Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review)

Cachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impair-ment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactiva -tion of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better under -standing the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity

International audienceCachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impairment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactiva-tion of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better understanding the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia

Does REDD1 act as an AMPK-like in skeletal muscle ?

Does REDD1 act as an AMPK-like in skeletal muscle ?. 45. European Muscle Conferenc

REDD1 Reduces Muscle Metabolism to Foster Adaptation under Fasting

International audienceAims and background : Regulated in Development and DNA Damage 1 (REDD1) is a stress‐induced protein responsible for the inhibition of the Akt/mTORC1 pathway. This pathway integrates energetic status and oxygen availability to promote protein and glycogen synthesis as well as mitochondrial biogenesis. REDD1 is expressed in response to exercise, hypoxia or fasting and has been observed in the mitochondrial fraction in vitro. Our aim is to characterize the role of REDD1 in skeletal muscle under energetic challenge. Methods and results : Wild‐type (WT) and REDD1 knockout (KO) mice were deprived of food for 16h and immediately killed before gastrocnemius and tibialis anterior muscles sampling. We observed an overactivation of the metabolic sensor AMPK and a greater glycogen depletion in skeletal muscle of REDD1 KO mice after fasting. In addition, REDD1 deficient mice displayed exacerbation of skeletal muscle atrophy in response to food deprivation compared to WT animals. We then used dexamethasone treatment to induce REDD1 protein expression and showed for the first time that REDD1 is (partly) localized at the mitochondrial‐associated endoplasmic reticulum membranes (MAM) of skeletal muscle fibers, where it is able to inhibit the Akt/mTORC1 pathway. Indeed, REDD1 binds to and reduces the interaction of MAM protein components, resulting in decreased mitochondrial O2 consumption and protein synthesis.Conclusions : Sustained activity of the Akt/mTORC1 pathway is known to promote anabolic processes and therefore to increase ATP consumption. Our results supports that REDD1 deletion contribute to maintain high fuel demand that in turn leads to skeletal muscle atrophy under fasting. We propose here that a physiological role for REDD1 is to foster skeletal muscle acclimatization during energetic challenges via reduction of O2 and ATP consumption assigned to synthesis processes. Support or Funding Information : This work was supported by the Agence Française de Lutte contre le Dopage (grant #4299)

Comparative evaluation of PD‐L1 expression in cytology imprints, circulating tumour cells and tumour tissue in non‐small cell lung cancer patients

Alternative sources of tumour information need to be explored in patients with non‐small cell lung cancer (NSCLC). Here, we compared programmed cell death ligand 1 (PD‐L1) expression on cytology imprints and circulating tumour cells (CTCs) with PD‐L1 tumour proportion score (TPS) from immunohistochemistry staining of tumour tissue from patients with NSCLC. We evaluated PD‐L1 expression using a PD‐L1 antibody (28‐8) in representative cytology imprints, and tissue samples from the same tumour. We report good agreement rates on PD‐L1 positivity (TPS ≥ 1%) and high PD‐L1 expression (TPS ≥ 50%). Considering high PD‐L1 expression, cytology imprints showed a PPV of 64% and a NPV of 85%. CTCs were detected in 40% of the patients and 80% of them were PD‐L1+. Seven patients with PD‐L1 expression of < 1% in tissue samples or cytology imprints had PD‐L1+ CTCs. The addition of PD‐L1 expression in CTCs to cytology imprints markedly improved the prediction capacity for PD‐L1 positivity. A combined analysis of cytological imprints and CTCs provides information on the tumoural PD‐L1 status in NSCLC patients, which might be used when no tumor tissue is available

Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress

International audienceSkeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses

Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress

Abstract Background: Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses. Results: Unexpectedly, we show here that REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation. Indeed, we demonstrate that REDD1 is required to decrease O2 and ATP consumption in skeletal muscle via reduction of the extent of mitochondrialassociated endoplasmic reticulum membranes (MAMs), a central hub connecting energy production by mitochondria and anabolic processes. In fact, REDD1 inhibits ATP-demanding processes such as glycogen storage and protein synthesis through disruption of the Akt/Hexokinase II and PRAS40/mTORC1 signaling pathways in MAMs. Our results uncover a new REDD1-dependent mechanism coupling mitochondrial respiration and anabolic processes during hypoxia, fasting, and exercise. Conclusions: Therefore, REDD1 is a crucial negative regulator of energy expenditure that is necessary for muscle adaptation during energetic stresses. This present study could shed new light on the role of REDD1 in several pathologies associated with energetic metabolism alteration, such as cancer, diabetes, and Parkinson’s disease

Peripheral and Portal Venous KRAS ctDNA Detection as Independent Prognostic Markers of Early Tumor Recurrence in Pancreatic Ductal Adenocarcinoma

BACKGROUND: KRAS circulating tumor DNA (ctDNA) has shown biomarker potential for pancreatic ductal adenocarcinoma (PDAC) but has not been applied in clinical routine yet. We aim to improve clinical applicability of ctDNA detection in PDAC and to study the impact of blood-draw site and time point on the detectability and prognostic role of KRAS mutations. METHODS: 221 blood samples from 108 PDAC patients (65 curative, 43 palliative) were analyzed. Baseline peripheral and tumor-draining portal venous (PV), postoperative, and follow-up blood were analyzed and correlated with prognosis. RESULTS: Significantly higher KRAS mutant detection rates and copy numbers were observed in palliative compared to curative patients baseline blood (58.1% vs 24.6%; P = 0.002; and P < 0.001). Significantly higher KRAS mutant copies were found in PV blood compared to baseline (P < 0.05) samples. KRAS detection in pre- and postoperative and PV blood were significantly associated with shorter recurrence-free survival (all P < 0.015) and identified as independent prognostic markers. KRAS ctDNA status was also an independent unfavorable prognostic factor for shorter overall survival in both palliative and curative cohorts (hazard ratio [HR] 4.9, P = 0.011; HR 6.9, P = 0.008). CONCLUSIONS: KRAS ctDNA detection is an independent adverse prognostic marker in curative and palliative PDAC patients-at all sites of blood draw and a strong follow-up marker. The most substantial prognostic impact was seen for PV blood, which could be an effective novel tool for identifying prognostic borderline patients-guiding future decision-making on neoadjuvant treatment despite anatomical resectability. In addition, higher PV mutant copy numbers contribute to an improved technical feasibility

Additional file 3: of Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress

Individual data values for all experiments in an Excel file. Data sets are sorted by figure. (XLSX 35 kb