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Purpose:This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer–induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with breast cancer experiencing muscle fatigue.Experimental Design:Eight female BC-PDOX–bearing mice were produced via transplantation of tumor tissue from 8 female patients with breast cancer. Individual hind limb muscles from BC-PDOX mice were isolated at euthanasia for RNA-sequencing, gene and protein analyses, and an ex vivo muscle contraction protocol to quantify tumor-induced aberrations in SkM function. Differentially expressed genes (DEG) in the BC-PDOX mice relative to control mice were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs.Results:We found that SkM from BC-PDOX–bearing mice showed greater fatigability than control mice, despite no differences in absolute muscle mass. PPAR, mTOR, IL6, IL1, and several other signaling pathways were implicated in the transcriptional changes observed in the BC-PDOX SkM. Moreover, 3 independent in silico analyses identified PPAR signaling as highly dysregulated in the SkM of both BC-PDOX–bearing mice and human patients with early-stage nonmetastatic breast cancer.Conclusions:Collectively, these data demonstrate that the BC-PDOX model recapitulates the expected breast cancer–induced SkM fatigue and further identify aberrant PPAR signaling as an integral factor in the pathology of this condition.

Table S3 shows data for correlational analyses between muscle contractile parameters and STAT activation

Figure S1 shows additional data from Enrichr in silico analyses, and protein analyses of STAT 3 and STAT5.

Supplemental legend

A hippocampus-specific IL15RαKO mouse (hipIl15ra fl/fl /Cre+) was generated to test the hypothesis that the targeted deletion of interleukin-15 receptor alpha (IL-15Rα) in the hippocampus contributes to altered behavior, including greater levels of anxiety and ambulatory activity. Using Cre-loxP, exons 2 and 3 of the IL-15Rα gene were excised within the hippocampus, while normal expression was maintained within the rest of the brain. In the open field test (OFT), hipIl15ra fl/fl /Cre+ spent a greater amount of time in the periphery and less time in the central portions of the chamber, and there was also a noticeable trend for decreased rearing activity; these behaviors are consistent with greater levels of anxiety-like behavior in these mice. However, there were no differences in the overall locomotor counts in the OFT when comparing hipIl15ra fl/fl /Cre+ mice to their littermate controls. These data implicate IL-15-related signaling within the hippocampus has a role in anxiety-like behavior.

Purpose: This study tested the hypothesis that a patient-derived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer–induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with breast cancer experiencing muscle fatigue. Experimental Design: Eight female BC-PDOX–bearing mice were produced via transplantation of tumor tissue from 8 female patients with breast cancer. Individual hind limb muscles from BC-PDOX mice were isolated at euthanasia for RNA-sequencing, gene and protein analyses, and an ex vivo muscle contraction protocol to quantify tumor-induced aberrations in SkM function. Differentially expressed genes (DEG) in the BC-PDOX mice relative to control mice were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs. Results: We found that SkM from BC-PDOX–bearing mice showed greater fatigability than control mice, despite no differences in absolute muscle mass. PPAR, mTOR, IL6, IL1, and several other signaling pathways were implicated in the transcriptional changes observed in the BC-PDOX SkM. Moreover, 3 independent in silico analyses identified PPAR signaling as highly dysregulated in the SkM of both BC-PDOX–bearing mice and human patients with early-stage nonmetastatic breast cancer. Conclusions: Collectively, these data demonstrate that the BC-PDOX model recapitulates the expected breast cancer–induced SkM fatigue and further identify aberrant PPAR signaling as an integral factor in the pathology of this condition.

Exercise promotes cardiovascular health through its direct impact on the vascular endothelium. Conversely, poor sleep quality is associated with endothelial dysfunction, which may explain the increased cardiovascular disease amongst poor sleepers. Yet, the influence of physical activity and poor sleep quality on vascular health is not clear. This study examined the relationships between forearm vasodilatory capacity, self-reported sleep quality and free-living, actigraphy-derived energy expenditure in a group of young and older community dwelling adults. Venous occlusion plethysmography determined baseline and peak forearm blood flow following reactive hyperemia. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Measures of body composition were assessed using dual energy X-ray absorptiometry. A total of 104 (61 young; 43 old) participants completed the study. In general, younger participants were more active, as determined by steps per day and average daily energy expenditure, but reported poorer sleep quality. In the combined sample, those who reported moderate sleep disturbances (PSQI total score; 11–15) had significantly lower vasodilatory capacity (16.8 ± 7.6 ml/100 ml/min) compared to those who reported no sleep disturbance (PSQI total score; 0–5) (22.3 ± 7.2 ml/100 ml/min) or mild sleep disturbance (PSQI total score; 6–10) (22.3 ± 8.1 ml/100 ml/min) (p