Withaferin A and Ovarian Cancer Antagonistically Regulate Skeletal Muscle Mass.
Ontology highlight
ABSTRACT:
SUBMITTER: Straughn AR
PROVIDER: S-EPMC7947350 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:Ovarian cancer is the fifth leading cause of cancer-related deaths amongst women in the United States. Cachexia is the primary cause of death in approximately 30% of cancer patients, and is often evidenced in ovarian cancer patients. We tested the steroidal lactone Withaferin A to examine if it could ameliorate ovarian cancer-induced cachexia. METHODS:Six-week-old severely immunodeficient female mice were xenografted with the ovarian cancer cell line A2780 followed by treatment with Withaferin A or vehicle. Changes in functional grip strength were assessed on a weekly basis. Postmortem, H&E staining was performed on skeletal muscle sections and immunofluorescent immunohistochemistry was performed on skeletal muscle and tumor sections. The levels of NF-?B-related proinflammatory cytokines were assessed in the xenografted tumors and in resident host skeletal muscle. RESULTS:Xenografting of the A2780 cell line resulted in a significant rate of mortality, which was attenuated by a therapeutic dosage of Withaferin A. Mice that received vehicle treatment following xenografting exhibited functional muscle decline over the course of the study. The therapeutic dosage Withaferin A treatment attenuated this reduction in grip strength, whereas the supratherapeutic dosage of Withaferin A was found to be toxic/lethal and demonstrated a further decline in functional muscle strength and an increased rate of mortality on par with vehicle treatment. At a histological level, the vehicle treated tumor-bearing mice exhibited a profound reduction in myofibrillar cross-sectional area compared to the vehicle treated tumor-free control group. The atrophic changes induced by the xenografted tumor were significantly ameliorated by treatment with Withaferin A. The combination of functional muscle weakening and induction of myofibrillar atrophy corroborate a cachectic phenotype, which was functionally rescued by Withaferin A. Further, treatment completely abolished the slow-to-fast myofiber type conversion observed in the settings of cancer-induced cachexia. In both host resident skeletal muscle and the xenografted tumors, we report an increase in NF-?B-related proinflammatory cytokines that was reversed by Withaferin A treatment. Finally, we demonstrated that Withaferin A significantly downregulates cytosolic and nuclear levels of phospho-p65, the active canonical NF-?B transcription factor, in xenografted tumors. CONCLUSIONS:Cumulatively, our results demonstrate a previously overlooked role of Withaferin A in a xenograft model of ovarian cancer. We propose mechanisms by which Withaferin A reduces NF-?B-dependent pro-inflammatory cytokine production leading to an attenuation of the cachectic phenotype in an i.p. xenograft model of ovarian cancer.
| S-EPMC6878639 | biostudies-literature
Project description:PurposeTo evaluate the feasibility of using skeletal muscle mass (SMM) at C3 (C3 SMM) as a diagnostic marker for sarcopenia in head and neck cancer (HNC) patients.MethodsWe evaluated 165 HNC patients and 42 healthy adults who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans. The paravertebral muscle area at C3 and skeletal muscle area at L3 were measured by CT. Pearson's correlation was used to assess the relationship between L3 and C3 SMMs. The prediction model for L3 SMM was developed by multiple linear regression. Then the correlation and the agreement between actual and predicted L3 SMMs were assessed. To evaluate the diagnostic value of C3 SMM for sarcopenia, the receiver operating characteristics (ROC) curves were analyzed.ResultsOf the 165 HNC patients, 61 (37.0%) were sarcopenic and 104 (63.0%) were non-sarcopenic. A very strong correlation was found between L3 SMM and C3 SMM in both healthy adults (r = 0.864) and non-sarcopenic patients (r = 0.876), while a fair association was found in sarcopenic patients (r = 0.381). Prediction model showed a very strong correlation between actual SMM and predicted L3 SMM in both non-sarcopenic patients and healthy adults (r > 0.9), whereas the relationship was moderate in sarcopenic patients (r = 0.7633). The agreement between two measurements was good for healthy subjects and non-sarcopenic patients, while it was poor for sarcopenic patients. On ROC analysis, predicted L3 SMM showed poor diagnostic accuracy for sarcopenia.ConclusionsA correlation between L3 and C3 SMMs was weak in sarcopenic patients. A prediction model also showed a poor diagnostic accuracy. Therefore, C3 SMM may not be a strong predictor for L3 SMM in sarcopenic patients with HNC.
| S-EPMC8289025 | biostudies-literature
Project description:BackgroundA typical assessment for sarcopenia involves the use of abdominal computed tomography (CT) for calculating the skeletal muscle index (SMI) at the level of the third lumbar vertebra (L3). However, abdominal CT is not regularly performed on patients with head and neck cancer (HNC). We investigated whether masticatory SMI (M-SMI) measurements based on head and neck CT scans can be used to conduct sarcopenia assessments by evaluating whether M-SMI is correlated with L3-SMI.MethodsAbdominal and head and neck CT images of patients with trauma (n = 50) and HNC (n = 52) were analyzed retrospectively. Both manual delineation and threshold selection methods were used to measure cross-sectional areas of masticatory muscles and those of muscles at the L3 level on CT images. Muscle cross-sectional areas were normalized to height squared to calculate SMI, and a multivariate linear regression model was established to evaluate the correlation between the M-SMI and L3-SMI. Receiver operating characteristic curve analysis was used to assess the ability of the M-SMI to identify sarcopenia, and Cox logistic regression was used to identify predictors of sarcopenia.ResultsPatients with HNC had significantly lower M-SMI and L3-SMI than did patients with trauma (p = 0.011 and 0.03, respectively). M-SMI and L3-SMI were strongly correlated (r = 0.901, p < 0.001); in the multivariate model that included sex, the correlation was stronger (r = 0.913, p < 0.001). The associations of sarcopenia with a lower M-SMI (p < 0.001), male sex (p = 0.028), and advanced age (p = 0.011) were significant, and multivariate logistic analysis demonstrated that an M-SMI of <5.5 was an independent predictor of sarcopenia (hazard ratio = 5.37, p < 0.001).ConclusionsM-SMI assessment in routine head and neck CT scans is feasible and can be an alternative for detecting sarcopenia in patients with HNC.
| S-EPMC8109770 | biostudies-literature
Project description:BackgroundIncreasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first-line maintenance treatment with capecitabine + bevacizumab (CAP-B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX-B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose-limiting toxicities (DLTs) during CAP-B and CAPOX-B.MethodsSarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs.ResultsOne hundred eighty-two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP-B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX-B. At the start of CAP-B and CAPOX-B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non-sarcopenic at the start of CAP-B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX-B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2 ). Sarcopenia at the start of CAP-B was not associated with DLTs [relative risk 0.87 (95% confidence interval 0.64-1.19)], whereas patients with >2% SMI loss had a significantly higher risk of DLTs [1.29 (1.01-1.66)]. At the start of subsequent CAPOX-B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss [1.78 (1.06-3.01)] or sarcopenia [1.75 (1.08-2.86)]. After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX-B [sarcopenia vs. non-sarcopenic: 0.86 (0.69-1.08) and SMI loss vs. stable/gain: 0.83 (0.65-1.07)]. In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs.ConclusionsIn this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.
| S-EPMC6711417 | biostudies-literature
Project description:We have previously reported that the expression of mitochondrial deacetylase SIRT3 is high in the slow oxidative muscle and that the expression of muscle SIRT3 level is increased by dietary restriction or exercise training. To explore the function of SIRT3 in skeletal muscle, we report here the establishment of a transgenic mouse model with muscle-specific expression of the murine SIRT3 short isoform (SIRT3M3). Calorimetry study revealed that the transgenic mice had increased energy expenditure and lower respiratory exchange rate (RER), indicating a shift towards lipid oxidation for fuel usage, compared to control mice. The transgenic mice exhibited better exercise performance on treadmills, running 45% further than control animals. Moreover, the transgenic mice displayed higher proportion of slow oxidative muscle fibers, with increased muscle AMPK activation and PPARδ expression, both of which are known regulators promoting type I muscle fiber specification. Surprisingly, transgenic expression of SIRT3M3 reduced muscle mass up to 30%, likely through an up-regulation of FOXO1 transcription factor and its downstream atrophy gene MuRF-1. In summary, these results suggest that SIRT3 regulates the formation of oxidative muscle fiber, improves muscle metabolic function, and reduces muscle mass, changes that mimic the effects of caloric restriction.
| S-EPMC3893254 | biostudies-literature
Project description:Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF-β-activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown. Here, we report that inducible inactivation of TAK1 causes severe muscle wasting, leading to kyphosis, in both young and adult mice.. Inactivation of TAK1 inhibits protein synthesis and induces proteolysis, potentially through upregulating the activity of the ubiquitin-proteasome system and autophagy. Phosphorylation and enzymatic activity of AMPK are increased, whereas levels of phosphorylated mTOR and p38 MAPK are diminished upon inducible inactivation of TAK1 in skeletal muscle. In addition, targeted inactivation of TAK1 leads to the accumulation of dysfunctional mitochondria and oxidative stress in skeletal muscle of adult mice. Inhibition of TAK1 does not attenuate denervation-induced muscle wasting in adult mice. Finally, TAK1 activity is highly upregulated during overload-induced skeletal muscle growth, and inactivation of TAK1 prevents myofiber hypertrophy in response to functional overload. Overall, our study demonstrates that TAK1 is a key regulator of skeletal muscle mass and oxidative metabolism.
| S-EPMC5821216 | biostudies-literature
Project description:ObjectiveTumor cachexia is an important prognostic parameter in epithelial ovarian cancer (EOC). Tumor cachexia is characterized by metabolic and inflammatory disturbances. These conditions might be reflected by body composition measurements (BCMs) ascertained by pre-operative computed tomography (CT). Thus, we aimed to identify the prognostically most relevant BCMs assessed by pre-operative CT in EOC patients.MethodsWe evaluated muscle BCMs and well established markers of nutritional and inflammatory status, as well as clinical-pathological parameters in 140 consecutive patients with EOC. Furthermore, a multiplexed inflammatory marker panel of 25 cytokines was used to determine the relationship of BCMs with inflammatory markers and patient's outcome. All relevant parameters were evaluated in uni- and multivariate survival analysis.ResultsMuscle attenuation (MA)-a well established BCM parameter-is an independent prognostic factor for survival in multivariate analysis (HR 2.25; p = 0.028). Low MA-reflecting a state of cachexia-is also associated with residual tumor after cytoreductive surgery (p = 0.046) and with an unfavorable performance status (p = 0.015). Moreover, MA is associated with Eotaxin and IL-10 out of the 25 cytokine multiplex marker panel in multivariate linear regression analysis (p = 0.021 and p = 0.047, respectively).ConclusionMA-ascertained by routine pre-operative CT-is an independent prognostic parameter in EOC patients. Low MA is associated with the inflammatory, as well as the nutritional component of cachexia. Therefore, the clinical value of pre-operative CT could be enhanced by the assessment of MA.
| S-EPMC4601693 | biostudies-literature
Project description:Cisplatin derivatives are used as the mainline treatment of ovarian cancer, despite their severe side effects and development of resistance. We developed a novel combination therapy by combining cisplatin with withaferin A. Treatment of ovarian cancer cell lines with combination therapy acted synergistically to induce cell death, thus required a lower dose of cisplatin to achieve the same therapeutic effect. WFA and cisplatin combination induced cell death through the generation of reactive oxygen species (ROS) for WFA, while DNA damage for cisplatin, suggesting that cisplatin binds directly to DNA to form adducts while WFA indirectly damages DNA through ROS generation. Our results for the first time suggest that combining low dose of cisplatin with suboptimal dose of WFA can serve as a potential combination therapy for the treatment of ovarian cancer with the potential to minimize/eliminate the side effects associated with high doses of cisplatin.
| S-EPMC3402232 | biostudies-literature
Project description:Low skeletal muscle mass is frequently observed in cancer patients and is known to be a poor prognostic factor for survival outcomes. The purposes of our study were to determine the prevalence of sarcopenia and its relation to mortality in biliary tract cancer. Body composition measurements (skeletal muscle index, total fat mass, bone mineral content) were evaluated by using dual-energy x-ray absorptiometry in 75 biliary tract cancer patients before chemotherapy. Muscle strength was measured by handgrip strength and gait speed. Overall survival and its associated factors were determined. The mean appendicular muscle mass was 17.8±2.7 kg in men and 14.0±2.1 kg in women (p < 0.05). Sarcopenia was diagnosed in 46 patients (61.3%) and higher proportion of men was classified as sarcopenia than women (69.0% vs 35.3%, p < 0.05). Multivariable analysis adjusted for chemotherapy regimen and age revealed that high appendicular muscle mass independently predicted better survival outcomes (HR 0.40; 95% CI, 0.18 to 0.88; p = 0.023). Sarcopenia is common in biliary tract cancer patients and low appendicular muscle mass was associated with poor survival outcome.
| S-EPMC6179280 | biostudies-literature
Project description:Although obesity has now been widely accepted to be an important risk factor for cancer survival, the associations between BMI and cancer mortality have not been consistently linear. Although morbid obesity has clearly been associated with worse survival, some studies have suggested a U-shaped association with no adverse association with overweight or lower levels of obesity. This 'obesity paradox' may be due to the fact that BMI likely incompletely captures key measures of body composition, including distribution of skeletal muscle and adipose tissue. Fat and lean body mass can be measured using clinically acquired computed tomography scans. Many of the earlier studies focused on patients with metastatic cancer. However, skeletal muscle loss in the metastatic setting may reflect end-stage disease processes. Therefore, this article focuses on the clinical implication of low skeletal muscle mass in early-stage non-metastatic breast and colorectal cancer where measures of body composition have been shown to be strong predictors of disease-free survival and overall survival and also chemotherapy toxicity and operative risk.
| S-EPMC6197885 | biostudies-literature