Biology subjects

Pistilli, E. E.

Publications and source records attributed to Pistilli, E. E..

7 recordsLinked to original sources

bioRxiv2025

A Model to Simulate the Interference Effects of Acute Aerobic Exercise on Rate of Force Development in Weightlifters

Compelling data supports the concept that concurrent strength and aerobic training can interfere with adaptations to strength training related to speed, power, and rate of force development (RFD). Studies on this topic have primarily utilized non-athlete participants, with data subsequently extrapolated to athlete populations. Since there may be hesitancy to have athletes involved in research on the interference effects of aerobic exercise on strength specific adaptations, we built a model to simulate these effects and develop an equation to predict interference. The hypothesis tested in this project was that aerobic exercise is the main driver of interference on weightlifting-associated RFD, and that this interference can be modeled to generate an equation to predict changes in RFD. Python software was used to generate the model, perform the simulation and optimize variables that contribute to the interference effect. A nonlinear exponential interference model was created that simulates the changes in RFD from a force-time curve in response to acute aerobic exercise lasting from 2-minutes to 60-minutes in duration. RFD sensitivity to aerobic exercise was modeled such that values were reduced by approximately 70% after aerobic exercise less than 10 minutes, with further reduction to 80% with durations greater than 10-minutes. The prediction equation can be used by strength coaches to predict the interference of acute aerobic exercise on RFD and subsequently allow the coach to make informed decisions on training program design if there is a need to include aerobic exercise in a strength and/or power-based periodized plan.

physiology↗

bioRxiv2025

ACE-031, a Soluble Activin Type IIB Receptor, Increases Muscle Mass and Strength in the Common Marmoset (Callithrix jacchus)

AimPharmacological blockade of ligands for the activin receptor type IIB (ActRIIB) e.g., myostatin and activin A is associated with improvements in murine skeletal muscle mass and function. The efficacy of a similar treatment approach in a non-human primate (NHP) model would suggest a greater likelihood of success in the treatment of humans suffering from chronic myopathies. In the present study, we elucidate the potential therapeutic benefit of ACE-031, a therapeutic protein consisting of the ActRIIB extracellular region fused to human IgG1, in the common marmoset (Callithrix jacchus). MethodsMarmosets were randomized to receive ACE-031 or vehicle control (10 mM Tris buffered saline; TBS) for 14 weeks. Body composition was measured weekly throughout the experimental period and morphometric analysis and contractile properties of skeletal muscle were assessed terminally. ResultsMarmosets administered ACE-031 showed a significant increase in body weight and lean body mass from baseline, while no change was seen in the vehicle-treated controls. Biceps brachii exhibited a significant increase in the cross-sectional area of both type I and type II fibers and ex vivo contractile properties of the EDL showed an increase in absolute and specific force production. ConclusionThe efficacy of ACE-031 in non-human primates provides optimism that a therapeutic strategy that targets multiple negative regulators of skeletal muscle may be beneficial in treating myopathies in humans.

physiology↗

bioRxiv2024

Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts

Breast cancer (BC) is the most prevalent cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle. MethodsThe pioglitazone and vehicle groups were treated orally for 4 weeks upon reaching a tumor volume of 600 mm3. Whole-animal indirect calorimetry was used to evaluate systemic metabolic states. The transcriptome was profiled using short-read bulk RNA sequencing (RNA-seq). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to profile the metabolome and lipidome. Fast and slow skeletal muscle function were evaluated using isolated ex vivo testing. ResultsPioglitazone was associated with a significant overall decrease in metabolic rate, with no changes in substrate utilization. RNA-seq supported the downstream effects of pioglitazone on target genes and displayed considerable upregulation of mitochondrial bioenergetic pathways. Skeletal muscle metabolomic and lipidomic profiles exhibited dysregulation in response to BC, which was partially restored in pioglitazone-treated mice compared to vehicle-treated BC-PDOX mice. Despite molecular support for pioglitazones efficacy, isolated muscle function was not affected by pioglitazone treatment. ConclusionsBC induces multi-omic dysregulation in skeletal muscle, which pioglitazone partially ameliorates. Future research should focus on profiling systemic metabolic dysfunction, identifying molecular biomarkers of fatigue, and testing alternative pioglitazone treatment regimens. Statement of Translational RelevanceBreast cancer-induced fatigue is a prevalent and debilitating symptom that affects a majority of patients, leading to early treatment discontinuation and poorer outcomes. Despite its significant impact on patient quality of life, there are currently no approved therapies for this condition. Our previous work in the clinically relevant breast cancer patient-derived orthotopic xenograft (BC-PDOX) mouse model suggests that disruptions in the PPAR{gamma} signaling pathway may contribute to the development of cancer-related fatigue. Using this model that recapitulates the fatigue phenotype observed in patients, we conducted a preclinical trial evaluating the FDA-approved PPAR{gamma} agonist, pioglitazone, as a treatment for fatigue. Our multi-omic analysis of skeletal muscle from BC-PDOX mice revealed that pioglitazone treatment partially restored dysregulated lipid profiles and mitochondrial bioenergetic transcriptomic alterations. These findings suggest that pioglitazone may have potential as a therapeutic option for managing cancer-related fatigue in breast cancer patients.

cancer biology↗

bioRxiv2023

Sexual Dimorphism of Skeletal Muscle in a Mouse Model of Breast Cancer: A Functional and Molecular Analysis

1.Breast cancer incidence in men is statistically rare; however, given the lack of screening in males, more advanced stages at initial diagnosis results in lower 5-year survival rates for men with breast cancer compared to women. A sexual dimorphism, with respect to the effect of tumor growth on cachexia incidence and severity, has also been reported across cancer types. The purpose of this study was to examine the sexual dimorphism of breast cancer as it pertains to skeletal muscle function and molecular composition. Using female and male transgenic PyMT mice, we tested the hypothesis that isometric contractile properties and molecular composition of skeletal muscle would be differentially affected by breast tumors. PyMT tumor-bearing mice of each sex, corresponding to maximal tumor burden, were compared to their respective controls. RNA-sequencing of skeletal muscle revealed different pathway alterations that were exclusive to each sex. Further, differentially expressed genes and pathways were substantially more abundant in female tumor mice, with only minimal dysregulation in male tumor mice, each compared to their respective controls. These differences in the transcriptome were mirrored in isometric contractile properties, with greater tumor-induced dysfunction in females than male mice, as well as muscle wasting. Collectively, these data support the concept of sexually dimorphic responses to cancer in skeletal muscle and suggest these responses may be associated with the clinical differences in breast cancer between the sexes. The identified sex-dependent pathways within muscle of male and female mice provide a framework to evaluate therapeutic strategies targeting tumor-associated skeletal muscle alterations. Statement of significanceThe PyMT mouse model of breast cancer, which recapitulates clinical characteristics, exhibits differences in molecular and functional responses of skeletal muscle that are sex-dependent.

cancer biology↗

bioRxiv2021

Pioglitazone administration restores a PPARG-dependent transcriptional network and ATP levels within skeletal muscles of mice implanted with patient-derived breast tumors

BackgroundFatigue is common in patents with breast cancer (BC), and can occur in patients with early stage disease and in the absence of muscle wasting (i.e. cachexia). We have reported transcriptional and proteomic alterations in muscles from BC patients, which are associated with fatigue. Mice implanted with human BC xenografts recapitulate the muscle molecular composition changes seen in patients, coupled with a greater rate of contraction-induced fatigue. Multiple bioinformatics platforms in both human and mouse muscles have identified peroxisome proliferator activated receptor gamma (PPARG) as central to this phenotype, with multiple PPARG target genes downregulated in response to tumor growth. The current study tested the hypothesis that the PPARG agonist pioglitazone (pio), a commonly prescribed diabetes drug, would rescue the transcriptional alterations observed in muscles of tumor-bearing mice. MethodsSixteen female NSG mice were implanted with breast cancer patient-derived orthotopic xenografts (BC-PDOX) via transplantation of Her2/neu+ human tumor fragments. BC-PDOX mice were randomly assigned to a treatment group that received daily oral pio at 30 mg.kg-1 (n=8), or a control group that received a similar volume of vehicle (n=8). Treatment was initiated when tumors reached a volume of 600mm3, and lasted for 2-weeks. Hindlimb muscles were isolated from BC-PDOX and non-tumor bearing mice for RNA-sequencing, gene expression validation, and ATP quantification. Differentially expressed genes (DEGs) in muscles from BC-PDOX mice relative to non-tumor bearing controls were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs. ResultsWe found that the administration of pio restored the muscle gene expression patterns of BC-PDOX mice to a profile resembling muscles of non-tumor bearing NSG control mice. Validation of skeletal muscle gene expression by qPCR confirmed pio increased the expression of PPARG target genes in skeletal muscles. Isolated mitochondria from muscles of BC-PDOX mice treated with pio contained greater levels of ATP. There were no differences in body weights, muscle weights, or tumor volumes in pio vs. vehicle treated BC-PDOX mice. ConclusionsThese data demonstrate that oral pio supplementation rescues the BC-associated downregulation of PPARG target genes in skeletal muscle. Additionally, muscles from BC-PDOX mice treated with pio had greater levels of ATP, which would be associated a more fatigue-resistant muscle phenotype. Therefore, we propose that the FDA-approved and generic diabetes drug, pio, be considered as a supportive therapy for the treatment of BC-associated muscle fatigue.

cancer biology↗

bioRxiv2020

Breast cancer-associated skeletal muscle mitochondrial dysfunction and lipid accumulation is reversed by PPARG

The peroxisome-proliferator activated receptors (PPARs) have been previously implicated in the pathophysiology of skeletal muscle dysfunction in women with breast cancer (BC) and in animal models of BC. Here, we sought to describe the metabolic alterations induced in skeletal muscle by BC-derived factors in an in vitro conditioned media (CM) system and hypothesized that BC cells secrete a factor that represses PPAR-gamma (PPARG) expression and its transcriptional activity, leading to downregulation of PPARG target genes involved in mitochondrial function and other metabolic pathways. We found that BC-derived factors repress PPAR-mediated transcriptional activity without altering protein expression of PPARG. Further, we show that BC-derived factors induce significant alterations in skeletal muscle mitochondrial function and lipid metabolism, which are rescued with exogenous expression of PPARG. The PPARG agonist drug rosiglitazone was able to rescue BC-induced lipid accumulation, but did not rescue effects of BC-derived factors on PPAR-mediated transcription or mitochondrial function. These data suggest that BC-derived factors induce deficits in lipid metabolism and mitochondrial function via different mechanisms that are both related to PPARG signaling, with mitochondrial dysfunction likely being altered via repression of PPAR-mediated transcription, and lipid accumulation being altered via transcription-independent functions of PPARG.

cancer biology↗

bioRxiv2019

Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype

Increased susceptibility to fatigue is a negative predictor of survival commonly experienced by women with breast cancer. Here, we sought to identify molecular changes induced in human skeletal muscle by BC regardless of treatment history or tumor molecular subtype using RNA-sequencing and proteomic analyses. Mitochondrial dysfunction was apparent across all molecular subtypes, with the greatest degree of transcriptomic changes occurring in women with HER2/neu-overexpressing tumors, though muscle from patients of all subtypes exhibited similar pathway-level dysregulation. Interestingly, we found no relationship between anti-cancer treatments and muscle gene expression, suggesting that fatigue is a product of BC per se rather than clinical history. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial function and ATP content in muscle. These data suggest that interventions supporting muscle in the presence of BC-induced mitochondrial dysfunction may alleviate fatigue and improve the lives of women with BC.

cancer biology↗