atrophy (-49%) induced by 14 days of hindlimb unloading was reduced to only 32% under vitamin E. Vitamin E partly prevented the decrease in type I and IIa fiber size. Supplementation increased HSP72 content and suppressed the rise in muscle level of thiobarbituric acid-reactive substance caused by unloading but failed to modify the lower ratio of reduced vs oxidized glutathione, the higher uncoupling proteins mRNA, and the antioxidant enzyme activities (superoxide dismutase, catalase, and glutathione peroxidase) observed after unloading. Vitamin E treatment abolished the large upregulation of caspases-9 and -12 and MuRF1 transcripts in unloaded muscle and greatly decreased the upregulation of mu-calpain, caspase-3, and MAFbx mRNA. In conclusion, the protective effect of vitamin E might be due to modulation of muscle proteolysis-related genes rather than to its antioxidant function.

Fat intake reverses the beneficial effects of low caloric intake on skeletal muscle mitochondrial H(2)O(2) production.

Food restriction is the most effective modulator of oxidative stress and it is believed that a reduction in caloric intake per se is responsible for the reduced generation of reactive oxygen species (ROS) by mitochondria. Hydrogen peroxide (H(2)O(2)) generation and oxygen consumption (O(2)) by skeletal muscle mitochondria were determined in a peculiar strain of rats (Lou/C) characterized by a self-low-caloric intake and a dietary preference for fat. These rats were fed either with a standard high-carbohydrate (HC) or a high-fat (HF) diet and the results were compared to those measured in Wistar rats fed a HC diet. H(2)O(2) production was significantly reduced in Lou/C rats fed a HC diet; this effect was not due to a lower O(2) consumption but rather to a decrease in rotenone-sensitive NADH-ubiquinone oxidoreductase activity and increased expression of uncoupling proteins 2 and 3. The reduced H(2)O(2) generation displayed by Lou/C rats was accompanied by a significant inhibition of permeability transition pore (PTP) opening. H(2)O(2) production was restored and PTP inhibition was relieved when Lou/C rats were allowed to eat a HF diet, suggesting that the reduced oxidative stress provided by low caloric intake is lost when fat proportion in the diet is increased.

Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1.

The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research.

Implication of liver cardiolipins in mitochondrial energy metabolism disorder in cancer cachexia.

Mitochondrial membranes are essential for the good functioning of the organelle. For instance, the inner mitochondrial membrane contains the oxidative phosphorylation system that permits ATP synthesis. Phospholipids environment and especially cardiolipin are crucial for the mitochondrial energy metabolism. Indeed, cardiolipin is known to provide essential structural and functional support to several proteins involved in oxidative phosphorylation. Alterations in cardiolipin structure, content and fatty acids composition have been associated with mitochondrial dysfunction in several physiopathological conditions and diseases. Cancer cachexia is a complex and dynamic process characterized by a negative energy balance induced by anorexia and hypermetabolism which leads to a drastic loss in body weight that aggravate prognosis of cancer patients. The underlying mechanisms of hypermetabolism are not fully understood. Whether the mitochondrial energy metabolism is altered during this disease and may participate to hypermetabolism is not clear. This mini-review focuses on cardiolipin especially its biosynthesis and remodeling pathways, its relation with mitochondrial energy metabolism and its possible implication in the cancer cachexia syndrome.