Skeletal Muscle Depletion Research Articles

Skeletal muscle–specific knockout of DEP domain containing 5 protein increases mTORC1 signaling, muscle cell hypertrophy, and mitochondrial respiration

mTORC1 regulates protein synthesis and in turn is regulated by growth factors, energy status, and amino acid availability. In kidney cell (HEK293-T) culture, the GAP activity toward RAG (GATOR1) protein complex suppresses activation of the RAG A/B-RAG C/D heterodimer when amino acids are insufficient. During amino acid sufficiency, the RAG heterodimer recruits mTORC1 to the lysosomal membrane where its interaction with Ras homolog enriched in brain (Rheb) stimulates mTORC1's kinase activity. The DEP domain containing 5 (DEPDC5) protein, a GATOR1 subunit, causes familial focal epilepsy when mutated, and global knockout of the Depdc5 gene is embryonically lethal. To study the function of DEPDC5 in skeletal muscle, we generated a muscle-specific inducible Depdc5 knockout mouse, hypothesizing that knocking out Depdc5 in muscle would make mTORC1 constitutively active, causing hypertrophy and improving muscle function. Examining mTORC1 signaling, morphology, mitochondrial respiratory capacity, contractile function, and applied physical function (e.g. rotarod, treadmill, grip test, and wheel running), we observed that mTORC1 activity was significantly higher in knockout (KO) mice, indicated by the increased phosphorylation of mTOR and its downstream effectors (by 118% for p-mTOR/mTOR, 114% for p-S6K1/S6K1, and 35% for p-4E-BP1/4E-BP1). The KO animals also exhibited soleus muscle cell hypertrophy and a 2.5-fold increase in mitochondrial respiratory capacity. However, contrary to our hypothesis, neither physical nor contractile function improved. In conclusion, DEPDC5 depletion in adult skeletal muscle removes GATOR1 inhibition of mTORC1, resulting in muscle hypertrophy and increased mitochondrial respiration, but does not improve overall muscle quality and function.

Prognostic value of adipose tissue and muscle mass in advanced colorectal cancer: a post hoc analysis of two non-randomized phase II trials

BackgroundThe prognostic value of body composition in cancer patients has been widely studied during the last decade. The main finding of these studies is that sarcopenia, or skeletal muscle depletion, assessed by CT imaging correlates with a reduced overall survival (OS). By contrast, the prognostic value of fat mass remains ill-defined. This study aims to analyze the influence of body composition including both muscle mass and adipose tissue on OS in a homogeneous population of advanced colorectal cancer (CRC) patients.MethodsAmong 235 patients with chemorefractory advanced CRC included in the SoMore and RegARd-C trials, body composition was assessed in 217 patients on baseline CT images. The relationship between body composition (sarcopenia, muscle density, subcutaneous and visceral fat index and density), body mass index (BMI) and OS were evaluated.ResultsPatients with a higher BMI had a better OS (≥30 versus < 30, HR: 0.50; 0.33–0.76). Those with low muscle index and muscle density had an increased mortality (HR: 2.06; 1.45–2.93 and HR: 1.54; 1.09–2.18, respectively). Likewise, low subcutaneous and visceral fat index were associated with an increased risk of dying (HR: 1.63; 1.23–2.17 and 1.48; 1.09–2.02 respectively), as were a high subcutaneous and visceral adipose tissue density (HR: 1.93; 1.44–2.57 and 2.40; 1.79–3.20 respectively). In multivariate analysis, a high visceral fat density was the main predictor of poor survival.ConclusionsOur results confirm the protective role of obesity in CRC patients at an advanced stage, as well as the negative prognostic impact of muscle depletion on survival. More importantly, our data show for the first time that visceral adipose tissue density is an important prognostic factor in metastatic CRC.Trial registrationNCT01290926, 07/02/2011 and NCT01929616, 28/08/2013.

Emerging awareness on the importance of skeletal muscle in liver diseases: time to dig deeper into mechanisms!

Skeletal muscle is a tissue that represents 30-40% of total body mass in healthy humans and contains up to 75% of total body proteins. It is thus the largest organ in non-obese subjects. The past few years have seen increasing awareness of the prognostic value of appreciating changes in skeletal muscle compartment in various chronic diseases. Hence, a low muscle mass, a low muscle function and muscle fatty infiltration are linked with poor outcomes in many pathological conditions. In particular, an affluent body of evidence links the severity, the complications and mortality of chronic liver disease (CLD) with skeletal muscle depletion. Yet it is still not clear whether low muscle mass is a cause, an aggravating factor, a consequence of the ongoing disease, or an epiphenomenon reflecting general alteration in the critically ill patient. The mechanisms by which the muscle compartment influences disease prognosis are still largely unknown. In addition, whether muscle alterations contribute to liver disease progression is an unanswered question. Here, we first review basic knowledge about muscle compartment to draw a conceptual framework for interpreting skeletal muscle alteration in CLD. We next describe recent literature on muscle wasting in cirrhosis and liver transplantation. We then discuss the implication of skeletal muscle compartment in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), focusing on plausible metabolic disruption in muscle compartment that might participate in NAFLD progression. Finally, we discuss shortcomings and challenges we need to address in the near future prior to designate the muscle compartment as a therapeutic target in CLD.

NMR Metabolomic Analysis of Skeletal Muscle, Heart, and Liver of Hatchling Loggerhead Sea Turtles (Caretta caretta) Experimentally Exposed to Crude Oil and/or Corexit.

We used nuclear magnetic spectroscopy (NMR) to evaluate the metabolic impacts of crude oil, Corexit 5900A, a dispersant, and a crude oil Corexit 5900A mixture exposure on skeletal muscle, heart, and liver physiology of hatchling loggerhead sea turtles (Caretta caretta). Tissue samples were obtained from 22 seven-day-old hatchlings after a four day cutaneous exposure to environmentally relevant concentrations of crude oil, Corexit 5900A, a combination of crude oil and Corexit 9500A, or a seawater control. We identified 38 metabolites in the aqueous extracts of the liver, and 30 metabolites in both the skeletal and heart muscle aqueous extracts, including organic acids/osmolytes, energy compounds, amino acids, ketone bodies, nucleosides, and nucleotides. Skeletal muscle lactate, creatines, and taurine concentrations were significantly lower in hatchlings exposed to crude oil than in control hatchlings. Lactate, taurine, and cholines appeared to be the basis of some variation in hatchling heart samples, and liver inosine, uracil, and uridine appeared to be influenced by Corexit and crude oil exposure. Observed decreases in concentrations of lactate and creatines may reflect energy depletion in skeletal muscle of oil-exposed animals, while decreased taurine concentrations in these animals may reflect higher oxidative stress.

Sarcopenia is associated with postoperative complication after pancreaticoduodenectomy

Introduction: The sarcopenia which is skeletal muscle depletion has been reported to be associated with postoperative recurrence as well as postoperative complications. The aim of this study was to examine whether sarcopenia affects postoperative complications and cancer recurrence. Method: From January 2010 to December 2016, the data of 128 patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, distal bile duct cancer, or ampulla of Vater cancer were consecutively collected. Sarcopenia was validated by lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). The index was measured before surgery, within 1 month after surgery, and between 2 months and 8 months after surgery. The risk factors of postoperative complication and tumor recurrence were investigated. Result: The median age was 69 years (range, 23 to 95). The value obtained by dividing the measured muscle mass by BMI was associated with both postoperative general complications and severe complications in multivariate analysis (p = 0.008 and p = 0.033, respectively). However, the muscle mass index was not associated with clinically relevant pancreatic fistula (p = 0.253). The index measured between 2 months and 8 months after surgery was lower than that measured before surgery. However, the index was not associated with cancer recurrence or death in the survival analysis. Conclusion: The skeletal muscle index measured by CT image was associated with general complication but not pancreatic fistula or survival after pancreaticoduodenectomy.

Skeletal Muscle Depletion during Chemoradiotherapy and Radiomics Features as Prognostic Factors of Toxicity and Outcomes in Patients with Gastric Cancer

Skeletal Muscle Depletion during Chemoradiotherapy and Radiomics Features as Prognostic Factors of Toxicity and Outcomes in Patients with Gastric Cancer

Skeletal Muscle Depletion Predicts the Prognosis of Patients with Hepatocellular Carcinoma Treated with Radiation Therapy

Sarcopenia is gaining attention, being identified as a poor prognostic factor for various types of malignancies. Particularly, sarcopenia occurs frequently in cases of hepatocellular carcinoma (HCC) after treatment. However, the clinical significances of sarcopenia in patients underwent radiotherapy (RT) for HCC is not yet been identified. The purpose of this study is to evaluate the association between sarcopenia and survival in HCC patients underwent RT to the primary site. Between January 2009 and November 2016, a total number of 156 patients with stage I-IVB primary HCC underwent RT to the liver. Among these, 64 patients received RT with definitive aim, 43 patients with palliative aim, and 49 patients with salvage aim. Eighty-one patients were treated with concurrent chemotherapy (CTx), and 75 patients were treated with RT only. The median RT dose was 50.4 Gy (30 Gy-70 Gy). The cross-sectional area of muscle at the level of 3rd lumbar vertebra was measured using baseline CT images (L3 skeletal muscle index; L3-SMI). Sarcopenia was defined as a L3-SMI of less than 49 for men and less than 41 for women as proposed by Korean-specific cut off value. The sarcopenia was identified at two-time points; pre- and post-RT. Pre-RT sarcopenia was diagnosed with data from the simulation CT prior to RT, while post-RT sarcopenia was diagnosed with data from the follow-up CT taken within 3 months from the end of RT. Overall survival (OS) and progression-free survival (PFS) were estimated from the start of RT, and the prognostic factors associated with the survival were analyzed. Among a total of 156 patients, 3 patients were stage I, 15 patients were stage II, 48 patients were stage III, and 90 patients were stage IV, respectively. According to Korean-specific cut off value, 99 patients (63.5%) had pre-RT sarcopenia, while 109 patients (69.9%) had post-RT sarcopenia. Pre-RT sarcopenia group had higher percentage of patients with previous CTx (14.1 % vs 1.8 %), compared with those without pre-RT sarcopenia. At a median follow up 9.3 months, median OS were significantly differed according to the presence of pre-RT sarcopenia (7.1 vs. 15.3 months, p < 0.001) and post-RT sarcopenia (7.5 vs. 16.8 months, p < 0.001), while median PFS differed according to pre-RT sarcopenia with borderline significance (3.3 vs. 5.6 months, p = 0.051). In univariate analysis, total dose, Child-Pugh classification, cancer stage at time of RT, AFP level, Neutrophil-Lymphocyte ratio, Platelet-Lymphocyte ratio, pre-RT and post-RT sarcopenia have shown to be significant prognostic factors for OS. In multivariate analysis, total dose and pre-RT sarcopenia were identified as independent prognostic factors for OS. In our study, pre-RT sarcopenia was associated with a poor prognosis for HCC patients underwent RT to liver. This result suggests the possibility that the identification of sarcopenia in HCC patients before RT might enable the early intervention to maintain muscle mass and improve prognosis.

Low truncal muscle area on chest computed tomography: a poor prognostic factor for the cure of early-stage non-small-cell lung cancer†.

Depletion in skeletal muscle is closely associated with limited physical ability and high mortality. In this study, we evaluated the prognostic significance of skeletal muscle depletion in patients with early-stage non-small-cell lung cancer. A retrospective analysis of patients with pathological stages I-II lung cancer, who underwent curative resection between 2009 and 2013, was conducted. The truncal muscle index (TMI) (area/height2) at the first lumbar vertebral level was measured by preoperative axial computed tomography. Overall survival and recurrence-free survival were compared between the lowest gender-specific quartile of the TMI and the other quartiles. A total of 314 subjects were included in the study. The cumulative 5-year recurrence-free and overall survival rates were significantly shorter in patients with lower TMIs (69% vs 83.5%, P = 0.028; 64.8% vs 80.1%, P = 0.003, respectively). In multivariable models, the TMI was identified as an independent prognostic factor for overall survival (P = 0.017, hazard ratio 1.84, 95% confidence interval 1.12-3.05), after adjusting for age, gender, preoperative serum albumin, carcinoembryonic antigen, neutrophil to lymphocyte ratio and pathological stage. A low preoperative TMI was associated with a poor postoperative outcome in patients with early-stage non-small-cell lung cancer. This factor may be included in the preoperative assessment of patients, for whom surgical intervention is considered.

Effect of loop diuretics on skeletal muscle depletion in patients with liver cirrhosis

Sarcopenia, the loss of skeletal muscle mass, impairs prognosis of patients with liver cirrhosis. The aim of this study was to investigate the effect of loop diuretics, which are frequently used to treat hepatic edema/ascites, on skeletal muscle depletion and the prognosis in patients with liver cirrhosis. This retrospective study evaluated 226 patients with liver cirrhosis. The skeletal muscle cross-sectional area at the level of the third lumbar vertebra was measured using computed tomography. The relative change in skeletal muscle area per year (ΔSMA) was calculated, and the association between ΔSMA and therapeutic dosage of loop diuretics was examined. The therapeutic dosage of loop diuretics was inversely correlated with ΔSMA by simple (r = -0.27, P < 0.0001) and multiple regression analyses (t = -3.07, P = 0.002). During a median follow-up period of 49months, 82 patients died. Overall survival rates were lower in patients treated with loop diuretics at >20mg than in those who received ≤20mg (median, 66 vs. 97months; P = 0.002). Multivariate analysis revealed that loop diuretics of >20mg (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.03-3.24; P = 0.039) and ΔSMA of ≤-3.1% (HR, 3.87; 95% CI, 2.32-6.60; P < 0.0001) were independently associated with mortality. A higher dose of loop diuretic use was associated with more rapid skeletal muscle depletion and poor survival in patients with liver cirrhosis, independent of the severity of liver disease.

Effect of skeletal muscle depletion on prognosis in advanced biliary tract cancer treated with cisplatin and gemcitabine: A retrospective study

Effect of skeletal muscle depletion on prognosis in advanced biliary tract cancer treated with cisplatin and gemcitabine: A retrospective study

Association of low skeletal muscle index with increased systematic inflammatory responses and interferon γ-induced protein 10 levels in patients with colon cancer.

BackgroundSkeletal muscle depletion is a prognostic factor in patients with cancer. Here, we evaluated the association between the skeletal muscle index (SMI) and local and systemic responses in patients with colon cancer.Patients and methodsWe analyzed the relationships of the SMI with neutrophil, lymphocyte, monocyte, and platelet counts; the neutrophil-to-lymphocyte ratio; albumin levels; and C-reactive protein levels in a cohort of 561 patients, and with the circulating levels of 39 cytokines in a cohort of 125 patients. We also studied the association between the SMI and tumor local inflammatory response and the effect of SMI on survival.ResultsThe median SMIs for male and female subjects were 44.1 and 34.2 cm2/m2, respectively. We observed positive correlations of the SMI with neutrophil (p=0.022), lymphocyte (p=0.001), and monocyte counts (p=0.003). A low SMI correlated significantly with an increased platelet count (p=0.017), decreased albumin level (p=0.006), neutrophil-to-lymphocyte ratio >3 (p=0.021), and an increased interferon γ-induced protein 10 level (IP-10, r = −0.276, p=0.002). The SMI did not correlate significantly with local inflammatory reactions or the C-reactive protein level. Finally, the SMI was a significant prognosticator in patients with stage III colon cancer (3-year disease-free survival rates: 35.1% for the low SMI arms versus 46.0% in the high SMI arms; HR =2.036; p=0.034).ConclusionThis study highlights the association of a low SMI with a high systematic inflammatory response and IP-10 levels. Furthermore, low SMI is a predictor of poor disease-free survival in patients with stage III colon cancer.

L-Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis.

Liver cirrhosis (LC) is a major cause of secondary sarcopenia. Sarcopenia makes the prognosis worse; thus, novel therapeutic options for sarcopenia in patients with LC are urgently required as they are currently limited. In this retrospective study, 158 patients with LC were screened, and 35 of those patients who were treated with L‐carnitine for more than 6 months and for whom skeletal muscle mass changes could be evaluated by computer tomography were enrolled. Of the 158 patients, 79 patients who did not receive L‐carnitine supplementation served as controls. Cases and controls were propensity score matched for age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration, and changes in skeletal muscle mass and clinical data were compared. The 35 patients who received L‐carnitine supplementation and 35 propensity score‐matched patients who did not receive carnitine supplementation comprised the final enrollment. Compared with control patients, patients who received L‐carnitine had significantly worse liver function, which is associated with rapid progress of skeletal muscle depletion. However, loss of skeletal muscle mass was significantly suppressed in patients receiving L‐carnitine, and a significant effect was observed in patient subgroups stratified by age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration. The change ratios of most laboratory data, including vitamin D and insulin‐like growth factor 1 levels, were similar in the two groups, but ammonia levels were significantly less in those receiving L‐carnitine. However, even in patients receiving L‐carnitine but not showing an ammonia decrease, loss of skeletal muscle was significantly suppressed. Conclusion: L‐carnitine suppresses loss of skeletal muscle mass and may therefore be a novel therapeutic option for sarcopenia in patients with LC. (Hepatology Communications 2018; 00:000‐000)

Rapidly declining skeletal muscle mass predicts poor prognosis of hepatocellular carcinoma treated with transcatheter intra-arterial therapies

BackgroundThe impact of sarcopenia on the prognosis of patients with hepatocellular carcinoma (HCC) who receive transcatheter intra-arterial therapies, including transcatheter arterial chemoembolization and transcatheter arterial infusion chemotherapy, remains unclear. We investigated the prognostic value of skeletal muscle loss (SML) stratified by cutoffs for sarcopenia and rate of change in skeletal muscle mass over 6 months.MethodsWe retrospectively evaluated 102 patients with HCC treated with transcatheter intra-arterial therapies between 2005 and 2015. Computed tomography images of the third lumbar vertebra (L3) were analyzed to obtain the skeletal muscle area normalized for the height squared, defined as the skeletal muscle index at L3 (L3 SMI), before and 6 months after treatment. Low or high SMI was defined using cutoff values of 42 cm2/m2 in men and 38 cm2/m2 in women. The rate of change in skeletal muscle mass (ΔL3 SMI) over 6 months was calculated. Overall survival (OS) was compared in groups classified by baseline L3 SMI and ΔL3 SMI; prognostic significance was assessed with univariate and multivariate analyses, using Cox proportional hazards models.ResultsOS did not differ significantly between groups with low (n = 31) and high (n = 71) SMI at baseline (P = 0.172), but OS was significantly poorer in patients with SML (n = 41), defined as ΔL3 SMI < − 4.6% over 6 months than in those without SML (n = 61, P = 0.018). On multivariate analysis, SML (hazard ratio [HR], 1.675; 95% confidence interval [CI], 1.031–2.721; P = 0.037), serum alpha-fetoprotein ≥20 ng/mL (HR, 2.550; 95% CI, 1.440–4.515; P = 0.001), and maximum tumor diameter ≥ 30 mm (HR, 1.925; 95% CI, 1.166–3.179; P = 0.010) were independent predictors of poor OS. Baseline L3 SMI was not significantly associated with OS (HR, 1.405; 95% CI, 0.861–2.293; P = 0.174).ConclusionsΔL3 SMI was an independent prognostic factor in patients with HCC treated with transcatheter intra-arterial therapies. Further study is required to reveal whether prevention of skeletal muscle depletion might be a new therapeutic strategy to contribute to improved clinical outcomes in patients with HCC.

Abstract 4090: Generation of a new mouse to model pancreatic cancer-induced cachexia

Abstract Of all cancers, pancreatic cancer causes the third most fatalities, and incidence rates of this devastating disease continue to rise. Further, pancreatic cancer presents with the highest incidence of cachexia, a syndrome of weight loss due to depletion of skeletal muscle and adipose tissue. Clinically, cachexia is associated with increased mortality, poor quality of life, poor treatment responses, and increased treatment complications. Although clearly the best way to prevent cachexia is to address the cancer, pancreatic cancer has proven challenging to treat, with a dismal 9% 5-year survival rate. We believe effective anti-cachexia therapy will improve the care of pancreatic cancer patients, but the development of these therapies will require animal models that accurately recapitulate the etiology of pancreatic cancer-induced cachexia. To improve on the current, non-pancreas tumor xenograft models of cachexia, we generated a genetically engineered mouse model (GEMM) of pancreatic cancer, where induction of Kras and loss of the tumor suppressor Pten occurs in the pancreas of postnatal mice, which we refer to as the KPP model. KPP mice progressively lose skeletal muscle and adipose mass as a result of their cancer. We find that KPP mice exhibit histologic features of pancreatic ductal adenocarcinoma and reach endpoint criteria at an average of 107 days of age. Beginning at approximately 75 days of age, KPP mice undergo progressive loss of existing skeletal muscle mass, resulting in decreased muscle function. We also find that muscle loss from KPP mice exhibits a gene expression signature that closely aligns with the gene expression signature in muscle from cachectic pancreatic cancer patients. In summary, we expect KPP mice to serve as a useful model to elucidate the underlying mechanisms of muscle loss in pancreatic cancer-induced cachexia and to evaluate potential anti-cachexia therapies. Citation Format: Erin E. Talbert, Katherine J. Ladner, Maria Cecilia Cuitino, Gustavo W. Leone, Denis C. Guttridge. Generation of a new mouse to model pancreatic cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4090.

A Mouse Model of Creatine Transporter Deficiency Reveals Impaired Motor Function and Muscle Energy Metabolism.

Creatine serves as fast energy buffer in organs of high-energy demand such as brain and skeletal muscle. L-Arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase are responsible for endogenous creatine synthesis. Subsequent uptake into target organs like skeletal muscle, heart and brain is mediated by the creatine transporter (CT1, SLC6A8). Creatine deficiency syndromes are caused by defects of endogenous creatine synthesis or transport and are mainly characterized by intellectual disability, behavioral abnormalities, poorly developed muscle mass, and in some cases also muscle weakness. CT1-deficiency is estimated to be among the most common causes of X-linked intellectual disability and therefore the brain phenotype was the main focus of recent research. Unfortunately, very limited data concerning muscle creatine levels and functions are available from patients with CT1 deficiency. Furthermore, different CT1-deficient mouse models yielded conflicting results and detailed analyses of their muscular phenotype are lacking. Here, we report the generation of a novel CT1-deficient mouse model and characterized the effects of creatine depletion in skeletal muscle. HPLC-analysis showed strongly reduced total creatine levels in skeletal muscle and heart. MR-spectroscopy revealed an almost complete absence of phosphocreatine in skeletal muscle. Increased AGAT expression in skeletal muscle was not sufficient to compensate for insufficient creatine transport. CT1-deficient mice displayed profound impairment of skeletal muscle function and morphology (i.e., reduced strength, reduced endurance, and muscle atrophy). Furthermore, severely altered energy homeostasis was evident on magnetic resonance spectroscopy. Strongly reduced phosphocreatine resulted in decreased ATP/Pi levels despite an increased inorganic phosphate to ATP flux. Concerning glucose metabolism, we show increased glucose transporter type 4 expression in muscle and improved glucose clearance in CT1-deficient mice. These metabolic changes were associated with activation of AMP-activated protein kinase – a central regulator of energy homeostasis. In summary, creatine transporter deficiency resulted in a severe muscle weakness and atrophy despite different compensatory mechanisms.

Pre-operative Sarcopenia Identifies Patients at Risk for Poor Survival After Resection of Biliary Tract Cancers

IntroductionBiliary tract cancers (BTC) are aggressive malignancies that require complex surgical procedures. Patients with BTC can present with skeletal muscle depletion, yet the effects of muscle wasting (sarcopenia) on outcomes have not been well studied. The objective of the current study was to define the impact of sarcopenia on survival among patients undergoing resection of BTC. MethodsPatients who underwent exploration for BTC who had a pre-operative CT scan available for review were identified. Body composition variables including total and psoas muscle area (cm2), muscle density (Hounsfield units), visceral fat area, subcutaneous fat area, and waist-to-hip ratio were analyzed at the level of L3. Outcomes were assessed according to the presence or absence of sarcopenia defined using sex- and BMI-specific threshold values for Psoas Muscle Index (PMI, cm2/m2). ResultsAmong 117 patients with BTC, 78 (67%) underwent curative-intent resection and 39 (33%) were explored but did not undergo resection due to metastatic/locally advanced disease. Tumor type included distal cholangiocarcinoma (n=18, 15.4%), hilar cholangiocarcinoma (n=27, 23.1%), gallbladder carcinoma (n=52, 44.4%), and intrahepatic cholangiocarcinoma (n=20, 17.1%). Median patient age was 65.6 years and 43.6% were male. Mean patient BMI was 26.1 kg/m2 among men and 27.5 kg/m2 among women. Overall, 41 (35.0%) patients had sarcopenia. Sarcopenia was associated with an increased risk of death among patients who underwent resection (HR 3.52, 95%CI 1.60–7.78, p=0.002), which was comparable to patients with unresectable metastatic disease. Other factors such as low serum albumin (HR 3.17, 95% CI 1.30–7.74, p=0.011) and low psoas density (HR 2.96, 95% CI 1.21–7.21, p=0.017) were also associated with increased risk of death. Survival was stratified based on sarcopenia, psoas density, and serum albumin. The presence of each variable was associated with an incremental increased risk of death (0 variables ref.; 1 variable HR 3.8, 95% CI 1.0–14, p=0.043; 2 variables HR 13.1, 95% CI 3.0–57.7, p=0.001; 3 variables HR 14.6, 95% CI 2.5–87.1, p=0.003). Patients who had no adverse prognostic factors had a 3-year OS of 67% versus no survival among patients with all 3 factors. ConclusionsSarcopenia was common among patients undergoing resection of BTC, occurring in 1 of every 3 patients. Sarcopenia was associated with poor survival after resection, particularly among patients who experienced a recurrence. Body composition metrics such as sarcopenia and low psoas muscle density in addition to low albumin level were able to stratify patients into different prognostic categories.

Personal visceral fat index (PVF index), a new predictive factor for chemotherapy efficacy in patients with advanced gastric cancer.

e16049Background: It has been reported that skeletal muscle depletion is a poor prognostic factor for a variety of cancers. Whether the changes of visceral fat or skeletal muscle during chemotherap...

Sarcopenia in Resected NSCLC: Effect on Postoperative Outcomes.

Skeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with NSCLC after surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer. This retrospective study consisted of 328 patients with pathologically confirmed NSCLC who underwent curative resection between January 2005 and April 2017. Preoperative computed tomography imaging at the third lumbar vertebrae level was assessed to measure the psoas muscle mass index (PMI, cm2/m2). Sarcopenia was defined as a cutoff value of PMI less than 6.36 cm2/m2 for males and 3.92 cm2/m2 for females, based on PMI values from "healthy" subjects. The median patient age was 71 years and 59% were male. Sarcopenia was present in 183 (55.8%) and was significantly related with increasing age (p < 0.001), being male (p < 0.001), smoking habit (p < 0.001), lower body mass index (p < 0.001), and postoperative major complication (Clavien-Dindo grade ≥3, p= 0.036). The prevalence of sarcopenia was higher in men than in women, and the prevalence increased with age in men, whereas the prevalence did not increase in females older than 70 years. The 5-year survival rate was 61% in patients with sarcopenia and 91% in those without. Multivariate analysis revealed that sarcopenia was an independent unfavorable prognostic factor (p= 0.019). Sarcopenia as determined using preoperative computed tomography could be used to predict postoperative major complication and prognosis in patients with resected NSCLC. Our results may provide some important information for preoperative management.

Elevated Serum AA/EPA Ratio as a Predictor of Skeletal Muscle Depletion in Cachexic Patients with Advanced Gastro-intestinal Cancers.

In recent years, the number of cancer patients has increased. Cancer patients are prone to sarcopenia as a result of the decrease in muscle mass and muscle weakness which occurs in cancer cachexia. Attention has been given on the effects of fatty acid administration on cancer patients. We conducted a retrospective chart-review study of consecutive patients with unresectable advanced GI cancer (stage IV) (n=46) receiving chemotherapy treatment in an outpatient or in-hospital setting between December 2012 and September 2015 at our Institution. The collected data were characteristics, psoas muscle area as measured by computed tomography (CT), and biochemical blood test and serum fatty acid profiles. Three methods of analysis were evaluated: (i) Comparison of biomarkers between two groups: psoas muscle index change rate (ΔPMI) decrease group vs. ΔPMI increase group. (ii) Correlation between ΔPMI and biomarkers. (iii) Multiple regression of ΔPMI and biomarkers Results: In the ΔPMI decrease group, n-6/n-3 ratio and AA/EPA ratio in the decrease group were significantly higher than those in the increase group. Among all parameters, serum EPA was positively and significantly related to ΔPMI (CC=0.443, p=0.039). In contrast, serum CRP, AA/EPA ratio and n-6/n-3 ratio were negatively related to ΔPMI (CC=-0.566, CC=-0.501, CC=-0.476, p=0.006, p=0.018, p=0.025, respectively). On multiple regression analysis, serum CRP value was strongly related to ΔPMI (r2=0.421, β=-0.670, p=0.001). Higher n-6/n-3 and AA/EPA ratios were associated with a decrease in psoas muscle area, that lead to diagnosis of sarcopenia. Higher CRP was also associated with a decrease in psoas muscle area, suggesting that this might be an indicator of cachexic skeletal muscle depletion in cachexic patients with advanced gastro-intestinal cancers.

REDD1 Reduces Muscle Metabolism to Foster Adaptation under Fasting

Aims and backgroundRegulated 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 resultsWild‐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.ConclusionsSustained 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 InformationThis work was supported by the Agence Française de Lutte contre le Dopage (grant #4299).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.