Purpose: This study tested the hypothesis that a patientderived 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.

A hippocampus-specific IL15RαKO mouse (hipIl15ra /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 /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 /Cre mice to their littermate controls. These data implicate IL-15-related signaling within the hippocampus has a role in anxiety-like behavior.

Minor correlations between measurements for lower-extremity muscle strength and balance in individuals, regardless of the age, have been revealed. Similarly, maximal strength and balance have been individually investigated between an athletic population and a non-athletic population. However, comparisons between lower extremity strength (specifically ankle strength and hip strength) and balance between an athletic versus a non-athletic population have not been established. PURPOSE: The purpose of this pilot study was to find correlations in hip strength and balance versus ankle strength and balance in an athletic (NCAA athletes) and non-athletic population. METHODS: Twelve NCAA Division-1 athletes (age: 20.42 ± 1.51 years, height: 179.27 ± 11.2 cm, mass: 79.07 ± 14.89 kg, gender: 6M, 6F) and twelve healthy college students (age: 22.58 ± 2.47 years, height: 171.65 ± 8.00 cm, mass: 72.72 ± 14.21 kg, gender: 6M, 6F) participated. Following informed consent, balance on the dominant leg was measured using a BOSU ball in timed trials with eyes open and eyes closed. Using a Biodex System 4 Isokinetic Dynamometer, the isokinetic muscular strength and directional torque of eight muscle groups in the sagittal and frontal planes were measured. Lastly, multivariate regression models were performed (α=0.05). Eyes open and eyes closed analyses were performed separately. RESULTS: Athletes had a higher ability to balance (athletes: 61.61 ± 42.67s vs non-athletes: 26.48 ± 27.19s)(p=0.030) in the eyes open trial and presented a correlation for ankle dorsiflexion (R=0.674)(p=0.008) when regressed with eyes open and ankle eversion (R=0.833)(p=0.002) with eyes closed. Meanwhile, non-athletes demonstrated a correlation for hip extension when regressed with eyes closed (R=0.705)(p=0.005). CONCLUSIONS: This study revealed a stronger correlation for ankle strength and balance in an athletic population while a stronger correlation between hip strength and balance was observed for a non-athletic population. Hence coaches, clinicians, or physical therapists can use these findings to tailor exercise protocols specific to individual cases and potentially increase balance to prevent injuries and falls.

<p>Figure S3 shows muscle fatigue and twitch properties of EDL muscles form E0771 tumor bearing mice.</p>

<p>Table S3 shows data for correlational analyses between muscle contractile parameters and STAT activation</p>