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Time-restricted feeding (TRF) is becoming a popular way of eating in physically active populations, despite a lack of research on metabolic and performance outcomes as they relate to the timing of food consumption in relation to the time of exercise. The purpose of this study was to determine if the timing of feeding/fasting after exercise training differently affects muscle metabolic flexibility and response to an acute bout of exercise. Male C57BL/6 mice were randomized to one of three groups for 8 weeks. The control had ad libitum access to food before and after exercise training. TRF-immediate had immediate access to food for 6 h following exercise training and the TRF-delayed group had access to food 5-h post exercise for 6 h. The timing of fasting did not impact performance in a run to fatigue despite TRF groups having lower hindlimb muscle mass. TRF-delayed had lower levels of muscle HSL mRNA expression and lower levels of PGC-1α expression but displayed no changes in electron transport chain enzymes. These results suggest that in young populations consuming a healthy diet and exercising, the timing of fasting may not substantially impact metabolic flexibility and running performance.

Cancer cachexia contributes to 30% of cancer-related deaths. There is currently no treatment or standard of care for cancer cachexia. Many nutritional interventions show promise for the treatment and or prevention of cachexia. Supplementation with omega-3 fatty acids, protein and vitamins either alone or in combination has shown some beneficial effects in the prevention and treatment of cancer cachexia. The mechanisms through which many nutritional interventions work to attenuate cachexia are just beginning to be understood. Therefore, the purpose of this review is to examine several nutritional strategies that have been investigated in the prevention and or treatment of cancer cachexia and provide evidence for the use of additional nutritional interventions to combat cachexia.

OBJECTIVES: Food intake and exercise are considered modulators of the immune system. Specifically, intermittent fasting protocols have been demonstrated to reduce inflammation and alter cytokine responses. The objective of the current study was to determine if a form of intermittent fasting known as time-restricted feeding (TRF) would alter immune parameters in response to exercise. METHODS: 8-week-old C57BL/6 male mice were divided into three groups based on feeding schedule; group one had access to food ad libitum (Control) and groups two and three had access to food in a time restricted manner. Access was allowed for six hours per day either immediately after running (TRF-imm) or six hours after running (TRF-del). Mice ran on a treadmill for 1 hour, 5 days per week for eight weeks. Diet consisted of 21% protein, 16% fat and 64% carbohydrate. Weight, glucose and ketone levels, and immune populations were analyzed. Systemic IL-6 and TNF-α levels were measured before and after running. In a subpopulation, cytokine response to lipopolysaccharides (LPS) was also monitored. RESULTS: All mice gained weight during the eight-week intervention, but TRF-imm gained significantly less weight than Control (P = 0.02). No differences were detected in glucose levels. The ketone body β-hydroxybutyrate (BHB) was significantly higher at week eight in TRF groups (P ≤ 0.03) but running induced BHB in all groups to approximately 1 mM. Running reduced the blood lymphocytes levels (P

Cancer cachexia, an unintentional body weight loss due to cancer, affects patients' survival, quality of life, and response to chemotherapy. Although exercise training is a promising intervention to prevent and treat cancer cachexia, our mechanistic understanding of cachexia's effect on contraction-induced muscle adaptation has been limited to the examination of male mice. Because sex can affect muscle regeneration and response to contraction in humans and mice, the effect of cachexia on the female response to eccentric contraction warrants further investigation. Purpose The purpose of this study was to determine whether high-frequency electric stimulation (HFES) could attenuate muscle mass loss during the progression of cancer cachexia in female tumor-bearing mice. Methods Female wild-type (WT) and Apc (Min) mice (16-18 wk old) performed either repeated bouts or a single bout of HFES (10 sets of 6 repetitions, ~22 min), which eccentrically contracts the tibialis anterior (TA) muscle. TA myofiber size, oxidative capacity, anabolic signaling, and catabolic signaling were examined. Results Min had reduced TA muscle mass and type IIa and type IIb fiber sizes compared with WT. HFES increased the muscle weight and the mean cross-sectional area of type IIa and type IIb fibers in WT and Min mice. HFES increased mTOR signaling and myofibrillar protein synthesis and attenuated cachexia-induced AMPK activity. HFES attenuated the cachexia-associated decrease in skeletal muscle oxidative capacity. Conclusion HFES in female mice can activate muscle protein synthesis through mTOR signaling and repeated bouts of contraction can attenuate cancer-induced muscle mass loss.

Natural rewards, such as food and social interaction, as well as drugs of abuse elicit increased mesolimbic dopamine release in the nucleus accumbens (NAc). Drugs of abuse, however, increase NAc dopamine release to a greater extent and are known to induce lasting changes on the functioning of the mesolimbic dopamine pathway. Less is known about the long-term effects of diet composition on this reward pathway. In the present study, two diets were compared: a higher-fat diet (Western Diet: WD) and a control diet (standard lab chow) on their effect on the mesolimbic dopamine system. Twenty male C57BL/6 J mice were placed on one of these diets at 7 weeks old. After twelve weeks on the diet, in vivo fixed potential amperometry was used to measure real-time stimulation-evoked dopamine release in the NAc of anesthetized mice before and after an i.p. injection of the dopamine transporter (DAT) inhibitor nomifensine. Results indicated that diet altered mesolimbic dopamine functioning. Mice that consumed the WD demonstrated a hypodopaminergic profile, specifically reduced baseline dopamine release and an attenuated dopaminergic response to DAT inhibition compared to the control diet group. Thus, diet may play a role in mediating dopamine-related behavior, disorders associated with dopamine dysfunction, and pharmacological treatments aimed at altering dopamine transmission.

// Aditi A. Narsale 1, * , Melissa J. Puppa 1, * , Justin P. Hardee 1, * , Brandon N. VanderVeen 1 , Reilly T. Enos 2 , E. Angela Murphy 2 , James A. Carson 1, 3 1 Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA 2 Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA 3 Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina, USA * These authors have contributed equally to this work Correspondence to: James A. Carson, email: carsonj@mailbox.sc.edu Keywords: hepatomegaly, muscle atrophy, protein turnover, inflammation, metabolism Received: March 04, 2016 Accepted: July 09, 2016 Published: July 19, 2016 ABSTRACT Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to Apc Min/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age Apc Min/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control Apc Min/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.

Deep brain stimulation (DBS) is associated with substantial improvements in motor symptoms of PD. Emerging evidence has suggested that nonlinear measures of complexity may provide greater insight into the efficacy of anti-PD treatments. This study investigated sample entropy and complexity index values in individuals with PD when DBS was OFF compared to ON. Five individuals with PD using DBS performed a four-minute treadmill walking task while 3D kinematics were collected over two periods of 30 s. Participants were tested in the DBS-ON and DBS-OFF conditions. Sample entropy (SE) and complexity index (CI) values were calculated for ankle, knee and hip joint angles. Paired samples t-tests were used to compare mean SE and CI values between the DBS-OFF and DBS-ON conditions, respectively. No differences in SE or CI were observed between the DBS-ON and DBS-OFF conditions at the ankle. At the knee, the DBS-ON was associated with greater SE and CI values than the DBS-OFF condition. At the hip, DBS-ON was associated with greater SE and CI values than the DBS-OFF condition. DBS enhances complexity of movement at the hip and knee joints while complexity at the ankle joint is not significantly altered. Greater complexity of knee and hip joint motion may represent increased adaptability and a greater number of available strategies to complete the gait task.

Background. The purpose of this study was to determine the effect of two clinically relevant radiation doses on the susceptibility of mouse skeletal muscle to remodeling. Materials and methods. Alterations in muscle morphology and regulatory signaling were examined in tibialis anterior and gastrocnemius muscles after radiation doses that differed in total biological effective dose (BED). Female C57BL/6 (8-wk) mice were randomly assigned to non-irradiated control, four fractionated doses of 4 Gy (4x4 Gy; BED 37 Gy), or a single 16 Gy dose (16 Gy; BED 100 Gy). Mice were sacrificed 2 weeks after the initial radiation exposure. Results. The 16 Gy, but not 4x4 Gy, decreased total muscle protein and RNA content. Related to muscle regeneration, both 16 Gy and 4x4 Gy increased the incidence of central nuclei containing myofibers, but only 16 Gy increased the extracellular matrix volume. However, only 4x4 Gy increased muscle 4-hydroxynonenal expression. While both 16 Gy and 4x4 Gy decreased IIB myofiber mean cross-sectional area (CSA), only 16 Gy decreased IIA myofiber CSA. 16 Gy increased the incidence of small diameter IIA and IIB myofibers, while 4x4 Gy only increased the incidence of small diameter IIB myofibers. Both treatments decreased the frequency and CSA of low succinate dehydrogenase activity (SDH) fibers. Only 16 Gy increased the incidence of small diameter myofibers having high SDH activity. Neither treatment altered muscle signaling related to protein turnover or oxidative metabolism. Conclusions. Collectively, these results demonstrate that radiation dose differentially affects muscle remodeling, and these effects appear to be related to fiber type and oxidative metabolism.

Time-restricted feeding (TRF), alternate day fasting (ADF), and the dietary restriction model known as the Daniel Fast (DF, a vegan/non-processed food diet plan) have garnered attention recently as nutritional interventions to combat obesity. We compared the effects of various dietary models on body composition, physical performance, and metabolic health in C57BL/6 mice. Sixty young C57BL/6 male mice were assigned a diet of TRF, ADF, DF, caloric restriction (CR), a high-fat Western diet (HF) fed ad libitum, or standard rodent chow for eight weeks. Their body composition, run time to exhaustion, fasting glucose, insulin, and glucose tolerance test area under the glucose curve (AUC) were determined. Compared to the HF group, all groups displayed significantly less weight and fat mass gain, as well as non-significant changes in fat-free mass. Additionally, although not statistically significant, all groups displayed greater run time to exhaustion relative to the HF group. Compared to the HF group, all groups demonstrated significantly lower fasting glucose, insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as well as improved glucose tolerance, and the ADF group displayed the best fasting glucose and glucose tolerance results, with DF having the best HOMA-IR. All investigated fasting protocols may improve body composition, measures of insulin sensitivity, and physical performance compared to a high-fat Western diet. The DF and ADF protocols are most favorable with regards to insulin sensitivity and glucose tolerance. Since our selected dietary protocols have also been investigated in humans with success, it is plausible to consider that these dietary models could prove beneficial to men and women seeking improved body composition and metabolic health.

Cachexia arises secondary to many chronic diseases and accounts for about 30% of cancer-related deaths. Cachexia occurs in both sexes, but its etiology and progression have been almost exclusively ...

Cachexia is a multifactorial syndrome characterized by the loss of peripheral tissue and hypertrophy of visceral organs. The ApcMin/+ mouse model develops an IL-6 dependent cachexia, leading to gradual loss of muscle and fat and hypertrophy of spleen and liver. The purpose of this study was to examine liver function related to protein synthesis and glycogen storage during the progression of cancer cachexia. Livers collected from non-cachectic and cachectic ApcMin/+ mice were analyzed for marker of protein synthesis (p38) and degradation/angiogenesis marker - MMP2 protein expression. Liver glycogen content was examined by PAS staining intensity. The role of cachexia related inflammation on liver metabolism was studied by 10mg/kg/day administration of PDTC, a STAT3 and NF-ΚB inhibitor, for 2 weeks. As cachexia progressed there was suppression of Akt and p38 phosphorylation, and a reduction in liver glycogen content. MMP2 expression was also decreased 97% with severe cachexia. PDTC administration during seve...

Cancer cachexia is a devastating consequence of cancer. A multifactorial syndrome characterized by skeletal muscle and adipose tissue wasting, cachexia cannot be fully reversed by nutritional support. Cachexia occurs in up to one half of all cancer patients and correlates with poor performance status, reduced quality of life and high mortality. Cachexia results both from the tumor-host interaction, as well as from the anti-cancer therapies. The only cure for cachexia is definitive removal of the tumor. In ovarian cancer, cachexia is associated with malnutrition and a general inflammatory state, characterized by high levels of pro-inflammatory cytokines (such as IL-6, TNF) in ascites and blood. Due to the absence of proper experimental models, cachexia also represents a generally understudied aspect of ovarian cancer that deserves more attention. In order to establish novel experimental models for the study of ovarian cancer cachexia, we tested several human ovarian cancer cell lines with different degrees of differentiation for their capability to induce cachexia in vivo and muscle wasting in vitro. In a xenograft model, female Nu/Nu athymic nude mice were injected i.p. with 10x106 OVCAR-3, SK-OV-3 and ES-2 human ovarian cancer cells to mimic disseminated abdominal disease. After 60 days, the OVCAR-3 and SK-OV-3 cell lines did not result in detectable tumors. In contrast, beginning 8 days after inoculation, ES-2 cells caused severe cachexia with marked loss of body weight and with massive ascites accumulation in the peritoneal cavity. Within the ascites, ES-2 cells were not shown to aggregate, but existed more as a single-cell suspension or very small cell clumps. Some ES-2 cells also disseminated and infiltrated the pancreas, diaphragm and other organs, forming multiple solid tumors of histology consistent with clear cell carcinoma, characterized by sheets of cells with irregularly shaped nuclei and abundant cytoplasm. Muscles, including tibialis, gastrocnemius, quadriceps and heart, of tumor-bearing mice appeared markedly smaller than normal controls (~-20% vs. control; p In order to understand whether tumor-derived factors were directly responsible for the wasting effects observed in vivo, differentiated C2C12 murine myotubes were exposed to conditioned medium from ES-2 cell cultures and evaluated for effects on myotube size. After 48 hours, the average diameter of C2C12 myofibers was severely reduced (-28% vs. control; p In conclusion, here we report that ES-2 tumor cells directly induce muscle atrophy, both in vitro and in vivo. Thus this is a new experimental model for the study of ovarian cancer cachexia. This model and future similar models will aid in identifying novel molecular mediators that could be effectively targeted in order to improve muscle wasting associated with ovarian cancer. Citation Format: Andrea Bonetto, Melissa J. Puppa, James A. Carson, Teresa A. Zimmers. The ES-2 ovarian cancer causes muscle wasting in vitro and in vivo: A novel experimental model of cancer cachexia. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A6.

Background Cachexia involves unintentional body weight loss including diminished muscle and adipose tissue mass and is associated with an underlying disease. Systemic overexpression of IL-6 accelerates cachexia in the ApcMin/+ mouse, but does not induce wasting in control C57BL/6 mice. With many chronic diseases, chronic inflammation and metabolic dysfunction can be improved with moderate exercise. A direct effect of regular moderate exercise on the prevention of IL-6-induced cachexia in the ApcMin/+ mouse has not been investigated. The purpose of this study was to assess the effects of exercise on the development of cachexia in the ApcMin/+ mouse. Methods Mice were randomly assigned to moderate treadmill exercise (18 m/min, 1 h, 6 days/week, 5% grade) or cage control (CC) groups from 6 to 14 weeks of age. At 12 weeks of age, mice were electroporated with either IL-6-containing or control plasmid into the quadriceps muscle. Mice were killed after 2 weeks of systemic IL-6 overexpression or control treatment. Results IL-6 overexpression induced an 8% loss in body weight in CC mice, which was significantly attenuated by exercise. IL-6 overexpression in CC mice increased fasting insulin and triglyceride levels, which were normalized by exercise, and associated with increased oxidative capacity, an induction of AKT signaling, and a repression of AMPK signaling in muscle. These exercise-induced changes occurred despite elevated inflammatory signaling in skeletal muscle. Conclusion We conclude that moderate-intensity exercise can attenuate IL-6-dependent cachexia in ApcMin/+ mice, independent of changes in IL-6 concentration and muscle inflammatory signaling. The exercise effect was associated with improved insulin sensitivity and improved energy status in the muscle.