From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia.

PURPOSE OF REVIEW: Cancer cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here, we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers and potential therapies. RECENT FINDINGS: Both in mice and humans, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in precachexia. Inflammatory pathways, mitochondrial dysfunction and gut microbiota have recently been studied to play an important role in muscle fatigue in preclinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue. SUMMARY: Heightened inflammation within muscle, altered muscle function and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

Social Support, Insomnia, and Adherence to Cognitive Behavioral Therapy for Insomnia After Cancer Treatment.

OBJECTIVE/BACKGROUND: While cognitive-behavioral therapy for insomnia (CBT-I) has been shown to be efficacious in treating cancer survivors' insomnia, 30-60% of individuals have difficulty adhering to intervention components. Psychosocial predictors of adherence and response to CBT-I, such as social support, have not been examined in intervention studies for cancer survivors. PARTICIPANTS: Data from a randomized placebo-controlled 2 x 2 trial of CBT-I and armodafinil (a wakefulness promoting agent) were used to assess adherence. Ninety-six cancer survivors participated in the trial (mean age 56, 86% female, 68% breast cancer). METHODS: CBT-I and armodafinil were administered over the course of seven weeks, and participants were assessed at baseline, during intervention, postintervention, and at a three-month follow-up. Social support was assessed using a Functional Assessment of Chronic Illness Therapy subscale, insomnia severity was assessed using the Insomnia Severity Index, and adherence was measured based on CBT-I sleep prescriptions. RESULTS: At baseline, social support was negatively correlated with insomnia severity (r = -0.30, p = 0.002) and associations between social support, CBT-I, and insomnia were maintained through the three-month follow-up. Social support was positively associated with adherence to CBT-I during intervention weeks 3, 4, and 5, and with overall intervention adherence. At postintervention, both social support and treatment with CBT-I independently predicted decreased insomnia severity (p < 0.01) when controlling for baseline insomnia severity. CONCLUSIONS: Higher social support is associated with better intervention adherence and improved sleep independent of CBT-I. Additional research is needed to determine whether social support can be leveraged to improve adherence and response to CBT-I.

Yoga for the Management of Cancer Treatment-Related Toxicities.

PURPOSE OF REVIEW: To (1) explain what yoga is, (2) summarize published literature on the efficacy of yoga for managing cancer treatment-related toxicities, (3) provide clinical recommendations on the use of yoga for oncology professionals, and (4) suggest promising areas for future research. RECENT FINDINGS: Based on a total of 24 phase II and one phase III clinical trials, low-intensity forms of yoga, specifically gentle hatha and restorative, are feasible, safe, and effective for treating sleep disruption, cancer-related fatigue, cognitive impairment, psychosocial distress, and musculoskeletal symptoms in cancer patients receiving chemotherapy and radiation and cancer survivors. Clinicians should consider prescribing yoga for their patients suffering with these toxicities by referring them to qualified yoga professionals. More definitive phase III clinical trials are needed to confirm these findings and to investigate other types, doses, and delivery modes of yoga for treating cancer-related toxicities in patients and survivors.

Influence of obesity assessments on cardiometabolic risks in African and European American women.

OBJECTIVES: African American women (AAW) have increased odds of developing cardiometabolic (CME) risks and cardiovascular diseases (CVD) compared with European American women (EAW). The influence of obesity on other CME risks and the CVD disparity is unclear. The purpose of our study was to develop a CME index and evaluate the obesity and CME risk index relationships based on race. DESIGN: A comparative research design was employed in our study as 213 women (132 AAW; 81 EAW) from the Louisiana Delta were evaluated for CME risk clustering patterns by race, based on BMI, dual energy X-ray absorptiometry % body fat and waist conference. Fasting glucose, triglyceride (TC), high density lipoprotein cholesterol (HDL-C), systolic (SBP) and diastolic blood pressure (DBP) were the measured CME risks. FINDINGS: In summary, when the CME indexes were evaluated by obesity classification categories the ones that were CVD risk or near risk for the AAW were SBP and TG. The trend of CME index risk for the EAW was SBP and glucose. The stepwise regression equations indicate that HDL-C and SBP/DBP were the best indicators of the effects of obesity on CME risks in AAW and that SBP/DBP and glucose were the best indicators of CME risks in EAW. CONCLUSIONS: Our results indicate that CME risks as evaluated based on obesity categories are different for AAW than for EAW.

Validation of dual energy X-ray absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma.

Noninvasive imaging is central to preclinical, in vivo models of pancreatic ductal adenocarcinoma (PDAC). While bioluminescent imaging (BLI) is a gold standard, its signal is dependent on the metabolic activity of tumor cells. In contrast, dual energy X-ray absorptiometry (DEXA) is a direct measure of body composition. Thus, we aimed to assess its potential for longitudinal quantification of tumor burden versus BLI. We utilized the KCKO murine model of PDAC and subjected tumor-bearing (n = 20) and non-tumor control (NTC) (n = 10) animals to weekly BLI and DEXA measurements for up to 10 weeks. While BLI detected tumors at 1-week, it failed to detect tumor growth, displayed a decreasing trend overtime (slope = -9.0x108; p = 0.0028), and terminal signal did not correlate with ex vivo tumor mass (r = 0.01853; p = 0.6286). In contrast, DEXA did not detect elevated changes in abdominal cavity lean mass until week 2 post inoculation and tumors were not visible until week 3, but successfully quantified a tumor growth trend (slope = 0.7322; p<0.0001), and strongly correlated with final tumor mass (r = 0.9351; p<0.0001). These findings support the use of BLI for initial tumor engraftment and persistence but demonstrate the superiority of DEXA for longitudinal tumor burden studies. As tumor detection by DEXA is not restricted to luciferase expressing models, future studies to assess its value in various cancer models and as an in vivo outcome measure of treatment efficacy are warranted.

Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

Validation of Dual Energy X-ray Absorptiometry for longitudinal quantification of tumor burden in a murine model of pancreatic ductal adenocarcinoma.

Noninvasive imaging is central to preclinical, in vivo models of pancreatic ductal adenocarcinoma (PDAC). While bioluminescent imaging (BLI) is a gold standard, its signal is dependent on the metabolic activity of tumor cells. In contrast, dual energy X-ray absorptiometry (DEXA) is a direct measure of body composition. Thus, we aimed to assess its potential for longitudinal quantification of tumor burden versus BLI. We utilized the KCKO murine model of PDAC and subjected tumor-bearing (n = 20) and non-tumor control (NTC) (n = 10) animals to weekly BLI and DEXA measurements for up to 10 weeks. While BLI detected tumors at 1-week, it failed to detect tumor growth, displayed a decreasing trend overtime (slope = -9.0×108; p = 0.0028), and terminal signal did not correlate with ex vivo tumor mass (r = 0.01853; p = 0.6286). In contrast, DEXA did not detect elevated changes in abdominal cavity lean mass until week 2 post inoculation and tumors were not visible until week 3, but successfully quantified a tumor growth trend (slope = 0.7322; p<0.0001), and strongly correlated with final tumor mass (r = 0.9351; p<0.0001). These findings support the use of BLI for initial tumor engraftment and persistence but demonstrate the superiority of DEXA for longitudinal tumor burden studies. As tumor detection by DEXA is not restricted to luciferase expressing models, future studies to assess its value in various cancer models and as an in vivo outcome measure of treatment efficacy are warranted.

Implementation of automated behavior metrics to evaluate voluntary wheel running effects on inflammatory-erosive arthritis and interstitial lung disease in TNF-Tg mice.

BACKGROUND: Although treatment options and algorithms for rheumatoid arthritis (RA) have improved remarkably in recent decades, there continues to be no definitive cure or pharmacologic intervention with reliable long-term efficacy. For this reason, the combination of medications and healthy lifestyle modifications are essential for controlling joint disease, and extra-articular manifestations of RA, such as interstitial lung disease (ILD) and other lung pathologies, which greatly impact morbidity and mortality. Generally, exercise has been deemed beneficial in RA patients, and both patients and clinicians are motivated to incorporate effective non-pharmacologic interventions. However, there are limited evidence-based and specific exercise regimens available to support engagement in such activities for RA patients. Here, we provided the continuous opportunity for exercise to mice and implemented automated recording and quantification of wheel running behavior. This allowed us to describe the associated effects on the progression of inflammatory-erosive arthritis and ILD in the tumor necrosis factor transgenic (TNF-Tg) mouse model of RA. METHODS: Wild-type (WT; males, n=9; females, n=9) and TNF-Tg (males, n=12; females, n=14) mice were singly housed with free access to a running wheel starting at 2 months until 5 to 5.5 months of age. Measures of running included distance, rate, length, and number of run bouts, which were derived from continuously recorded data streams collected automatically and in real-time. In vivo lung, ankle, and knee micro-computed tomography (micro-CT), along with terminal micro-CT and histology were performed to examine the association of running behaviors and disease progression relative to sedentary controls. RESULTS: TNF-Tg males and females exhibited significantly reduced running distance, rate, length, and number of run bouts compared to WT counterparts by 5 months of age (p<0.0001). Compared to sedentary controls, running males and females showed increased aerated lung volumes (p<0.05) that were positively correlated with running distance and rate in female mice (WT: Distance, ρ=0.705/rate, ρ=0.693 (p<0.01); TNF-Tg: ρ=0.380 (p=0.06)/ρ=0.403 (p<0.05)). Talus bone volumes were significantly reduced in running versus sedentary males and negatively correlated with running distance and rate in TNF-Tg mice (male: ρ=-903/ρ=-0.865; female: ρ=-0.614/ρ=-0.594 (p<0.001)). Histopathology validated the lung and ankle micro-CT findings. CONCLUSIONS: Implementation of automated wheel running behavior metrics allows for evaluation of longitudinal activity modifications hands-off and in real-time to relate with biomarkers of disease severity. Through such analysis, we determined that wheel running activity increases aerated lung volumes, but exacerbates inflammatory-erosive arthritis in TNF-Tg mice. To the end of a clinically relevant model, additional functional assessment of these outcomes and studies of pain behavior are warranted.

Glutathione supports lipid abundance in vivo.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

Increased myocellular lipid and IGFBP-3 expression in a pre-clinical model of pancreatic cancer-related skeletal muscle wasting.

BACKGROUND: Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model. METHODS: Female C57BL/6J mice 6-8 weeks of age underwent orthotopic injection with KCKO-luc tumour cells. Solid tumour was verified on Day 5, post-tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual-energy X-ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of 'failure to thrive'. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction. RESULTS: We found a strong correlation between primary tumour size and survival (r2  = 0.83, P < 0.0001). A significant decrease in lower limb lean mass was first detected at Day 38 post-implantation vs. no tumour controls (NTCs) (P < 0.0001). SMW was confirmed by histology, which demonstrated a 38%, 32.7%, and 39.9% decrease in fibre size of extensor digitorum longus, soleus, and tibialis anterior muscles, respectively, in PDAC mice vs. NTC (P < 0.002). Histology also revealed a 67.6% increase in haematopoietic cells within the muscle of PDAC mice when compared with NTC. Bulk RNAseq on muscles from PDAC mice vs. NTC revealed significant increases in c/ebpß/Δ, il-1, il-6, and tnf gene expression. Pathway analyses to identify potential upstream factors revealed increased adipogenic gene expression, including a four-fold increase in igfbp-3. Histomorphometry of Oil Red-O staining for fat content in tibialis anterior muscles demonstrated a 95.5% increase in positively stained fibres from PDAC mice vs. NTC. CONCLUSIONS: Together, these findings support a novel model of PDAC-associated SMW and mortality in which systemic inflammation leads to inflammatory cell infiltration into skeletal muscle with up-regulated myocellular lipids.

Use of Fitbit Data to Evaluate the Effects of an Athletic Performance and Injury Prevention Training Program on Daily Physical Levels in Underrepresented Minority Female High School Athletes: A Prospective Study.

A marginal number of adolescents meet the recommended guidelines of 60 minutes of moderate to vigorous daily physical activity, and even fewer underrepresented minority females achieve this metric as compared to their male and white counterparts. While potential interventions exist to address these low levels of activity, which is a known risk for acute injuries and chronic disease, there is lack of consensus on the devices used to measure the intensity of daily activity levels. Wearable activity trackers such as Fitbit™ have been utilized to quantify human motion and exercise intensity, but there is little precedence for these measures being assessed in adolescent wearers. Thus, our objective was to assess the feasibility of using Fitbit to assess daily physical activity levels in underrepresented minority adolescent females, who attend an economically challenged urban high school, over the course of a physical activity intervention. We also aimed to identify candidate Fitbit outcome measures for future prospective studies. A 10-week physical activity intervention was implemented in a cohort of 24 high school female athletes. From within this cohort, a sample of five students were provided Fitbit™ devices, from which we obtained data sets from three students. Activity on the days of the exercise intervention was measured and compared to activity on non-intervention days. Post-hoc assessments were performed based on individual heart rate reserves, the predefined levels set by the Inspire Fitbit™ device and the American College of Sports Medicine (ACSM) 2009 guidelines. The results showed that while compliance is challenging, wearable devices can be used to assess daily physical activity levels and intensities in underrepresented minority high school female athletes during an extended physical activity intervention. Of the Fitbit outcomes currently available, assessment of moderate-vigorous activity (min/day) appeared to be the best as a measure of global physical activity. Prospective research is now warranted to validate these thresholds, and to test novel interventions for their ability to transition inactive adolescents at risk of sports-related injuries and long-term chronic disease, into a more active lifestyle.

Dual Energy X-ray Absorptiometry (DEXA) as a longitudinal outcome measure of cancer-related muscle wasting in mice.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its associated skeletal muscle wasting (SMW) and mortality. Currently, the relationships between PDAC, SMW, and survival are poorly understood. Thus, there is great need for a faithful small animal model with quantitative longitudinal outcome measures that recapitulate clinical PDAC, to define SMW onset and assess progression. Therefore, we aimed to validate dual energy X-ray absorptiometry (DEXA) as a longitudinal measure of lean mass, and demonstrate its utility to quantify SMW in the KCKO murine model of PDAC. METHODS: In vivo body composition of: 1) untreated mice at 5, 8, 12, 18, and 22 weeks of age (n = 4) and 2) a cohort of mice with (n = 5) and without PDAC (n = 5), was determined via DEXA and lean mass of the lower hind limbs was predicted via a region of interest analysis by two-independent observers. Total body weight was determined. Tibialis anterior (TA) muscles were weighed and processed for histomorphometry immediately post-mortem. Statistical differences between groups were assessed using ANOVA and Student's t-tests. Linear regression models and correlation analysis were used to measure the association between TA and DEXA mass, and reproducibility of DEXA was quantified via the intraclass correlation coefficient (ICC). RESULTS: Lean mass in growing untreated mice determined by DEXA correlated with TA mass (r2 = 0.94; p <0.0001) and body weight (r2 = 0.89; p <0.0001). DEXA measurements were highly reproducible between observers (ICC = 0.95; 95% CI: 0.89-0.98). DEXA and TA mass also correlated in the PDAC cohort (r2 = 0.76; p <0.0001). Significant SMW in tumor-bearing mice was detected within 38 days of implantation, by DEXA, TA mass, and histomorphometry. CONCLUSIONS: DEXA is a longitudinal outcome measure of lean mass in mice. The KCKO syngeneic model is a bona fide model of PDAC associated SMW that can be quantified with longitudinal DEXA.

Use of PROMIS and Functional Movement System (FMS) Testing to Evaluate the Effects of Athletic Performance and Injury Prevention Training in Female High School Athletes.

Two major health concerns with female high school athletes are: 1) psychosocial wellness, and 2) sports-related injuries. It is also known that these health concerns are much greater for minority students who attend high school in economically depressed cities. While it has been well-established that exercise is an effective intervention for these health concerns, there are no established outcome measures to quantitatively assess athletic performance and injury prevention training interventions in this population. Previously, we have demonstrated the utility of Patient-Reported Outcomes Measurement Information System (PROMIS) as a robust outcome measure following ACL reconstruction. Functional Movement Screening (FMS) has been used as a tool to determine injury risk in female collegiate athletes. Since these tools are broadly available, we completed a research study of urban underrepresented minority and suburban female high school athletes, to assess the feasibility and utility of these tools to measure changes in this population during 10-weeks of athletic training. No adverse events of the training or study were reported. A Kaplan-Meier assessment of the data revealed that there was high student retention throughout the 10 weeks. In addition, we found no difference in weekly attendance between the students that completed the intervention vs. the dropouts (while they were in the program), indicating that the students were highly motivated to attend when possible. While no significant differences were found for fatigue and physical function, the intervention significantly improved anxiety, peer relationships, pain interference, and trended towards significance for depression (p<0.05). In terms of physical performance, bench press, combined Pro Agility, and total FMS were all significantly improved (p<0.05). Surprisingly, there were 10 students (67%) in peril of sports- related injury (FM˂14) at the start of the intervention, and all but 1 (90%) eliminated this serious risk factor. Collectively, these results demonstrate the feasibility of PROMIS and FMS outcomes to assess the efficacy of physical training interventions, in underrepresented minority female high school students, which warrants investigation in a formal prospective study.

The Role of Systemic Inflammation in Cancer-Associated Muscle Wasting and Rationale for Exercise as a Therapeutic Intervention.

Progressive skeletal muscle wasting in cancer cachexia involves a process of dysregulated protein synthesis and breakdown. This catabolism may be the result of mal-nutrition, and an upregulation of both pro-inflammatory cytokines and the ubiquitin proteasome pathway (UPP), which can subsequently increase myostatin and activin A release. The skeletal muscle wasting associated with cancer cachexia is clinically significant, it can contribute to treatment toxicity or the premature discontinuation of treatments resulting in increases in morbidity and mortality. Thus, there is a need for further investigation into the pathophysiology of muscle wasting in cancer cachexia to develop effective prophylactic and therapeutic interventions. Several studies have identified a central role for chronic-systemic inflammation in initiating and perpetuating muscle wasting in patients with cancer. Interestingly, while exercise has shown efficacy in improving muscle quality, only recently have investigators begun to assess the impact that exercise has on chronic-systemic inflammation. To put this new information into context with established paradigms, here we review several biological pathways (e.g. dysfunctional inflammatory response, hypothalamus pituitary adrenal axis, and increased myostatin/activin A activity) that may be responsible for the muscle wasting in patients with cancer. Additionally, we discuss the potential impact that exercise has on these pathways in the treatment of cancer-related muscle wasting. Exercise is an attractive intervention for muscle wasting in this population, partially because it disrupts chronic-systemic inflammation mediated catabolism. Most importantly, exercise is a potent stimulator of muscle synthesis, and therefore this therapy may reverse muscle damage caused by cancer cachexia.

Research priorities in cancer cachexia: The University of Rochester Cancer Center NCI Community Oncology Research Program Research Base Symposium on Cancer Cachexia and Sarcopenia.

PURPOSE OF REVIEW: Cancer cachexia remains understudied and there are no standard treatments available despite the publication of an international consensus definition and the completion of several large phase III intervention trials in the past 6 years. In September 2015, The University of Rochester Cancer Center NCORP Research Base led a Symposium on Cancer Cachexia and Sarcopenia with goals of reviewing the state of the science, identifying knowledge gaps, and formulating research priorities in cancer cachexia through active discussion and consensus. RECENT FINDINGS: Research priorities that emerged from the discussion included the implementation of morphometrics into clinical decision making, establishing specific diagnostic criteria for the stages of cachexia, expanding patient selection in intervention trials, identifying clinically meaningful trial endpoints, and the investigation of exercise as an intervention for cancer cachexia. SUMMARY: Standardizing how we define and measure cancer cachexia, targeting its complex biologic mechanisms, enrolling patients early in their disease course, and evaluating exercise, either alone or in combination, were proposed as initiatives that may ultimately result in the improved design of cancer cachexia therapeutic trials.

Exercise Recommendations for the Management of Symptoms Clusters Resulting From Cancer and Cancer Treatments.

OBJECTIVE: To review existing exercise guidelines for cancer patients and survivors for the management of symptom clusters. DATA SOURCES: Review of PubMed literature and published exercise guidelines. CONCLUSION: Cancer and its treatments are responsible for a copious number of incapacitating symptoms that markedly impair quality of life. The exercise oncology literature provides consistent support for the safety and efficacy of exercise interventions in managing cancer- and treatment-related symptoms, as well as improving quality of life in cancer patients and survivors. IMPLICATIONS FOR NURSING PRACTICE: Effective management of symptoms enhances recovery, resumption of normal life activities and quality of life for patients and survivors. Exercise is a safe, appropriate, and effective therapeutic option before, during, and after the completion of treatment for alleviating symptoms and symptom clusters.