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1.
Article in English | MEDLINE | ID: mdl-38844159

ABSTRACT

OBJECTIVE: We have previously reported that the interleukin-23 p19 subunit (IL-23p19) is required for experimental inflammatory arthritic pain-like behavior and disease. Even though inflammation is often a characteristic feature of osteoarthritis (OA), IL-23 is not usually considered as a therapeutic target in OA. We began to explore the role of IL-23p19 in OA pain and disease utilizing mouse models of OA and patient samples. DESIGN: The role of IL-23p19 in two mouse models of OA, namely collagenase-induced OA and monosodium iodoacetate-induced OA, was investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. In knee synovial tissues from a small cohort of human OA patients, a correlation analysis was performed between IL-23A gene expression and Oxford knee score (OKS), a validated Patient Reported Outcome Measure. RESULTS: We present evidence that i) IL-23p19 is required for the development of pain-like behavior and optimal disease, including cartilage damage and osteophyte formation, in two experimental OA models and ii) IL-23A gene expression in OA knee synovial tissues correlates with a lower OKS (r = -0.742, p = 0.0057). CONCLUSIONS: The findings support the possible targeting of IL-23 as a treatment for OA pain and disease progression.

2.
Cytokine ; 179: 156619, 2024 07.
Article in English | MEDLINE | ID: mdl-38669908

ABSTRACT

Interleukin (IL)-23 is implicated in the pathogenesis of several inflammatory diseases and is usually linked with helper T cell (Th17) biology. However, there is some data linking IL-23 with innate immune biology in such diseases. We therefore examined the effects of IL-23p19 genetic deletion and/or neutralization on in vitro macrophage activation and in an innate immune-driven peritonitis model. We report that endogenous IL-23 was required for maximal macrophage activation by zymosan as determined by pro-inflammatory cytokine production, including a dramatic upregulation of granulocyte-colony stimulating factor (G-CSF). Furthermore, both IL-23p19 genetic deletion and neutralization in zymosan-induced peritonitis (ZIP) led to a specific reduction in the neutrophil numbers, as well as a reduction in the G-CSF levels in exudate fluids. We conclude that endogenous IL-23 can contribute significantly to macrophage activation during an inflammatory response, mostly likely via an autocrine/paracrine mechanism; of note, endogenous IL-23 can directly up-regulate macrophage G-CSF expression, which in turn is likely to contribute to the regulation of IL-23-dependent neutrophil number and function during an inflammatory response, with potential significance for IL-23 targeting particularly in neutrophil-associated inflammatory diseases.


Subject(s)
Inflammation , Interleukin-23 , Myeloid Cells , Neutrophils , Zymosan , Animals , Inflammation/metabolism , Inflammation/immunology , Interleukin-23/metabolism , Mice , Neutrophils/metabolism , Neutrophils/immunology , Myeloid Cells/metabolism , Peritonitis/metabolism , Peritonitis/immunology , Mice, Inbred C57BL , Granulocyte Colony-Stimulating Factor/metabolism , Macrophage Activation , Macrophages/metabolism , Macrophages/immunology , Interleukin-23 Subunit p19/metabolism , Interleukin-23 Subunit p19/genetics , Mice, Knockout
3.
J Acoust Soc Am ; 155(3): 1825-1839, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38445985

ABSTRACT

This paper presents inversion results for three datasets collected on three spatially separated mud depocenters (hereafter called mud ponds) during the 2022 Seabed Characterization Experiment (SBCEX). The data considered here represent modal time-frequency (TF) dispersion as estimated from a single hydrophone. Inversion is performed using a trans-dimensional (trans-D) Bayesian inference method that jointly estimates water-column and seabed properties along with associated uncertainties. This enables successful estimation of the seafloor properties, consistent with in situ acoustic core measurements, even when the water column is dynamical and mostly unknown. A quantitative analysis is performed to (1) compare results with previous modal TF trans-D studies for one mud pond but under different oceanographic condition, and (2) inter-compare the new SBCEX22 results for the three mud ponds. Overall, the estimated mud geoacoustic properties show no significant temporal variability. Further, no significant spatial variability is found between two of the mud ponds while the estimated geoacoustic properties of the third are different. Two hypotheses, considered to be equally likely, are explored to explain this apparent spatial variability: it may be the result of actual differences in the mud properties, or the mud properties may be similar but the inversion results are driven by difference in data information content.

4.
iScience ; 26(10): 108079, 2023 Oct 20.
Article in English | MEDLINE | ID: mdl-37860753

ABSTRACT

Glucocorticoids (GCs) are potent anti-inflammatory agents and are broadly used in treating rheumatoid arthritis (RA) patients, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action. We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CCL17 has a non-redundant role in inflammatory arthritis. Here, we provide molecular evidence that GCs can suppress GM-CSF-mediated upregulation of IRF4 and CCL17 expression via downregulating JMJD3 expression and activity. In mouse models of inflammatory arthritis, GC treatment inhibited CCL17 expression and ameliorated arthritic pain-like behavior and disease. Significantly, GC treatment of RA patient peripheral blood mononuclear cells ex vivo resulted in decreased CCL17 production. This delineated pathway potentially provides new therapeutic options for the treatment of many inflammatory conditions, where GCs are used as an anti-inflammatory drug but without the associated adverse side effects.

5.
Osteoarthritis Cartilage ; 31(10): 1327-1341, 2023 10.
Article in English | MEDLINE | ID: mdl-37225052

ABSTRACT

OBJECTIVES: We have previously identified a granulocyte macrophage-colony stimulating factor (GM-CSF)/C-C motif ligand 17 (CCL17) pathway in monocytes/macrophages, in which GM-CSF regulates the formation of CCL17, and it is important for an experimental osteoarthritis (OA) model. We explore here additional OA models, including in the presence of obesity, such as a requirement for this pathway. DESIGN: The roles of GM-CSF, CCL17, CCR4, and CCL22 in various experimental OA models, including those incorporating obesity (eight-week high-fat diet), were investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. Cell populations (flow cytometry) and cytokine messenger RNA (mRNA) expression (qPCR) in knee infrapatellar fat pad were analyzed. Human OA sera were collected for circulating CCL17 levels (ELISA) and OA knee synovial tissue for gene expression (qPCR). RESULTS: We present evidence that: i) GM-CSF, CCL17, and CCR4, but not CCL22, are required for the development of pain-like behavior and optimal disease in three experimental OA models, as well as for exacerbated OA development due to obesity, ii) obesity alone leads to spontaneous knee joint damage in a GM-CSF- and CCL17-dependent manner, and iii) in knee OA patients, early indications are that BMI correlates with a lower Oxford Knee Score (r = -0.458 and p = 0.0096), with elevated circulating CCL17 levels (r = 0.2108 and p = 0.0153) and with elevated GM-CSF and CCL17 gene expression in OA synovial tissue. CONCLUSIONS: The above findings indicate that GM-CSF, CCL17, and CCR4 are involved in obesity-associated OA development, broadening their potential as targets for possible treatments for OA.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor , Osteoarthritis, Knee , Humans , Male , Animals , Mice , Cytokines , Pain , Osteoarthritis, Knee/etiology , Synovial Membrane/metabolism , Chemokine CCL17
6.
Immunol Cell Biol ; 101(7): 600-609, 2023 08.
Article in English | MEDLINE | ID: mdl-36975092

ABSTRACT

Chemokine (C-C) ligand 17 (CCL17) was first identified as thymus- and activation-regulated chemokine when it was found to be constitutively expressed in the thymus and identified as a T-cell chemokine. This chemoattractant molecule has subsequently been found at elevated levels in a range of autoimmune and inflammatory diseases, as well as in cancer. CCL17 is a C-C chemokine receptor type 4 (CCR4) ligand, with chemokine (C-C) ligand 22 being the other major ligand and, as CCR4 is highly expressed on helper T cells, CCL17 can play a role in T-cell-driven diseases, usually considered to be via its chemotactic activity on T helper 2 cells; however, given that CCR4 is also expressed by other cell types and there is elevated expression of CCL17 in many diseases, a broader CCL17 biology is suggested. In this review, we summarize the biology of CCL17, its regulation and its potential contribution to the pathogenesis of various preclinical models. Reference is made, for example, to recent literature indicating a role for CCL17 in the control of pain as part of a granulocyte macrophage-colony-stimulating factor/CCL17 pathway in lymphocyte-independent models and thus not as a T-cell chemokine. The review also discusses the potential for CCL17 to be a biomarker and a therapeutic target in human disorders.


Subject(s)
Autoimmunity , Receptors, Chemokine , Humans , Ligands , Receptors, Chemokine/metabolism , Chemokine CCL17/metabolism , Chemokines , Inflammation
7.
JASA Express Lett ; 3(1): 010801, 2023 01.
Article in English | MEDLINE | ID: mdl-36725540

ABSTRACT

Acoustic propagation measurements were collected in a seagrass meadow in a shallow lagoon for periods of over 65 h in winter and 93 h in summer. A bottom-deployed sound source transmitted chirps (0.1-100 kHz) every 10 min that were received on a four-receiver horizontal hydrophone array. Oceanographic probes measured various environmental parameters. Daytime broadband acoustic attenuation was 2.4 dB greater in summer than winter, and the median received acoustic energy levels were 8.4 dB lower in summer compared to winter. These differences were attributed in part to seasonal changes in photosynthesis bubble production and above-ground seagrass biomass.


Subject(s)
Hydrocharitaceae , Seasons , Acoustics , Biomass , Sound
8.
J Acoust Soc Am ; 152(4): 2456, 2022 10.
Article in English | MEDLINE | ID: mdl-36319245

ABSTRACT

Infauna influence geoacoustic parameters in surficial marine sediments. To investigate these effects, an experiment was conducted in natural sand-silt sediment in the northern Gulf of Mexico. In situ acoustic measurements of sediment sound speed, attenuation, and shear speed were performed, and sediment cores were collected from the upper 20 cm of the seabed. Laboratory measurements of sound speed and attenuation in the cores were conducted, after which the core contents were analyzed for biological and physical properties. Since no model currently accounts for the effects of infauna, a deviation from model predictions is expected. To assess the extent of this, acoustic measurements were compared with the viscous grain shearing model from Buckingham [J. Acoust. Soc. Am. 122, 1486 (2007); J. Acoust. Soc. Am. 148, 962 (2020)], for which depth-dependent profiles of sediment porosity and mean grain size measured from the cores were used as input parameters. Comparison of acoustic results with distributions of infauna, worm tubes, and shell hash suggests biogenic impacts on acoustic variability and model accuracy are important in surficial marine sediments. The presence of infauna and worm tubes were correlated with higher variability in both sound speed and attenuation and greater deviation from the model near the sediment-water interface.


Subject(s)
Acoustics , Geologic Sediments , Sound , Viscosity , Porosity
9.
JASA Express Lett ; 2(3): 036001, 2022 Mar.
Article in English | MEDLINE | ID: mdl-36154634

ABSTRACT

A simplified model is presented describing acoustic scattering from a toroidal gas bubble in a compressible liquid. It is assumed that the volume oscillations of the bubble are small enough that a linear approximation is appropriate, and furthermore, that the bubble is large enough that the dominant loss mechanism is radiation damping. An expression for the scattering cross section for such a bubble is derived, and the results are compared with finite-element calculations of the full fluid-fluid scattering problem.

10.
Arthritis Res Ther ; 24(1): 89, 2022 04 25.
Article in English | MEDLINE | ID: mdl-35468842

ABSTRACT

Current understanding of IL-23 biology, with its link to other pro-inflammatory cytokines, for example, IL-17 and granulocyte macrophage-colony stimulating factor (GM-CSF), is primarily focused on T lymphocyte-mediated inflammation/autoimmunity. Pain is a significant symptom associated with many musculoskeletal conditions leading to functional impairment and poor quality of life. While the role of IL-23 in arthritis has been studied in mouse models of adaptive immune-mediated arthritis using targeted approaches (e.g., monoclonal antibody (mAb) neutralization), the literature on IL-23 and arthritis pain is limited. Encouragingly, the anti-IL-23p19 mAb, guselkumab, reduces pain in psoriatic arthritis patients. Recent evidence has suggested a new biology for IL-23, whereby IL-23 is required in models of innate immune-mediated arthritis and its associated pain with its action being linked to a GM-CSF-dependent pathway (the so-called GM-CSF➔CCL17 pathway). This Commentary discusses the current understanding of potential cytokine networks involving IL-23 in arthritis pain and provides a rationale for future clinical studies targeting IL-23p19 in arthritis pain.


Subject(s)
Arthritis , Granulocyte-Macrophage Colony-Stimulating Factor , Animals , Humans , Interleukin-23 , Interleukin-23 Subunit p19 , Mice , Pain , Quality of Life
11.
Semin Immunol ; 54: 101523, 2021 04.
Article in English | MEDLINE | ID: mdl-34776300

ABSTRACT

Granulocyte macrophage-colony stimulating factor (GM-CSF) was originally identified as a growth factor for its ability to promote the proliferation and differentiation in vitro of bone marrow progenitor cells into granulocytes and macrophages. Many preclinical studies, using GM-CSF deletion or depletion approaches, have demonstrated that GM-CSF has a wide range of biological functions, including the mediation of inflammation and pain, indicating that it can be a potential target in many inflammatory and autoimmune conditions. This review provides a brief overview of GM-CSF biology and signaling, and summarizes the findings from preclinical models of a range of inflammatory and autoimmune disorders and the latest clinical trials targeting GM-CSF or its receptor in these disorders.


Subject(s)
Autoimmune Diseases , Granulocyte-Macrophage Colony-Stimulating Factor , Autoimmune Diseases/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Granulocytes/metabolism , Humans , Inflammation , Macrophages
12.
Immunotargets Ther ; 9: 225-240, 2020.
Article in English | MEDLINE | ID: mdl-33150139

ABSTRACT

The cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), was firstly identified as being able to induce in vitro the proliferation and differentiation of bone marrow progenitors into granulocytes and macrophages. Much preclinical data have indicated that GM-CSF has a wide range of functions across different tissues in its action on myeloid cells, and GM-CSF deletion/depletion approaches indicate its potential as an important therapeutic target in several inflammatory and autoimmune disorders, for example, rheumatoid arthritis. In this review, we discuss briefly the biology of GM-CSF, raise some current issues and questions pertaining to this biology, summarize the results from preclinical models of a range of inflammatory and autoimmune disorders and list the latest clinical trials evaluating GM-CSF blockade in such disorders.

13.
J Acoust Soc Am ; 148(4): EL370, 2020 Oct.
Article in English | MEDLINE | ID: mdl-33138538

ABSTRACT

A rupture induced underwater sound source (RIUSS) is being developed as an alternative to other impulsive sound sources commonly utilized in underwater acoustics experiments and surveys. The device is comprised of a graphite rupture disk mounted over an evacuated chamber. After the disk breaks, an inrush of water creates a high amplitude acoustic pulse. A field test was conducted to measure the acoustic output as a function of depth for a given source configuration, and high speed underwater video was simultaneously captured with an acoustic recording system to correlate the features of the acoustic output to the ensuing bubble activity.

14.
Nat Rev Immunol ; 20(8): 507-514, 2020 08.
Article in English | MEDLINE | ID: mdl-32576980

ABSTRACT

Therapeutics against coronavirus disease 2019 (COVID-19) are urgently needed. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myelopoietic growth factor and pro-inflammatory cytokine, plays a critical role in alveolar macrophage homeostasis, lung inflammation and immunological disease. Both administration and inhibition of GM-CSF are currently being therapeutically tested in COVID-19 clinical trials. This Perspective discusses the pleiotropic biology of GM-CSF and the scientific merits behind these contrasting approaches.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Pneumonia, Viral/drug therapy , COVID-19 , Clinical Trials as Topic , Humans , Pandemics , SARS-CoV-2
15.
J Immunol ; 205(1): 213-222, 2020 07 01.
Article in English | MEDLINE | ID: mdl-32461237

ABSTRACT

It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from Ccl17E/+ reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4+ non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.


Subject(s)
Arthritis, Experimental/immunology , Chemokine CCL17/metabolism , Pain/immunology , Peritonitis/immunology , Pneumonia/immunology , Animals , Arthritis, Experimental/complications , Arthritis, Experimental/pathology , Calcitonin Gene-Related Peptide/metabolism , Chemokine CCL17/genetics , Genes, Reporter/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Mice , Mice, Transgenic , Nerve Growth Factor/metabolism , Pain/diagnosis , Pain/pathology , Pain Measurement , Peritonitis/complications , Peritonitis/pathology , Pneumonia/complications , Pneumonia/pathology , Signal Transduction/immunology , Substance P/metabolism
16.
Arthritis Res Ther ; 22(1): 123, 2020 05 29.
Article in English | MEDLINE | ID: mdl-32471485

ABSTRACT

BACKGROUND: The cytokine, interleukin-23 (IL-23), can be critical for the progression of inflammatory diseases, including arthritis, and is often associated with T lymphocyte biology. We previously showed that certain lymphocyte-independent, inflammatory arthritis and pain models have a similar requirement for tumour necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF), and C-C motif ligand 17 (CCL17). Given this correlation in cytokine requirements, we explored whether IL-23 might interact with this cytokine cluster in the control of arthritic and inflammatory pain. METHODS: The role of IL-23 in the development of pain-like behaviour was investigated using mouse arthritis models (zymosan-induced arthritis and GM-CSF-, TNF-, and CCL17-driven monoarticular arthritis) and inflammatory pain models (intraplantar zymosan, GM-CSF, TNF, and CCL17). Additionally, IL-23-induced inflammatory pain was measured in GM-CSF-/-, Tnf-/-, and Ccl17E/E mice and in the presence of indomethacin. Pain-like behaviour and arthritis were assessed by relative weight distribution in hindlimbs and histology, respectively. Cytokine mRNA expression in knees and paw skin was analysed by quantitative PCR. Blood and synovial cell populations were analysed by flow cytometry. RESULTS: We report, using Il23p19-/- mice, that innate immune (zymosan)-driven arthritic pain-like behaviour (herein referred to as pain) was completely dependent upon IL-23; optimal arthritic disease development required IL-23 (P < 0.05). Zymosan-induced inflammatory pain was also completely dependent on IL-23. In addition, we found that exogenous TNF-, GM-CSF-, and CCL17-driven arthritic pain, as well as inflammatory pain driven by each of these cytokines, were absent in Il23p19-/- mice; optimal disease in these mBSA-primed models was dependent on IL-23 (P < 0.05). Supporting this cytokine connection, it was found conversely that IL-23 (200 ng) can induce inflammatory pain at 4 h (P < 0.0001) with a requirement for each of the other cytokines as well as cyclooxygenase activity. CONCLUSIONS: These findings indicate a role for IL-23 in innate immune-mediated arthritic and inflammatory pain with potential links to TNF, GM-CSF, CCL17, and eicosanoid function.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor , Interleukin-23 , Animals , Cytokines , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Mice , Pain , Tumor Necrosis Factor-alpha
17.
J Acoust Soc Am ; 147(3): 2002, 2020 03.
Article in English | MEDLINE | ID: mdl-32237865

ABSTRACT

Seagrasses provide a multitude of ecosystem services and serve as important organic carbon stores. However, seagrass habitats are declining worldwide, threatened by global climate change and regional shifts in water quality. Acoustical methods have been applied to assess changes in oxygen production of seagrass meadows since sound propagation is sensitive to the presence of bubbles, which exist both within the plant tissue and freely floating the water as byproducts of photosynthesis. This work applies acoustic remote sensing techniques to characterize two different regions of a seagrass meadow: a densely vegetated meadow of Thalassia testudinum and a sandy region sparsely populated by isolated stands of T. testudinum. A Bayesian approach is applied to estimate the posterior probability distributions of the unknown model parameters. The sensitivity of sound to the void fraction of gas present in the seagrass meadow was established by the narrow marginal probability distributions that provided distinct estimates of the void fraction between the two sites. The absolute values of the estimated void fractions are biased by limitations in the forward model, which does not capture the full complexity of the seagrass environment. Nevertheless, the results demonstrate the potential use of acoustical methods to remotely sense seagrass health and density.


Subject(s)
Ecosystem , Hydrocharitaceae , Bayes Theorem , Carbon , Remote Sensing Technology
18.
J Acoust Soc Am ; 147(2): 812, 2020 02.
Article in English | MEDLINE | ID: mdl-32113278

ABSTRACT

The activities of infaunal organisms, including feeding, locomotion, and home building, alter sediment physical properties including grain size and sorting, porosity, bulk density, permeability, packing, tortuosity, and consolidation behavior. These activities are also known to affect the acoustic properties of marine sediments, although previous studies have demonstrated complicated relationships between infaunal activities and geoacoustic properties. To avoid difficulties associated with real animals, whose exact locations and activities are unknown, this work uses artificial burrows and simulates infaunal activities such as irrigation, compaction, and tube building in controlled laboratory experiments. The results show statistically significant changes in sound speed and attenuation over a frequency range of 100-400 kHz, corresponding to wavelengths on the order of the burrow diameter. The greatest effects were observed for tubes constructed of hard shells which increased the attenuation by ∼30 dB m-1 across the measurement band. These results highlight the importance of biogenic hard structures such as tubes on sound attenuation and suggest that organisms that create hard structures may be good targets for acoustic mapping of infaunal abundance and distribution.

19.
J Acoust Soc Am ; 146(4): EL335, 2019 10.
Article in English | MEDLINE | ID: mdl-31671955

ABSTRACT

Acoustic propagation measurements were conducted in a Thalassia testudinum meadow in the Lower Laguna Madre, a shallow bay on the Texas Gulf of Mexico coast. A piezoelectric source transmitted frequency-modulated chirps (0.1 to 100 kHz) over a 24-h period during which oceanographic probes measured environmental parameters including dissolved oxygen and solar irradiance. Compared to a nearby less vegetated area, the received level was lower by as much as 30 dB during the early morning hours. At the peak of photosynthesis-driven bubble production in the late afternoon, an additional decrease in level of 11 dB was observed.

20.
Appl Physiol Nutr Metab ; 44(9): 997-1004, 2019 Sep.
Article in English | MEDLINE | ID: mdl-30768366

ABSTRACT

Many forms of cancer are associated with loss of lean body mass, commonly attributed to decreased protein synthesis and stimulation of proteolytic pathways within the skeletal muscle. Leucine has been shown to improve protein synthesis, insulin signaling, and mitochondrial biogenesis, which are key signaling pathways influenced by tumor signaling. The purpose of this study was to examine the effects of leucine supplementation on mitochondrial biogenesis and protein turnover in tumor-bearing mice. Twenty male C57BL/6 mice were divided into 4 groups (n = 5): Chow, leucine (Leu), Lewis lung carcinoma (LLC) implant, and LLC+Leu. At 9-10 weeks of age, mice were inoculated and supplemented with 5% leucine (w/w) in the diet. C2C12 myotubes were treated with 2.5 mmol/L leucine and 25% LLC conditioned media to further elucidate the direct influence of the tumor and leucine on the muscle. Measures of protein synthesis, mitochondrial biogenesis, and inflammation in the gastrocnemius were assessed via Western blot analysis. Gastrocnemius mass was decreased in LLC+Leu relative to LLC (p = 0.040). Relative protein synthesis rate was decreased in LLC mice (p = 0.001). No change in protein synthesis was observed in myotubes. Phosphorylation of STAT3 was decreased in the Leu group relative to the control in both mice (p = 0.019) and myotubes (p = 0.02), but did not significantly attenuate the inflammatory effect of LLC implantation (p = 0.619). LLC decreased markers of mitochondrial content; however, PGC-1α was increased in LLC+Leu relative to LLC (p = 0.001). While leucine supplementation was unable to preserve protein synthesis or mitochondrial content associated with LLC implantation, it was able to increase mitochondrial biogenesis signaling. Novelty This study provides novel insights on the effect of leucine supplementation on mitochondrial biogenesis and protein turnover in tumor-bearing mice. Leucine increased signaling for mitochondrial biogenesis in the skeletal muscle. Leucine supplementation decreased inflammatory signaling in skeletal muscle.


Subject(s)
Dietary Supplements , Leucine/pharmacology , Mitochondria/physiology , Muscle, Skeletal/drug effects , Proteins/metabolism , Animals , Carcinoma, Lewis Lung/metabolism , Leucine/administration & dosage , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal/physiology , Neoplasms, Experimental
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