TY  - JOUR
AB  - BACKGROUND: Cancer cachexia, affecting up to 80% of patients with cancer, is characterized by muscle and fat loss with functional decline. Preclinical research seeks to uncover the molecular mechanisms underlying cachexia to identify potential targets. Housing laboratory mice at ambient temperature induces cold stress, triggering thermogenic activity and metabolic adaptations. Yet, the impact of housing temperature on preclinical cachexia remains unknown. METHODS: Colon 26 carcinoma (C26)-bearing and PBS-inoculated (Ctrl) mice were housed at standard (ST; 20°C-22°C) or thermoneutral temperature (TN; 28°C-32°C). They were monitored for body weight, composition, food intake and systemic factors. Upon necropsy, tissues were weighed and used for evaluation of ex vivo force and respiration, or snap frozen for biochemical assays. RESULTS: C26 mice lost 7.5% body weight (p = 0.0001 vs. Ctrls), accounted by decreased fat mass (-35%, p < 0.0001 vs. Ctrls), showing mild cachexia irrespective of housing temperature. All C26 mice exhibited reduced force (-40%, p < 0.0001 vs. Ctrls) and increased atrogene expression (3-fold, p < 0.003 vs. Ctrls). Cancer altered white adipose tissue (WAT)'s functional gene signature (49%, p < 0.05 vs. Ctrls), whereas housing temperature reduced brown adipose tissue (BAT)'s (-78%, p < 0.05 vs. ST Ctrl). Thermogenic capacity measured by Ucp1 expression decreased upon cancer in both WAT and BAT (-93% and -63%, p < 0.0044 vs. Ctrls). Cancer-driven glucose intolerance was noted at ST (26%, p = 0.0192 vs. ST Ctrl), but restored at TN (-23%, p = 0.005 vs. ST C26). Circulating FGF21, GDF-15 and IL-6 increased in all C26 mice (4-fold, p < 0.009 vs. Ctrls), with a greater effect on IL-6 at TN (76%, p = 0.0018 vs. ST C26). Tumour and WAT Il6 mRNA levels remained unchanged, while cancer induced skeletal muscle (SkM) Il6 (2-fold, p = 0.0016 vs. Ctrls) at both temperatures. BAT Il6 was only induced in C26 mice at TN (116%, p = 0.0087 vs. ST C26). At the bioenergetics level, cancer increased SkM SERCA ATPase activity at ST (4-fold, p = 0.0108 vs. ST Ctrl) but not at TN. In BAT, O2 consumption enhanced in C26 mice at ST (119%, p < 0.03 vs. ST Ctrl) but was blunted at TN (-44%, p < 0.0001 vs. ST C26). Cancer increased BAT ATP levels regardless of temperature (2-fold, p = 0.0046 vs. Ctrls), while SERCA ATPase activity remained unchanged at ST and decreased at TN (-59%, p = 0.0213 vs. TN Ctrl). CONCLUSIONS: In mild cachexia, BAT and SkM bioenergetics are susceptible to different housing temperatures, which influences cancer-induced alterations in glucose metabolism and systemic responses.
AU  - Irazoki, A.*
AU  - Frank, E.*
AU  - Pham, T.C.P.*
AU  - Braun, J.L.*
AU  - Ehrlich, A.M.*
AU  - Haid, M.
AU  - Riols, F.
AU  - Hansen, C.H.F.*
AU  - Jørgensen, A.R.*
AU  - Andersen, N.R.*
AU  - Hidalgo-Corbacho, L.*
AU  - Meneses-Valdes, R.*
AU  - Ali, M.S.*
AU  - Raun, S.H.*
AU  - Modvig, J.L.*
AU  - Gallero, S.*
AU  - Larsen, S.*
AU  - Gerhart-Hines, Z.*
AU  - Jensen, T.E.*
AU  - Rohm, M.
AU  - Treebak, J.T.*
AU  - Fajardo, V.A.*
AU  - Sylow, L.*
C1  - 74125
C2  - 57313
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Housing temperature impacts the systemic and tissue-specific molecular responses to cancer in mice.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 16
IS  - 2
PB  - Wiley
PY  - 2025
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - BACKGROUND: Cachexia is a clinically challenging multifactorial and multi-organ syndrome, associated with poor outcome in cancer patients, and characterised by inflammation, wasting and loss of appetite. The syndrome leads to central nervous system (CNS) function dysregulation and to neuroinflammation; nevertheless, the mechanisms involved in human cachexia remain unclear. METHODS: We used in vivo structural and functional magnetic resonance imaging (Cohort 1), as well as postmortem neuropathological analyses (Cohort 2) in cachectic cancer (CC) patients compared to weight stable cancer (WSC) patients. Cohort 1 included treatment-naïve adults diagnosed with colorectal cancer, further divided into WSC (n = 12; 6/6 [male/female], 61.3 ± 3.89 years) and CC (n = 10; 6/4, 63.0 ± 2.74 years). Cohort 2 was composed by human postmortem cases where gastrointestinal carcinoma was the underlying cause of death (WSC n = 6; 3/3, 82.7 ± 3.33 years and CC n = 10; 5/5, 84.2 ± 2.28 years). RESULTS: Here we demonstrate that the CNS of CC patients presents regional structural differences within the grey matter (GM). Cachectic patients presented an augmented area within the region of the orbitofrontal cortex, olfactory tract and the gyrus rectus (coordinates X, Y, Z = 6, 20,-24; 311 voxels; pFWE = 0.023); increased caudate and putamen volume (-10, 20, -8; 110 voxel; pFWE = 0.005); and reduced GM in superior temporal gyrus and rolandic operculum (56,0,2; 156 voxels; pFWE = 0.010). Disrupted functional connectivity was found in several regions such as the salience network, subcortical and temporal cortical areas of cachectic patients (20 decreased and 5 increased regions connectivity pattern, pFDR < 0.05). Postmortem neuropathological analyses identified abnormal neuronal morphology and density, increased microglia/macrophage burden, astrocyte profile disruption and mTOR pathway related neuroinflammation (p < 0.05). CONCLUSIONS: Our results indicate that cachexia compromises CNS morphology mostly causing changes in the GM of cachectic patients, leading to alterations in regional volume patterns, functional connectivity, neuronal morphology, neuroglia profile and inducing neuroinflammation, all of which may contribute to the loss of homeostasis control and to deficient information processing, as well as to the metabolic and behavioural derangements commonly observed in human cachexia. This first human mapping of CNS cachexia responses will now pave the way to mechanistically interrogate these pathways in terms of their therapeutic potential.
AU  - Simoes Fernandez, E.
AU  - Uchida, R.*
AU  - Nucci, M.P.*
AU  - Duran, F.L.S.*
AU  - Lima, J.D.C.C.*
AU  - Gama, L.R.*
AU  - Costa, N.A.*
AU  - Otaduy, M.C.G.*
AU  - Bin, F.C.*
AU  - Otoch, J.P.*
AU  - Alcantara, P.*
AU  - Ramos, A.*
AU  - Laviano, A.*
AU  - Diaz, M.B.
AU  - Esiri, M.M.*
AU  - DeLuca, G.C.*
AU  - Herzig, S.
AU  - Filho, G.B.*
AU  - Seelaender, M.*
C1  - 73405
C2  - 57055
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Cachexia alters central nervous system morphology and functionality in cancer patients.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 16
IS  - 1
PB  - Wiley
PY  - 2025
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - BACKGROUND: There is increasing evidence that myosteatosis, which is currently not assessed in clinical routine, plays an important role in risk estimation in individuals with impaired glucose metabolism, as it is associated with the progression of insulin resistance. With advances in artificial intelligence, automated and accurate algorithms have become feasible to fill this gap. METHODS: In this retrospective study, we developed and tested a fully automated deep learning model using data from two prospective cohort studies (German National Cohort [NAKO] and Cooperative Health Research in the Region of Augsburg [KORA]) to quantify myosteatosis on whole-body T1-weighted Dixon magnetic resonance imaging as (1) intramuscular adipose tissue (IMAT; the current standard) and (2) quantitative skeletal muscle (SM) fat fraction (SMFF). Subsequently, we investigated the two measures for their discrimination of and association with impaired glucose metabolism beyond baseline demographics (age, sex and body mass index [BMI]) and cardiometabolic risk factors (lipid panel, systolic blood pressure, smoking status and alcohol consumption) in asymptomatic individuals from the KORA study. Impaired glucose metabolism was defined as impaired fasting glucose or impaired glucose tolerance (140-200 mg/dL) or prevalent diabetes mellitus. RESULTS: Model performance was high, with Dice coefficients of ≥0.81 for IMAT and ≥0.91 for SM in the internal (NAKO) and external (KORA) testing sets. In the target population (380 KORA participants: mean age of 53.6 ± 9.2 years, BMI of 28.2 ± 4.9 kg/m2, 57.4% male), individuals with impaired glucose metabolism (n = 146; 38.4%) were older and more likely men and showed a higher cardiometabolic risk profile, higher IMAT (4.5 ± 2.2% vs. 3.9 ± 1.7%) and higher SMFF (22.0 ± 4.7% vs. 18.9 ± 3.9%) compared to normoglycaemic controls (all P ≤ 0.005). SMFF showed better discrimination for impaired glucose metabolism than IMAT (area under the receiver operating characteristic curve [AUC] 0.693 vs. 0.582, 95% confidence interval [CI] [0.06-0.16]; P < 0.001) but was not significantly different from BMI (AUC 0.733 vs. 0.693, 95% CI [-0.09 to 0.01]; P = 0.15). In univariable logistic regression, IMAT (odds ratio [OR] = 1.18, 95% CI [1.06-1.32]; P = 0.004) and SMFF (OR = 1.19, 95% CI [1.13-1.26]; P < 0.001) were associated with a higher risk of impaired glucose metabolism. This signal remained robust after multivariable adjustment for baseline demographics and cardiometabolic risk factors for SMFF (OR = 1.10, 95% CI [1.01-1.19]; P = 0.028) but not for IMAT (OR = 1.14, 95% CI [0.97-1.33]; P = 0.11). CONCLUSIONS: Quantitative SMFF, but not IMAT, is an independent predictor of impaired glucose metabolism, and discrimination is not significantly different from BMI, making it a promising alternative for the currently established approach. Automated methods such as the proposed model may provide a feasible option for opportunistic screening of myosteatosis and, thus, a low-cost personalized risk assessment solution.
AU  - Jung, M.*
AU  - Rieder, H.*
AU  - Reisert, M.*
AU  - Rospleszcz, S.
AU  - Nattenmueller, J.*
AU  - Peters, A.
AU  - Schlett, C.L.*
AU  - Bamberg, F.*
AU  - Weiss, J.*
C1  - 71163
C2  - 55906
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Association between myosteatosis and impaired glucose metabolism: A deep learning whole-body magnetic resonance imaging population phenotyping approach.
JO  - J. Cachexia Sarcopenia Muscle
PB  - Wiley
PY  - 2024
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - Background: Intervertebral disc degeneration (IVDD) may be linked to dysregulations of skeletal muscle glucose metabolism and fatty alterations of muscle composition (Myosteatosis). Our aim was to evaluate the different associations of magnetic resonance imaging (MRI)-based paravertebral myosteatosis with lumbar disc degeneration in individuals with impaired glucose metabolism and normoglycaemic controls. Methods: In total, 304 individuals (mean age: 56.3 ± 9.1 years, 53.6% male sex, mean body mass index [BMI]: 27.6 ± 4.7 kg/m2) from a population-based cohort study who underwent 3-Tesla whole-body chemical-shift-encoded (six echo times) and T2-weighted single-shot-fast-spin-echo MRI were included. Lumbar disc degeneration was assessed at motion segments L1 to L5, categorized according to the Pfirrmann score and defined as Pfirrmann grade > 2 and/or disc bulging/herniation on at least one segment. Fat content of the autochthonous back muscles and the quadratus lumborum muscle was quantified as proton density fat fraction (PDFFmuscle). Logistic regression models adjusted for age, sex, BMI and regular physical activity were calculated to evaluate the association between PDFFmuscle and outcome IVDD. Results: The overall prevalence of IVDD was 79.6%. There was no significant difference in the prevalence or severity distribution of IVDD between participants with or without impaired glucose metabolism (77.7% vs. 80.7%, P = 0.63 and P = 0.71, respectively). PDFFmuscle was significantly and positively associated with an increased risk for the presence of IVDD in participants with impaired glycaemia when adjusted for age, sex and BMI (PDFFautochthonous back muscles: odds ratio [OR] 2.16, 95% confidence interval [CI] [1.09, 4.3], P = 0.03; PDFFquadratus lumborum: OR 2.01, 95% CI [1.04, 3.85], P = 0.04). After further adjustment for regular physical activity, the results attenuated, albeit approaching statistical significance (PDFFautochthonous back muscles: OR 1.97, 95% CI [0.97, 3.99], P = 0.06; PDFFquadratus lumborum: OR 1.86, 95% CI [0.92, 3.76], P = 0.09). No significant associations were shown in healthy controls (PDFFautochthonous back muscles: OR 0.62, 95% CI [0.34, 1.14], P = 0.13; PDFFquadratus lumborum: OR 1.06, 95% CI [0.6, 1.89], P = 0.83). Conclusions: Paravertebral myosteatosis is positively associated with intervertebral disc disease in individuals with impaired glucose metabolism, independent of age, sex and BMI. Regular physical activity may confound these associations. Longitudinal studies will help to better understand the pathophysiological role of skeletal muscle in those with concomitant disturbed glucose haemostasis and intervertebral disc disease, as well as possible underlying causal relationships.
AU  - Diallo, T.D.*
AU  - Rospleszcz, S.
AU  - Fabian, J.*
AU  - Walter, S.S.*
AU  - Maurer, E.*
AU  - Storz, C.*
AU  - Roemer, F.*
AU  - Rathmann, W.*
AU  - Peters, A.
AU  - Jungmann, P.M.*
AU  - Jung, M.*
AU  - Bamberg, F.*
AU  - Kiefer, L.S.*
C1  - 67592
C2  - 54054
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1249-1258
TI  - Associations of myosteatosis with disc degeneration: A 3T magnetic resonance imaging study in individuals with impaired glycaemia.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 14
IS  - 3
PB  - Wiley
PY  - 2023
SN  - 2190-5991
ER  - 

TY  - JOUR
AU  - Ko, H.S.*
AU  - Denehy, L.*
AU  - Edbrooke, L.*
AU  - Albarqouni, S.
AU  - Attenberger, U.*
AU  - Parker, B.L.*
AU  - Cox, A.*
AU  - Le, B.*
AU  - Cheng, L.*
C1  - 68776
C2  - 54986
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 4-7
TI  - Enhancing oncological care: A guide to setting up a new multidisciplinary cancer cachexia clinic within a tertiary centre.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 15
IS  - 1
PB  - Wiley
PY  - 2023
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - Background: Skeletal muscle mass is subjected to constant changes and is considered a good predictor for outcome in various diseases. Bioelectrical-impedance analysis (BIA) and magnetic resonance imaging (MRI) are approved methodologies for its assessment. However, muscle mass estimations by BIA may be influenced by excess intramuscular lipids and adipose tissue in obesity. The objective of this study was to evaluate the feasibility of quantitative assessment of skeletal muscle mass by MRI as compared with BIA. Methods: Subjects from a population-based cohort underwent BIA (50 kHz, 0.8 mA) and whole-body MRI including chemical-shift encoded MRI (six echo times). Abdominal muscle mass by MRI was quantified as total and fat-free cross-sectional area by a standardized manual segmentation-algorithm and normalized to subjects' body height2 (abdominal muscle mass indices: AMMIMRI). Results: Among 335 included subjects (56.3 ± 9.1 years, 56.1% male), 95 (28.4%) were obese (BMI ≥ 30 kg/m2). MRI-based and BIA-based measures of muscle mass were strongly correlated, particularly in non-obese subjects [r < 0.74 in non-obese (P < 0.001) vs. r < 0.56 in obese (P < 0.001)]. Median AMMITotal(MRI) was significantly higher in obese as compared with non-obese subjects (3246.7 ± 606.1 mm2/m2 vs. 2839.0 ± 535.8 mm2/m2, P < 0.001, respectively), whereas the ratio AMMIFat-free/AMMITotal (by MRI) was significantly higher in non-obese individuals (59.3 ± 10.1% vs. 53.5 ± 10.6%, P < 0.001, respectively). No significant difference was found regarding AMMIFat-free(MRI) (P = 0.424). In analyses adjusted for age and sex, impaired glucose tolerance and measures of obesity were significantly and positively associated with AMMITotal(MRI) and significantly and inversely with the ratio AMMIFat-free(MRI)/AMMITotal(MRI) (P < 0.001). Conclusions: MRI-based assessment of muscle mass is feasible in population-based imaging and strongly correlated with BIA. However, the observed weaker correlation in obese subjects may explain the known limitation of BIA in obesity and promote MRI-based assessments. Thus, skeletal muscle mass parameters by MRI may serve as practical imaging biomarkers independent of subjects' body weight.
AU  - Kiefer, L.S.*
AU  - Fabian, J.*
AU  - Rospleszcz, S.
AU  - Lorbeer, R.*
AU  - Machann, J.
AU  - Kraus, M.S.*
AU  - Fischer, M.*
AU  - Roemer, F.*
AU  - Rathmann, W.*
AU  - Meisinger, C.
AU  - Heier, M.
AU  - Nikolaou, K.*
AU  - Peters, A.
AU  - Storz, C.*
AU  - Schlett, C.L.*
AU  - Bamberg, F.*
C1  - 64193
C2  - 51804
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 976-986
TI  - Population-based cohort imaging: skeletal muscle mass by magnetic resonance imaging in correlation to bioelectrical-impedance analysis.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 13
IS  - 2
PB  - Wiley
PY  - 2022
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - BACKGROUND: The coexistence of low muscle mass and high fat mass, two interrelated conditions strongly associated with declining health status, has been characterized by only a few protein biomarkers. High-throughput proteomics enable concurrent measurement of numerous proteins, facilitating the discovery of potentially new biomarkers. METHODS: Data derived from the prospective population-based Cooperative Health Research in the Region of Augsburg S4/FF4 cohort study (median follow-up time: 13.5 years) included 1478 participants (756 men and 722 women) aged 55-74 years in the cross-sectional and 608 participants (315 men and 293 women) in the longitudinal analysis. Appendicular skeletal muscle mass (ASMM) and body fat mass index (BFMI) were determined through bioelectrical impedance analysis at baseline and follow-up. At baseline, 233 plasma proteins were measured using proximity extension assay. We implemented boosting with stability selection to enable false positives-controlled variable selection to identify new protein biomarkers of low muscle mass, high fat mass, and their combination. We evaluated prediction models developed based on group least absolute shrinkage and selection operator (lasso) with 100× bootstrapping by cross-validated area under the curve (AUC) to investigate if proteins increase the prediction accuracy on top of classical risk factors. RESULTS: In the cross-sectional analysis, we identified kallikrein-6, C-C motif chemokine 28 (CCL28), and tissue factor pathway inhibitor as previously unknown biomarkers for muscle mass [association with low ASMM: odds ratio (OR) per 1-SD increase in log2 normalized protein expression values (95% confidence interval (CI)): 1.63 (1.37-1.95), 1.31 (1.14-1.51), 1.24 (1.06-1.45), respectively] and serine protease 27 for fat mass [association with high BFMI: OR (95% CI): 0.73 (0.61-0.86)]. CCL28 and metalloproteinase inhibitor 4 (TIMP4) constituted new biomarkers for the combination of low muscle and high fat mass [association with low ASMM combined with high BFMI: OR (95% CI): 1.32 (1.08-1.61), 1.28 (1.03-1.59), respectively]. Including protein biomarkers selected in ≥90% of group lasso bootstrap iterations on top of classical risk factors improved the performance of models predicting low ASMM, high BFMI, and their combination [delta AUC (95% CI): 0.16 (0.13-0.20), 0.22 (0.18-0.25), 0.12 (0.08-0.17), respectively]. In the longitudinal analysis, N-terminal prohormone brain natriuretic peptide (NT-proBNP) was the only protein selected for loss in ASMM and loss in ASMM combined with gain in BFMI over 14 years [OR (95% CI): 1.40 (1.10-1.77), 1.60 (1.15-2.24), respectively]. CONCLUSIONS: Proteomic profiling revealed CCL28 and TIMP4 as new biomarkers of low muscle mass combined with high fat mass and NT-proBNP as a key biomarker of loss in muscle mass combined with gain in fat mass. Proteomics enable us to accelerate biomarker discoveries in muscle research.
AU  - Huemer, M.-T.
AU  - Bauer, A.
AU  - Petrera, A.
AU  - Scholz, M.*
AU  - Hauck, S.M.
AU  - Drey, M.*
AU  - Peters, A.
AU  - Thorand, B.
C1  - 62316
C2  - 50712
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1011–1023
TI  - Proteomic profiling of low muscle and high fat mass: A machine learning approach in the KORA S4/FF4 study.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 12
PB  - Wiley
PY  - 2021
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - BACKGROUND: Cancer cachexia (CCx) is a multifactorial wasting disorder characterized by involuntary loss of body weight that affects many cancer patients and implies a poor prognosis, reducing both tolerance to and efficiency of anticancer therapies. Actual challenges in management of CCx remain in the identification of tumour-derived and host-derived mediators involved in systemic inflammation and tissue wasting and in the discovery of biomarkers that would allow for an earlier and personalized care of cancer patients. The aim of this study was to identify new markers of CCx across different species and tumour entities. METHODS: Quantitative secretome analysis was performed to identify specific factors characteristic of cachexia-inducing cancer cell lines. To establish the subsequently identified phospholipase PLA2G7 as a marker of CCx, plasma PLA2G7 activity and/or protein levels were measured in well-established mouse models of CCx and in different cohorts of weight-stable and weight-losing cancer patients with different tumour entities. Genetic PLA2G7 knock-down in tumours and pharmacological treatment using the well-studied PLA2G7 inhibitor darapladib were performed to assess its implication in the pathogenesis of CCx in C26 tumour-bearing mice. RESULTS: High expression and secretion of PLA2G7 were hallmarks of cachexia-inducing cancer cell lines. Circulating PLA2G7 activity was increased in different mouse models of CCx with various tumour entities and was associated with the severity of body wasting. Circulating PLA2G7 levels gradually rose during cachexia development. Genetic PLA2G7 knock-down in C26 tumours only partially reduced plasma PLA2G7 levels, suggesting that the host is also an important contributor. Chronic treatment with darapladib was not sufficient to counteract inflammation and tissue wasting despite a strong inhibition of the circulating PLA2G7 activity. Importantly, PLA2G7 levels were also increased in colorectal and pancreatic cancer patients with CCx. CONCLUSIONS: Overall, our data show that despite no immediate pathogenic role, at least when targeted as a single entity, PLA2G7 is a consistent marker of CCx in both mice and humans. The early increase in circulating PLA2G7 levels in pre-cachectic mice supports future prospective studies to assess its potential as biomarker for cancer patients.
AU  - Morigny, P.
AU  - Kaltenecker, D.
AU  - Zuber, J.
AU  - Machado, J.
AU  - Mehr, L.
AU  - Tsokanos, F.-F.
AU  - Kuzi, H.*
AU  - Hermann, C.D.*
AU  - Voelkl, M.*
AU  - Monogarov, G.*
AU  - Springfeld, C.*
AU  - Laurent, V.
AU  - Engelmann, B.*
AU  - Friess, H.*
AU  - Zörnig, I.*
AU  - Krüger, A.*
AU  - Krijgsveld, J.*
AU  - Prokopchuk, O.*
AU  - Schmidt, S.F.
AU  - Rohm, M.
AU  - Herzig, S.
AU  - Berriel Diaz, M.
C1  - 62883
C2  - 51138
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Association of circulating PLA2G7 levels with cancer cachexia and assessment of darapladib as a therapy.
JO  - J. Cachexia Sarcopenia Muscle
PB  - Wiley
PY  - 2021
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - Background Cachexia is the direct cause of at least 20% of cancer-associated deaths. Muscle wasting in skeletal muscle results in weakness, immobility, and death secondary to impaired respiratory muscle function. Muscle proteins are massively degraded in cachexia; nevertheless, the molecular mechanisms related to this process are poorly understood. Previous studies have reported conflicting results regarding the amino acid abundances in cachectic skeletal muscle tissues. There is a clear need to identify the molecular processes of muscle metabolism in the context of cachexia, especially how different types of molecules are involved in the muscle wasting process. Methods New in situ -omics techniques were used to produce a more comprehensive picture of amino acid metabolism in cachectic muscles by determining the quantities of amino acids, proteins, and cellular metabolites. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging, we determined the in situ concentrations of amino acids and proteins, as well as energy and other cellular metabolites, in skeletal muscle tissues from genetic mouse cancer models (n = 21) and from patients with cancer (n = 6). Combined results from three individual MALDI mass spectrometry imaging methods were obtained and interpreted. Immunohistochemistry staining for mitochondrial proteins and myosin heavy chain expression, digital image analysis, and transmission electron microscopy complemented the MALDI mass spectrometry imaging results. Results Metabolic derangements in cachectic mouse muscle tissues were detected, with significantly increased quantities of lysine, arginine, proline, and tyrosine (P = 0.0037, P = 0.0048, P = 0.0430, and P = 0.0357, respectively) and significantly reduced quantities of glutamate and aspartate (P = 0.0008 and P = 0.0124). Human skeletal muscle tissues revealed similar tendencies. A majority of altered amino acids were released by the breakdown of proteins involved in oxidative phosphorylation. Decreased energy charge was observed in cachectic muscle tissues (P = 0.0101), which was related to the breakdown of specific proteins. Additionally, expression of the cationic amino acid transporter CAT1 was significantly decreased in the mitochondria of cachectic mouse muscles (P = 0.0133); this decrease may play an important role in the alterations of cationic amino acid metabolism and decreased quantity of glutamate observed in cachexia. Conclusions Our results suggest that mitochondrial dysfunction has a substantial influence on amino acid metabolism in cachectic skeletal muscles, which appears to be triggered by diminished CAT1 expression, as well as the degradation of mitochondrial proteins. These findings provide new insights into the pathobiochemistry of muscle wasting.
AU  - Kunzke, T.
AU  - Buck, A.
AU  - Prade, V.M.
AU  - Feuchtinger, A.
AU  - Prokopchuk, O.*
AU  - Martignoni, M.E.*
AU  - Heisz, S.*
AU  - Hauner, H.*
AU  - Janssen, K.P.*
AU  - Walch, A.K.
AU  - Aichler, M.
C1  - 57387
C2  - 47777
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 226-240
TI  - Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 11
IS  - 1
PB  - Wiley
PY  - 2020
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - Background Cancer cachexia (CCx) is a multifactorial energy-wasting syndrome reducing the efficiency of anti-cancer therapies, quality of life, and survival of cancer patients. In the past years, most studies focused on the identification of tumour and host-derived proteins contributing to CCx. However, there is still a lack of studies addressing the changes in bioactive lipids. The aim of this study was to identify specific lipid species as a hallmark of CCx by performing a broad range lipid analysis of plasma from well-established CCx mouse models as well as cachectic and weight stable cancer patients. Methods Plasma from non-cachectic (PBS-injected mice, NC26 tumour-bearing mice), pre-cachectic and cachectic mice (C26 and LLC tumour-bearing mice, Apc(Min/+)mutant mice), and plasma from weight stable and cachectic patients with gastrointestinal cancer, were analysed using the Lipidyzer (TM) platform. In total, 13 lipid classes and more than 1100 lipid species, including sphingolipids, neutral and polar glycerolipids, were covered by the analysis. Correlation analysis between specific lipid species and readouts of CCx were performed. Lipidomics data were confirmed by gene expression analysis of metabolic organs to analyse enzymes involved in sphingolipid synthesis and degradation. Results A decrease in several lysophosphatidylcholine (LPC) species and an increase in numerous sphingolipids including sphingomyelins (SMs), ceramides (CERs), hexosyl-ceramides (HCERs) and lactosyl-ceramides (LCERs), were mutual features of CCx in both mice and cancer patients. Notably, sphingolipid levels gradually increased during cachexia development. Key enzymes involved in ceramide synthesis were elevated in liver but not in adipose, muscle, or tumour tissues, suggesting that ceramide turnover in the liver is a major contributor to elevated sphingolipid levels in CCx. LPC(16:1), LPC(20:3), SM(16:0), SM(24:1), CER(16:0), CER(24:1), HCER(16:0), and HCER(24:1) were the most consistently affected lipid species between mice and humans and correlated negatively (LPCs) or positively (SMs, CERs and HCERs) with the severity of body weight loss. Conclusions High levels of sphingolipids, specifically ceramides and modified ceramides, are a defining feature of murine and human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the inhibition of anabolic signals. The progressive increase in sphingolipids during cachexia development supports their potential as early biomarkers for CCx.
AU  - Morigny, P.
AU  - Zuber, J.
AU  - Haid, M.
AU  - Kaltenecker, D.
AU  - Riols, F.
AU  - Lima, J.D.C.*
AU  - Simoes, E.*
AU  - Otoch, J.P.*
AU  - Schmidt, S.F.
AU  - Herzig, S.
AU  - Adamski, J.
AU  - Seelaender, M.*
AU  - Berriel Diaz, M.
AU  - Rohm, M.
C1  - 60289
C2  - 49264
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1459-1475
TI  - High levels of modified ceramides are a defining feature of murine and human cancer cachexia.
JO  - J. Cachexia Sarcopenia Muscle
VL  - 11
IS  - 1
PB  - Wiley
PY  - 2020
SN  - 2190-5991
ER  - 

TY  - JOUR
AB  - Traditionally, skeletal muscle and adipose tissue have been the focus of
       research on cancer cachexia. Recent studies suggest that cancer 
      cachexia (CC) is a multi‐organ syndrome which involves not only the 
      direct effects of tumour‐derived cachexia‐inducing factors on target 
      organs but also the crosstalk of these dysfunctional organs. Despite its
       central role in other metabolic diseases, the liver has received little
       attention in the context of CC. However, CC is associated with systemic
       inflammation, and the activation of the hepatic acute phase response 
      (APR) is well‐documented in cachectic patients. Serum amyloid A 1 and 2 
      (SAA 1/2) are classical APR proteins that are mainly produced by the 
      liver and strongly induced in response to inflammatory cytokines. To 
      assess the potential contribution of SAA to tissue wasting in vitro,
       we treated 3T3‐L1 adipocytes and C2C12 myotubes with recombinant SAA1. 
      While lipolysis rates remained unaffected, we found a significant 
      reduction in myotube diameter in response to SAA1 treatment, indicative 
      of an atrophic effect. Next, we addressed the contribution of SAA 1/2 to
       cachexia development in vivo using a liver‐specific knock‐down 
      (KD) approach. For this purpose, we injected an AAV‐miRNA targeting 
      SAA1/2 or an AAV‐control‐miRNA into C26 tumour bearing mice. Despite a 
      four‐fold reduction in circulating serum levels in the SAA1/2 KD group, 
      SAA1 was still highly up‐regulated in tumour bearing mice and no 
      differences were observed in cachexia progression. In order to define 
      novel liver‐secreted factors that can potentially impact cachexia 
      development, we integrated hepatocyte specific RNAseq and serum proteome
       analyses of C26 cachectic animals and observed a high degree of 
      overlap. We are currently functionally characterizing a panel of these 
      hepatocyte‐secreted proteins in order to investigate their potential 
      adipocyte lipolysis and/or myotube atrophy‐mediating properties. These 
      studies might contribute to a better understanding of the 
      pathophysiology of CC and the liver‐specific contribution to its 
      development.
AU  - Molocea, C.-E.*
AU  - Schmidt, S.F.*
AU  - Krahmer, N.
AU  - Herzig, S.
AU  - Diaz, M.B.
C1  - 57882
C2  - 47971
SP  - 1387
TI  - Exploring the contribution of the liver to cancer cachexia development.
JO  - J. Cachexia Sarcopenia Muscle
PY  - 2019
SN  - 2190-5991
ER  -