High-Frequency Stimulation on Skeletal Muscle Maintenance in Female Cachectic Mice.

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.

Dietary selenium protects adiponectin knockout mice against chronic inflammation induced colon cancer.

Selenium (Se) is an essential dietary micronutrient that has been examined for protection against different types of cancers including colon cancer. Despite an established inverse association between Se and chronic inflammation induced colon cancer (CICC), the mechanistic understanding of Se's protective effects requires additional in-vivo studies using preclinical animal models of CICC. Adiponectin (APN) is an adipocytokine that is protective against CICC as well. However, its role in the anti-mutagenic effects of the Se-diet remains unknown. To address this knowledge gap, here we examine the ability of dietary Se in reducing CICC in APN knockout mice (KO) and its wild-type C57BL/6. CICC was induced with the colon cancer agent 1,2 dimethyl hydrazine (DMH) along with dextran sodium sulfate (DSS). Se-enhanced diet increased selenoproteins, Gpx-1 and Gpx-2, in the colon tissues, thereby reducing oxidative stress. Se-mediated reduction of CICC was evident from the histopathological studies in both mouse models. In both mice, reduction in inflammation and tumorigenesis associated well with reduced p65 phosphorylation and elevated 53 phosphorylation. Finally, we show that in both models Se-administration promotes goblet cell differentiation with a concomitant increase in the levels of associated proteins, Muc-2 and Math-1. Our findings suggest that Se's protection against CICC involves both colonic epithelial protection and anti-tumor effects that are independent of APN.

Quercetin supplementation attenuates the progression of cancer cachexia in ApcMin/+ mice.

Although there are currently no approved treatments for cancer cachexia, there is an intensified interest in developing therapies because of the high mortality index associated with muscle wasting diseases. Successful treatment of the cachectic patient focuses on improving or maintaining body weight and musculoskeletal function. Nutraceutical compounds, including the natural phytochemical quercetin, are being examined as potential treatments because of their anti-inflammatory, antioxidant, and anticarcinogenic properties. The purpose of this study was to determine the effect of quercetin supplementation on the progression of cachexia in the adenomatous polyposis coli (Apc)(Min/+) mouse model of colorectal cancer. At 15 wk of age, C57BL/6 and male Apc(Min/+) mice were supplemented with 25 mg/kg of quercetin or vehicle solution mix of Tang juice and water (V) daily for 3 wk. Body weight, strength, neuromuscular performance, and fatigue were assessed before and after quercetin or V interventions. Indicators of metabolic dysfunction and inflammatory signaling were also assessed. During the treatment period, the relative decrease in body weight in the Apc(Min/+) mice gavaged with V (Apc(Min/+)V; -14% ± 2.3) was higher than in control mice gavaged with V (+0.6% ± 1.0), control mice gavaged with quercetin (-2% ± 1.0), and Apc(Min/+) mice gavaged with quercetin (Apc(Min/+)Q; -9% ± 1.3). At 18 wk of age, the loss of grip strength and muscle mass shown in Apc(Min/+)V mice was significantly attenuated (P < 0.05) in Apc(Min/+)Q mice. Furthermore, Apc(Min/+)V mice had an induction of plasma interleukin-6 and muscle signal transducer and activator of transcription 3 phosphorylation, which were significantly (P < 0.05) mitigated in Apc(Min/+)Q mice, despite having a similar tumor burden. Quercetin treatment did not improve treadmill run-time-to-fatigue, hyperglycemia, or hyperlipidemia in cachectic Apc(Min/+) mice. Overall, quercetin supplementation positively affected several aspects of cachexia progression in mice and warrants further exploration as a potential anticachectic therapeutic.

Cachectic skeletal muscle response to a novel bout of low-frequency stimulation.

While exercise benefits have been well documented in patients with chronic diseases, the mechanistic understanding of cachectic muscle's response to contraction is essentially unknown. We previously demonstrated that treadmill exercise training attenuates the initiation of cancer cachexia and the development of metabolic syndrome symptoms (Puppa MJ, White JP, Velazquez KT, Baltgalvis KA, Sato S, Baynes JW, Carson JA. J Cachexia Sarcopenia Muscle 3: 117-137, 2012). However, cachectic muscle's metabolic signaling response to a novel, acute bout of low-frequency contraction has not been determined. The purpose of this study was to determine whether severe cancer cachexia disrupts the acute contraction-induced response to low-frequency muscle contraction [low-frequency stimulation (LoFS)]. Metabolic gene expression and signaling was examined 3 h after a novel 30-min bout of contraction (10 Hz) in cachectic Apc(Min/+) (Min) and C57BL/6 (BL-6) mice. Pyrrolidine dithiocarbamate, a STAT/NF-κB inhibitor and free radical scavenger, was administered systemically to a subset of mice to determine whether this altered the muscle contraction response. Although glucose transporter-4 mRNA was decreased by cachexia, LoFS increased muscle glucose transporter-4 mRNA in both BL-6 and Min mice. LoFS also induced muscle peroxisome proliferator-activated receptor-γ and peroxisome proliferator-activated receptor-α coactivator-1 mRNA. However, in Min mice, LoFS was not able to induce muscle proliferator-activated receptor-α coactivator-1 targets nuclear respiratory factor-1 and mitochondrial transcription factor A mRNA. LoFS induced phosphorylated-S6 in BL-6 mice, but this induction was blocked by cachexia. Administration of pyrrolidine dithiocarbamate for 24 h rescued LoFS-induced phosphorylated-S6 in cachectic muscle. LoFS increased muscle phosphorylated-AMP-activated protein kinase and p38 in BL-6 and Min mice. These data demonstrate that cachexia alters the muscle metabolic response to acute LoFS, and combination therapies in concert with muscle contraction may be beneficial for improving muscle mass and function during cachexia.

Differential release of corticotropin-releasing hormone (CRH) in the amygdala during different types of stressors.

The purpose of this study was to determine if differences exist between the effects of acute treadmill running and restraint stress on corticotropin-releasing hormone (CRH) release within the amygdala of rats. Extracellular CRH immunoreactivity (CRH-IR) was measured in microdialysate collected from the central nucleus of the amygdala (CeA) during exposure to an inactivated treadmill (TC), during 1 h treadmill running to exhaustion (RUN), and 1 h restraint (RES). Extracellular CRH-IR increased from control levels during the first 20-min period for TC, RUN, and RES, with the largest increase during RES. During the second 20-min period, only RES maintained levels higher than control values. CRH release was higher than control during the third 20-min period of RES and RUN. A second experiment consisted of four groups of either cage controls (CC), TC, RUN, or RES. Immediately following the 60-min treatment, brains were removed and trunk blood collected for analysis of tissue CRH-IR and plasma corticosterone. While amygdala tissue CRH-IR was not different in the CC, TC and RUN rats, these groups had significantly lower levels than the RES animals. Hypothalamic tissue CRH-IR was not different between the CC and TC rats, but the levels were significantly higher in the RES and RUN rats than in the two control groups. Plasma corticosterone levels were elevated only in RES and RUN rats. Results from tissue analysis indicate that increased tissue CRH-IR in the amygdala and hypothalamus can be elicited by RES, while only the hypothalamus shows an increase following RUN. Further, extracellular CRH release in the CeA is increased throughout the period of RES, when rats are placed on the treadmill, and when the animals are approaching physical exhaustion. No increase is observed during the running period between placement on the treadmill and intense exertion. Overall, the data suggest that amygdala CRH release is regulated differently during treadmill running and restraint.