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. Author manuscript; available in PMC: 2024 Feb 1.
Published in final edited form as: Brain Behav Immun. 2022 Nov 24;108:45–54. doi: 10.1016/j.bbi.2022.11.008

The GDF15-GFRAL axis mediates chemotherapy-induced fatigue in mice

Brandon Chelette 1, Chinenye L Chidomere 1, Robert Dantzer 1
PMCID: PMC9868083  NIHMSID: NIHMS1850306  PMID: 36427806

Abstract

Cancer-related fatigue is defined as a distressing persistent subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and that interferes with usual functioning. This form of fatigue is highly prevalent during cancer treatment and in some patients, it can persist for years after treatment has ended. An understanding of the mechanisms that drive cancer-related fatigue is still lacking, which hampers the identification of effective treatment options. Various chemotherapeutic agents including cisplatin are known to induce mitochondrial dysfunction and this effect is known to mediate chemotherapy-induced peripheral neuropathy and cognitive dysfunction. Mitochondrial dysfunction results in the release of mitokines that act locally and at distance to promote metabolic and behavioral adjustments to this form of cellular stress. One of these mitokines, growth differentiation factor 15 (GDF15) and its receptor, growth derived neurotrophic factor family receptor α–like (GFRAL), have received special attention in oncology as activation of GFRAL mediates the anorexic response that is responsible for cancer anorexia. The present study was initiated to determine whether GDF15 and GFRAL are involved in cisplatin-induced fatigue. We first tested the ability of cisplatin to increase circulating GDF15 in mice before assessing whether GDF15 can induce behavioral fatigue measured by decreased wheel running in healthy mice and increase behavioral fatigue induced by cisplatin. Mice administered a long acting form of GDF15, mGDF15-fc, decreased their voluntary wheel running activity. When the same treatment was administered to mice receiving cisplatin, it increased the amplitude and duration of cisplatin-induced decrease in wheel running. To determine whether endogenous GDF15 mediates the behavioral fatigue induced by cisplatin, we then administered a neutralizing monoclonal antibody to GFRAL to mice injected with cisplatin. The GFRAL neutralizing antibody mostly prevented cisplatin-induced decrease in wheel running and accelerated recovery. Taken together these findings demonstrate for the first time the role of the GDF15/GFRAL axis in cisplatin-induced behaviors and indicate that this axis could be a promising therapeutic target for the treatment of cancer-related fatigue.

Keywords: Fatigue, cisplatin, mitokine, GDF15, GFRAL, wheel running, mice

1. INTRODUCTION

Cancer-related fatigue is defined as a distressing persistent subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and that interferes with usual functioning (Servaes et al. 2002; Hofman et al. 2004; Goedendorp et al. 2008; Berger et al. 2015; Hanna et al. 2015). Fatigue is one of the most common symptoms experienced by cancer patients. Estimates of its prevalence vary, ranging from 25%–99% depending on the way it is assessed, the cancer type, and the phase of cancer therapy (Bower 2014). Moderate and severe levels of fatigue are distressing and impactful, interfering with an individual’s normal ability to function and decreasing quality of life. Further, an estimated one-quarter to one-third of cancer survivors continue to suffer from fatigue several years after the cessation of treatment (Bower 2006; Servaes et al. 2007). Despite this prevalence, persistence, and severity of impact on patients, our understanding of fatigue in the context of cancer and cancer therapies is incomplete. Proposed mechanisms range from inflammation to disruption of sleep rhythms while potential treatment options include psychosocial interventions, exercise, and psychostimulants in worst cases (Cohen et al. 2019; Thong et al. 2020). A better understanding of the mechanisms that underlie cancer-related fatigue could serve to improve the clinical outcomes for patients by providing therapeutic options to restore, even if only partially, the quality of life for cancer survivors.

The prevalence and severity of fatigue commonly increase dramatically during cancer therapy. Many forms of chemo- and radiotherapy damage mitochondria, the organelles responsible for energy production. Doses of radiation that are high enough to be therapeutically effective are in turn damaging to mitochondria and reduce their efficiency (Averbeck & Rodriguez-Lafrasse 2021). Commonly prescribed chemotherapy drugs like cisplatin and oxaliplatin also damage mitochondria both directly and indirectly (Yang et al. 2019, Wang et al. 2021). For example, Chiu et al. observed abnormal mitochondrial morphology in the synaptosomes of cisplatin-treated mice that was associated with blunted respiratory capacity (Chiu et al. 2017). Further, intranasal delivery of mitochondria was shown to reverse cisplatin-induced cognitive deficits (Alexander et al. 2022). The biochemical pathways that drive mitochondrial dysfunction during cancer therapy and the signaling molecules responsible for transmitting the consequential cellular stress from the periphery to the brain are therefore therapeutic targets with great potential. Their role has been mainly studied in the context of chemotherapy-induced peripheral neuropathy and cognitive dysfunction but not yet in the context of cancer-related fatigue (Chiu et al. 2017; Ma et al. 2018; Trecarichi & Flatters 2019; Alexander et al. 2021) despite the accumulating evidence for a role of deficiencies in energy metabolism as a causal factor for this condition (Vichaya et al. 2015; Grossberg et al. 2018; Grossberg et al. 2020; Vichaya et al. 2020).

Growth differentiation factor 15 (GDF15) is a mitokine that was first cloned and characterized in the late 1990s by several different research groups (Bootcov et al. 1997; Lawton et al. 1997; Paralkar et al. 1998). Early investigations revealed that increased GDF15 is associated with a wide range of inflammatory diseases in which it acts as an anti-inflammatory cytokine (Tsai et al. 2018). This explains why one of its earliest denominations was macrophage inhibitory cytokine 1 (MIC-1). However, the role of GDF15 was found to be more general than the regulation of inflammation as it is produced in response to mitochondrial stress in several cell types and not just immune cells (Moore et al. 2000; Lajer et al. 2010; Spanopoulou & Gkretsi 2020). Additional work demonstrated a pronounced role for GDF15 in body weight regulation and energy homeostasis (Macia et al. 2012). These effects combined with the recent discovery of the GDF15 receptor, growth derived neurotrophic factor family receptor α–like (GFRAL), and its specific localization in the area postrema and nucleus tractus solitarius, have encouraged researchers to investigate the role of the GDF15/GFRAL axis in complex metabolic disorders like obesity, anorexia, and cachexia (Emmerson et al. 2017; Baek & Eling 2019; Suriben et al. 2020; Wang et al. 2021; Patel et al. 2022). Upon binding of GDF15, GFRAL binds to its co-receptor RET tyrosine kinase that initiates a signaling cascade with activation of many potential intracellular mediator pathways (Breit el al. 2021). It is now apparent that the GDF15/GFRAL/RET axis plays a major role in anorexia and other metabolic alterations that develop in several forms of cancer and culminate in cachexia (Suriben et al. 2020). This has led to the development of clinical trials with biologics targeting either GDF15 itself or GFRAL to treat this condition. Surprisingly, little attention has been paid to fatigue even though situations requiring metabolic adjustments run into the risk of getting worse if the organism spends its energy on non-useful behavioral activities.

The present experiments were designed to test the hypothesis that the GDF15/GFRAL axis mediates cancer-related fatigue. We used for this purpose a murine model of cisplatin-induced toxicity that in addition to inducing peripheral neuropathy and cognitive dysfunction leads to robust decrements in voluntary wheel running activity used as an index of behavioral fatigue (Laumet et al. 2019; Alexander et al 2021; Grossberg et al 2018; Grossberg et al 2020). We first confirmed that cisplatin enhances circulating levels of GDF15. We then assessed the ability of exogenous GDF15 to induce behavioral fatigue per se and enhance the behavioral fatigue typically observed in cisplatin-treated mice. We next investigated whether endogenous GDF15 mediates the fatigue inducing effects of cisplatin by administering a monoclonal neutralizing antibody to murine GFRAL to cisplatin-treated mice. The results we have obtained demonstrate for the first time the role of the GDF15/GFRAL axis in cisplatin-induced behavioral fatigue.

2. METHODS

2.1. Animal care and ethical statement

All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Texas MD Anderson Cancer Center (UT MDACC; Houston, TX, USA) under protocol #00002034-RN00 and were performed according to the guidelines provided in the NIH Guide for the Care and Use of Laboratory Animals.

2.2. Animals

Male and female, 10–12 weeks old, C57BL/6J mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA) and housed in the animal vivarium at MDACC. Following a 1-week quarantine/acclimation period after arrival in the vivarium, mice were singly housed with ad libitum access to food (5053 Irradiated Rodent Diet 20; 24.5% kcal from protein, 13.1% fat, 62.4% carbohydrates; LabDiet, St Louis, MO, USA) and water and maintained on a 12:12h light:dark cycle in which the lights turned off at 19:00 CST and on at 07:00 CST. In experiments quantifying fatigue via wheel running, mice were provided a Low-Profile Wireless Running Wheel (Med Associates Inc., St Albans, VT, USA) in their home cage. Every 30 seconds, each wheel sends a data packet to a central hub recording the number of wheel revolutions. This data is archived by the accompanying Wheel Manager software (Med Associates Inc.) and can be exported for further analysis.

2.3. Reagent preparation and administration

Cisplatin (Accord Healthcare Inc.; Durham, NC, USA) was diluted in sterile PBS and administered via intraperitoneal injection at a dose of 2.83 mg/kg daily. This dose is commonly used by our lab to induce neurotoxicity when administered for one or several cycles of 5 daily injections (Laumet et al. 2019; Alexander et al. 2021; Scott et al. 2023). A recombinant, long-acting version of murine GDF15 (mGDF15-fc) and its corresponding control were generously provided by Dr. Harding Luan (NGM Biopharmaceuticals Inc., San Francisco, CA, USA). The mGDF15-fc was diluted in sterile PBS and injected subcutaneously at a dose of 1.25 mg/kg, a dose slightly higher than the daily dose of mGDF15 used in a sepsis model for at least 5 days (Luan et al. 2019). To assess the ability of GDF15 to enhance the effects of cisplatin, administration of mGDF15-fc consisted of a single dose of 1.25 mg/kg starting on the same day as the first dose of cisplatin. Control mice received an injection of sterile PBS replicating the timing, volume, and route of the cisplatin injections and an isotype control compound that replicated the aspects of the mGDF15-fc injection.

A proprietary anti-murine GFRAL neutralizing antibody (GFRALna) and its corresponding isotype control were generously provided by Dr. Paul Emmerson (Eli Lilly and Company; Indianapolis, IN, USA). This compound was diluted in sterile PBS and administered via subcutaneous injection at a dose of 10 mg/kg of bodyweight, a dose previously shown to block the anorectic effects of exogenous GDF15 as well as those of cisplatin (Emmerson et al. 2017; Worth et al. 2020). To assess the role of endogenous GDF15 in cisplatin-induced fatigue, cisplatin treatment consisted of 5 consecutive daily injections of the 2.83 mg/kg dose. Administration of GFRALna consisted of 3 doses at 10 mg/kg with 48 h between them, starting on the day before the first dose of cisplatin. Control mice received an injection of sterile PBS replicating the timing, volume, and route of the cisplatin injections and an isotype control compound that replicated the aspects of the GFRALna injections.

2.4. Experimental design

2.4.1. Experiment #1: Cisplatin increases circulating levels of GDF15 in healthy mice

To measure whether cisplatin treatment induced GDF15, mice were injected with 2.83 mg/kg/day of cisplatin for 5 consecutive days, then plasma samples were collected 24 h, 8 days, or 12 days after the final dose. At their respective timepoints following injection, mice were anesthetized by CO2 exposure and a cardiac puncture blood draw was performed using 22-gauge needles and 1 mL syringes coated in EDTA. Blood samples were held on ice until centrifugation at 4000 × g at 4°C. The supernatant (plasma) was then collected and stored at −80°C until analysis. GDF15 concentration in the plasma samples was determined via ELISA (Mouse GDF15 DuoSet ELISA; Cat #DY6385; R&D Systems, Inc., Minneapolis, MN, USA). The assay was performed and the standard curve was calculated according to the manufacturer’s instructions.

2.4.2: Experiment #2: Long-acting mGDF15-fc effect on cisplatin-induced fatigue

Male mice were allowed to run on their wheels for a 12-day training period that also served to establish a baseline for each mouse. Using this baseline, mice were assigned to four different treatment groups using a 2 (+/− cisplatin) × 2 (+/− mGDF15-fc) factorial design balanced in terms of the amount of wheel running with n=6 mice per group. Mice assigned to receive cisplatin were dosed at 2.83 mg/kg/day for 5 consecutive days and mice assigned to receive mGDF15-fc were dosed a single time at 1.25 mg/kg (Fig 2A). Bodyweight was measured daily starting on the first day of injections for 9 consecutive days and then again immediately prior to termination. The first recorded bodyweight served as the baseline and daily body weights are reported as a percentage of this baseline. Wheel running data is presented starting 3 days prior to the first injection and the number of wheel revolutions during the 12h dark phase is averaged for these 3 days to determine a baseline for each mouse. The percent baseline wheel running for a given day is therefore the number of wheel revolutions a mouse performed during the 12h dark phase that starts on that day divided by the baseline value for that same mouse. Since the smallest bin size the Wheel Manager software allows is 1 minute, active wheel usage was calculated as the number of minutes during the 12h dark phase that a mouse performed an arbitrarily selected number of wheel revolutions (more than 3). Wheel running velocity is calculated as the average revolutions per minute for all minutes in the 12h dark phase during which the mouse was actively using the wheel. Mice were monitored through the recovery from their respective treatments until 8 days after the final injection of cisplatin, at which point the mice were terminated by CO2 exposure followed by cardiac perfusion with PBS. The epidydimal fat pad was manually excised and weighed following perfusion.

Fig. 2 – Exogonous GDF15 induces body weight loss, decreases voluntary wheel running activity, and reduces food disappearance in naïve mice, and these effects are enhanced in cisplatin-treated mice.

Fig. 2 –

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A) Timeline of experiment (Created with Biorender). B,C,D,F) Line graphs comparing the treatment groups over time in terms of percent baseline wheel running, active wheel usage, running velocity, and percent baseline bodyweight, respectively. E) Line graph showing the circadian rhythm of wheel running for each treatment group over a subset of the experimental period. G) bar graph of the weights of gonadal fat pads. Bars represent group means and error bars represent SEM. For B,C,D,F: Symbols on line represent treatment group means and the error bars represent SEM. Symbols above lines represent statistically significant group mean differences according to Tukey’s multiple comparison tests as follows: # = Cisplatin+Isotype differs from PBS+Isotype | ♦ = Cisplatin+Isotype differs from PBS+mGDF15-fc | * = Cisplatin+Isotype differs from Cisplatin+mGDF15-fc | • = Cisplatin+mGDF15-fc differs from PBS+mGDF15-fc | ○ = Cisplatin+mGDF15-fc differs from PBS+Isotype | ◊ = PBS+mGDF15-fc differs from PBS+Isotype. Samples size = 6 mice for each treatment group.

2.4.3. Experiment #3: GFRALna effect on cisplatin-induced fatigue in male mice

Male mice were allowed to run on their wheels for a 10-day training period that also served to establish a baseline for each mouse. Using this baseline, mice were assigned to four different treatment groups using a 2 (+/− cisplatin) × 2 (+/− GFRALna) factorial design with n=8 per group, balanced in terms of the amount of wheel running. Mice assigned to receive cisplatin were dosed at 2.83 mg/kg/day for 5 consecutive days and mice assigned to receive GFRALna were dosed at 10 mg/kg/day on 3 occasions separated by 48 hours (Fig 3A). Bodyweight was measured daily starting two days before the first antibody injection. The two days prior to injections were averaged for each mouse to determine a baseline and daily body weights are expressed as percent of baseline bodyweight. Food disappearance was measured by weighing the food pellets present in the cage lid food hopper each day immediately before the injections, also starting two days prior to the first antibody injections. Daily food disappearance was recorded by subtracting the weight of the food pellets on a given day from the weight of the food pellets on the previous day. Cumulative food disappearance on a given day was calculated by summating the daily food disappearance values up to and including that day. Percent baseline wheel running, usage, and velocity were calculated in the same manner as in Experiment #2. Mice were monitored through the recovery from their respective treatments until wheel running recovered to baseline for all groups.

Fig. 3 – Endogenous GDF15 mediates the fatigue inducing effects of cisplatin in male mice.

Fig. 3 –

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A) Timeline of experiment (Created with Biorender). B,C,D,F,G) Line graphs comparing the treatment groups over time in terms of percent baseline wheel running, active wheel usage, running velocity, and percent baseline bodyweight, and cumulative food disappearance, respectively. E) Line graph showing the circadian rhythm of wheel running for each treatment group over a subset of the experimental period. For B,C,D,F: Symbols on line represent treatment group means and the error bars represent SEM. Symbols above lines represent statistically significant group mean differences according to Tukey’s multiple comparison tests as follows: # = Cisplatin+Isotype differs from PBS+Isotype | ♦ = Cisplatin+Isotype differs from PBS+GFRALna | * = Cisplatin+Isotype differs from Cisplatin+GFRALna | • = Cisplatin+GFRALna differs from PBS+GFRALna | ○ = Cisplatin+GFRALna differs from PBS+Isotype | ◊ = PBS+GFRALna differs from PBS+Isotype. Samples size = 8 mice for each treatment group.

2.4.4. Experiment #4: GFRALna effect on cisplatin-induced fatigue in female mice

Female mice were allowed to run on their wheels for a 13-day training period that also served to establish a baseline for each mouse. Using this baseline, mice were assigned to four different treatment groups using a 2 (+/− cisplatin) × 2 (+/− GFRALna) factorial design with n=8 per group, balanced in terms of the amount of wheel running. Mice assigned to receive cisplatin were dosed at 2.83 mg/kg/day for 5 consecutive days and mice assigned to receive GFRALna were dosed at 10 mg/kg/day on 3 occasions separated by 48 hours (Fig 4A). Bodyweight was measured daily starting two days before the first antibody injection. The two days prior to injections were averaged for each mouse to determine a baseline and daily body weights are expressed as percent of baseline bodyweight. Percent baseline wheel running, usage, and velocity were calculated in the same manner as in Experiment #2. Mice were monitored through the recovery from their respective treatments until wheel running recovered to baseline for all groups. One mouse in the Cisplatin + Isotype group died several days after the last dose of cisplatin and is excluded from all analyses.

Fig. 4 – Endogenous GDF15 mediates the fatigue inducing effects of cisplatin in female mice.

Fig. 4 –

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A) Timeline of experiment (Created with Biorender). B,C,D,E) Line graphs comparing the treatment groups over time in terms of percent baseline wheel running, active wheel usage, running velocity, and percent baseline bodyweight, respectively. F) Line graph showing the circadian rhythm of wheel running for each treatment group over a subset of the experimental period. For B,C,D,E: Symbols on line represent treatment group means and the error bars represent SEM. Symbols above lines represent statistically significant group mean differences according to Tukey’s multiple comparison tests as follows: # = Cisplatin+Isotype differs from PBS+Isotype | ♦ = Cisplatin+Isotype differs from PBS+GFRALna | * = Cisplatin+Isotype differs from Cisplatin+GFRALna | • = Cisplatin+GFRALna differs from PBS+GFRALna | ○ = Cisplatin+GFRALna differs from PBS+Isotype | ◊ = PBS+GFRALna differs from PBS+Isotype. Samples size = 8 mice for each treatment group.

2.5. Statistical analysis

Concentration of GDF15 in the plasma samples of the PBS injected and cisplatin injected mice were compared using an unpaired Student’s t-test at each time point. The epididymal fat pad weights were analyzed using a 2-way ANOVA with +/− cisplatin and +/− mGDF15-fc as between-subjects factors. Percent of baseline bodyweight, cumulative food disappearance, percent baseline wheel running, wheel running velocity, and active wheel usage were analyzed using 3-way ANOVA with experimental day as a repeated measure, within-subject factor, and +/− cisplatin and +/− GFRALna as between-subjects factors. Post hoc analysis of group differences were compared at each time point using the Tukey method to correct for multiple comparisons. The threshold for statistical significance for all analyses performed was α=0.05. Data in graphs are presented as group means ± standard error of the mean (SEM). Data were organized and archived using Microsoft Excel. Running velocity and active wheel usage were calculated using the open-source software RStudio (R Foundation for Statistical Computing, Vienna, Austria). Statistical analyses were performed, and graphs were constructed using GraphPad Prism (Version 9.0.0, GraphPad Software, San Diego, CA, USA). Graphical figures were designed using the open-source software Inkscape (Inkscape Project, inkscape.org).

3. RESULTS

3.1. Cisplatin increases circulating GDF15

The cisplatin treated mice had significantly higher plasma GDF15 concentrations than the PBS treated mice at each time point measured (24 h: t(14)=8.73 with p<0.0001 | 8 days: t(10) = 7.41 with p<0.0001 | 12 days: t(14)=5.23 with p=0.0001)(Fig 1).

Fig. 1 – Cisplatin increases circulating levels of GDF15.

Fig. 1 –

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Bar graphs showing the concentration of GDF15 expressed in pg/ml in plasma samples as determined by ELISA. Symbols represent individual mice, bars represent group means, and error bars represent group SEM. Asterisk indicates statistical significance as determined by unpaired Student’s t test. Sample sizes: 24 h = 8 mice/group | 8 day = 6 mice/group | 12 day = 8 mice/group.

3.2. Exogenous GDF15 induces behavioral fatigue and exacerbates cisplatin-induced behavioral fatigue

Mice administered mGDF15-fc lost bodyweight. The 3-way ANOVA on percent baseline bodyweight revealed a statistically significant main effect of mGDF15-fc (p<0.0001). Mice treated with PBS and mGDF15-fc weighed less than mice treated with PBS and the Fc isotype control (Fig 2F). GDF15 also reduced wheel running. The main effect of mGDF15-fc was significant for both percent baseline wheel running and wheel usage (Table 1). On Days 3–5, mice treated with PBS and mGDF15-fc ran at between 59 and 62% of their baseline on average, respectively, whereas mice treated with PBS and the Fc isotype control ran at 92 and 100% in the same time period (Fig 2B). It is worth noting that there was a statistically significant main effect of time on the percent baseline wheel running in the PBS + Fc isotype group following the injection (Tukey multiple comparison test: Day −1 vs Day 0; p=0.003 | Day −1 vs Day 1; p=0.064 | Day −1 vs Day 2; p=0.058). This indicates that administration of the isotype caused a small decrease in wheel running independent of cisplatin. A similar effect on wheel usage is apparent as well (Tukey multiple comparison test: Day −1 vs Day 0; p=0.062 | Day −1 vs Day 1; p=0.005 | Day −1 vs Day 2; p=0.13). These effects, however, were smaller in amplitude and recovered more quickly than the decreases caused by cisplatin, mGDF15-fc, and their combined effect.

Table 1 – Output of statistical analyses.

Three-way ANOVA with time as a repeated measures, within-subjects factor and +/− cisplatin and +/− mGDF15-fc as between-subjects factors were performed on the wheel running and bodyweight data sets for Experiment #2. Two-way ANOVA with +/− mGDF15-fc and +/− cisplatin as between subjects factors was performed on the weights of the excised gonadal fat pads for Experiment #2. Three-way ANOVA with time as a repeated measures, within-subjects factor and +/− GFRALna and +/− cisplatin as between-subjects factors were performed on the wheel running, bodyweight, and food disappearance data sets for Experiment #3. Three-way ANOVA with time as a repeated measures, within-subjects factor and +/− GFRALna and +/− cisplatin as between-subjects factors were performed on the wheel running and bodyweight data sets for Experiment #4.

Experiment #2 Experiment #3 Experiment #4
mGDF15-fc × Cis GFRALna × Cis Males GFRALna × Cis Females
Wheel Running Wheel Running
time F(14,280)=50.35 ; p <0.0001* time F(19,532)=7.65 ; p <0.0001* F(20,540)=3.89 ; p <0.0001*
cisplatin F(1,20)=53.76 ; p <0.0001* cisplatin F(1,28)=11.23 ; p =0.002* F(1,27)=9.85 ; p =0.004*
mGDF15-fc F(1,20)=10.51 ; p =0.004* GFRALna F(1,28)=7.71 ; p =0.01* F(1,27)=2.77 ; p =0.11
time*cisplatin F(14,280)=16.55 ; p <0.0001* time*cisplatin F(19,532)=7.97 ; p <0.0001* F(20,540)=6.76 ; p <0.0001*
time*mGDF15-fc F(14,280)=3.13 ; p =0.0001* time*GFRALna F(19,532)=2.27 ; p =0.002* F(20,540)=2.08 ; p =0.004*
cisplatin*mGDF15-fc F(1,20)=0.18 ; p =0.68 cisplatin*GFRALna F(1,28)=1.62 ; p =0.21 F(1,27)=2.95 ; p =0.10
time*cisplatin*mGDF15-fc F(14,280)=4.38 ; p <0.0001* time*cisplatin*GFRALna F(19,532)=2.26 ; p =0.002* F(20,540)=2.43 ; p =0.0005*
Wheel Usage Wheel Usage
time F(14,280)=65.23 ; p <0.0001* time F(19,532)=8.73 ; p <0.0001* F(20,540)=7.6 ; p <0.0001*
cisplatin F(1,20)=35.19 ; p <0.0001* cisplatin F(1,28)=2.35 ; p =0.14 F(1,27)=11.20 ; p =0.002*
mGDF15-fc F(1,20)=16.58 ; p =0.0006* GFRALna F(1,28)=1.76 ; p =0.20 F(1,27)=4.62 ; p =0.04*
time*cisplatin F(14,280)=17.11 ; p <0.0001* time*cisplatin F(19,532)=7.53 ; p <0.0001* F(20,540)=10.01 ; p <0.0001*
time*mGDF15-fc F(14,280)=4.67 ; p< 0.0001* time*GFRALna F(19,532)=2.17 ; p =0.003* F(20,540)=3.09 ; p <0.0001*
cisplatin*mGDF15-fc F(1,20)=0.06 ; p =0.80 cisplatin*GFRALna F(1,28)=0.37 ; p =0.55 F(1,27)=0.73 ; p =0.40
time*cisplatin*mGDF15-fc F(14,280)=4.29 ; p <0.0001* time*cisplatin*GFRALna F(19,532)=2.60 ; p =0.0003* F(20,540)=3.54 ; p <0.0001*
Wheel Velocity Wheel Velocity
time F(14,280)=5.16 ; p <0.0001* time F(19,532)=11.94 ; p <0.0001* F(20,540)=2.61 ; p =0.0002*
cisplatin F(1,20)=4.67 ; p = 0.043* cisplatin F(1,28)=0.35 ; p =0.56 F(1,27)=3.39 ; p =0.08
mGDF15-fc F(1,20)=0.21 ; p =0.65 GFRALna F(1,28)=0.17 ; p =0.68 F(1,27)=1.26 ; p =0.27
time*cisplatin F(14,280)=6.01 ; p <0.0001* time*cisplatin F(19,532)=4.5 ; p <0.0001* F(20,540)=1.07 ; p =0.38
time*mGDF15-fc F(14,280)=1.73 ; p = 0.049* time*GFRALna F(19,532)=0.33 ; p =0.99 F(20,540)=1.51 ; p =0.07
cisplatin*mGDF15-fc F(1,20)=0.33 ; p =0.57 cisplatin*GFRALna F(1,28)=0.02 ; p =0.89 F(1,27)=0.06 ; p =0.80
time*cisplatin*mGDF15-fc F(14,280)=0.58 ; p =0.88 time*cisplatin*GFRALna F(19,532)=0.97 ; p =0.49 F(20,540)=0.99 ; p =0.48
Bodyweight Bodyweight
time F(9,180)=53.62. ; p <0.0001* time F(18,504)=20.33 ; p <0.0001* F(15,405)=35.18 ; p <0.0001*
cisplatin F(1,20)=92.63 ; p <0.0001* cisplatin F(1,28)=13.27 ; p =0.001* F(1,27)=53.95 ; p <0.0001*
mGDF15-fc F(1,20)=45.17 ; p <0.0001* GFRALna F(1,28)=7.23 ; p =0.012* F(1,27)=17.87 ; p =0.0002*
time*cisplatin F(9,180)=28.63 ; p <0.0001* time*cisplatin F(18,504)=9.53 ; p <0.0001* F(15,405)=22.92 ; p <0.0001*
time*mGDF15-fc F(9,180)=10.46. ; p <0.0001* time*GFRALna F(18,504)=5.11 ; p <0.0001* F(15,405)=8.38 ; p <0.0001*
cisplatin*mGDF15-fc F(1,20)=0.90 ; p =0.35 cisplatin*GFRALna F(1,28)=15.34 ; p =0.0005* F(1,27)=18.7 ; p =0.0002*
time*cisplatin*mGDF15-fc F(9,180)=2.73 ; p =0.005* time*cisplatin*GFRALna F(18,504)=5.90 ; p <0.0001* F(15,405)=10.93 ; p <0.0001*
Gonadal Fat Pad Cumulative Food Disappearance
Cisplatin F(1,20)=1.64 ; p =0.22 time F(18,504)=1712 ; p <0.0001*
mGDF15-fc F(1,20)=14.19 ; p =0.001* cisplatin F(1,28)=4.64 ; p =0.04*
Cisplatin*mGDF15-fc F(1,20)=1.30 ; p =0.27 GFRALna F(1,28)=0.003 ; p =0.96
time*cisplatin F(18,504)=3.88 ; p <0.0001*
time*GFRALna F(18,504)=0.43 ; p =0.98
cisplatin*GFRALna F(1,28)=2.17 ; p =0.15
time*cisplatin*GFRALna F(18,504)=1.72 ; p =0.03*
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Mice treated with cisplatin lost bodyweight and decreased their voluntary wheel running. The main effect of cisplatin on percent baseline bodyweight, percent baseline wheel running, wheel usage, and running velocity were significant (Table 1). Mice treated with cisplatin and the Fc isotype control dropped to 86% on average of their baseline bodyweight at their lowest point and performed at 23% of their percent baseline wheel running on average on the day after the final dose of the cisplatin.

Though mGDF15-fc and cisplatin had independent significant effects, their combination exacerbated the bodyweight and wheel running decrements. The mGDF15-fc × cisplatin × time interactions were significant for percent baseline bodyweight, percent baseline wheel running, and wheel usage (Table 1). Peak weight loss in mice treated with PBS+mGDF15-fc and mice treated with cisplatin and the Fc isotype control were on average 94% and 83%, respectively. However, peak weight loss in mice treated with cisplatin and mGDF15-fc was 79% on average. In terms of wheel running, following the first dose of cisplatin, mice that received the isotype control ran at 75% baseline on average while the mice that received mGDF15-fc ran at 34% baseline on average (Fig 2B). Group mean comparisons showed that wheel running of mice treated with cisplatin and mGDF15-fc was significantly different from mice that received cisplatin and the Fc isotype control on the first day of injections and on Day 9 - Day 11 and was also significantly different from the mice treated with PBS and mGDF15-fc over the Day 0 - Day 11 period. During the Baseline period, all treatment groups used their wheels for 6.5h per dark phase on average. By Day 11 (7 days after the final dose of cisplatin), mice treated with cisplatin and the Fc isotype control had returned to running 6h per dark phase while the mice that received mGDF15-fc were actively running only 3h per dark phase on average (Fig 2C). Of note, there was no apparent disruption to the circadian rhythm of wheel running in any of the treatment groups (Fig 2E). Two-way ANOVA analysis of the excised gonadal fat pads showed a significant effect of mGDF15-fc administration but not of cisplatin (mGDF15-fc: F(1,20)=14.2 ; p=0.001 | Cisplatin: F(1,20)=1.6 ; p=0.22 | Interaction: F(1,20)=1.3 ; p=0.27)(Fig 2G).

3.3. Immunoneutralization of GFRAL attenuates cisplatin-induced decrease in wheel running and improves recovery in male mice

Cisplatin decreased wheel running activity, an effect that was attenuated by administration of GFRALna (Fig. 3). The cisplatin × GFRALna × time interaction was statistically significant (Table 1). Mice treated with cisplatin and the isotype control ran at 37% of their baseline on average at their lowest performance (following the fourth injection of cisplatin) while mice treated with cisplatin and GFRALna ran at 75% of their baseline on average on their lowest performing day (following the second injection of cisplatin)(Fig 3B). Group mean comparisons showed that the wheel running activity of mice treated with cisplatin and the isotype control was significantly different from that of the other three groups during Day 4 - Day 7. Analysis of wheel usage also showed a statistically significant 3-way interaction (Table 1). At baseline, all four treatment groups actively used their wheels for 5.5 h on average out of a possible 12 h through the duration of the dark phase. During treatment, wheel usage of mice treated with cisplatin and the isotype control dropped to less than 2.5h on average while that of mice treated with cisplatin and GFRALna dropped to ~4 h (Fig 3C). Analysis of wheel running velocity revealed a statistically significant main effect of Time and a statistically significant Time × Cisplatin interaction (Table1), but multiple comparison tests revealed no group mean differences among any of the treatment groups for the duration of the experiment (Fig 3D). Similarly to Experiment #2, the temporal pattern of wheel running was not disturbed in any of the treatment groups (Fig 3E).

Analysis of percent bodyweight change showed a statistically significant 3-way interaction (Table 1). Peak weight loss in mice treated with cisplatin and the isotype control occurred on the last day of cisplatin injections during which mice reached on average ~88% of their baseline bodyweight whereas in mice treated with cisplatin and GFRALna, peak weight loss on the same day was ~96% of the baseline bodyweight (Fig 3F). There was a statistically significant 3-way interaction for food disappearance (Table 1). By the final day of the experiment, the amount of food that was displaced was the lowest in mice treated with cisplatin and the isotype control compound and this was effect was decreased by GFRALna that had no effect of its own (Total food disappearance (g): PBS + Isotype = 95.1 ± 10.3 | PBS + GFRALna = 91.4 ± 6.4 | Cisplatin + Isotype = 81.5 ± 9.3 | Cisplatin + GFRALna = 87.8 ± 11.3)(Fig 3G).

3.4. Immunoneutralization of GFRAL attenuates cisplatin-induced decrease in wheel running and improves recovery in female mice

Similar results to the male cohort in terms of bodyweight and wheel running behavior were observed in female mice that underwent comparable experimental procedure. Cisplatin induced significant decreases in wheel running that were mostly prevented by GFRALna administration. 3-way ANOVA revealed a statistically significant 3-way cisplatin × GFRALna × time interaction for percent baseline wheel running, wheel usage, and percent baseline bodyweight (Table 1). The cisplatin treated mice that received isotype control ran 43% of their baseline at their lowest performance (following the 5th dose of cisplatin) whereas the cisplatin treated mice that received GFRALna ran at 67% of their baseline as their lowest performance (following the 4th dose of cisplatin)(Fig 4B). According to group mean comparisons the mice treated with cisplatin and the isotype control ran significantly less than both PBS treated groups on Day 2 – Day 11 and significantly less than the cisplatin group that received GFRALna on Day 5, Day 7 – Day 10, and Day 12. A similar pattern was observed in percent baseline bodyweight: the mice treated with cisplatin and the isotype control displayed a bodyweight nadir of 85.5% on average whereas the cisplatin treated mice that received the GFRALna had a lower percent baseline body weight of 95.3% on average (Fig 4E). Also, similarly to the male cohort, wheel running velocity and the circadian rhythm of wheel activity were minimally affected by cisplatin and/or GFRALna administration (Fig 4D + Fig 4F).

4. DISCUSSION

The present findings confirm that cisplatin enhances circulating levels of GDF15 and that exogenous GDF15 not only decreases wheel running in mice, but also enhances the detrimental effects of cisplatin on wheel running. The decrease in wheel running induced by GDF15 is not purely pharmacological as immunoneutralization of its receptor attenuates cisplatin-induced decrease in wheel running and facilitates recovery. These original findings are the first to indicate the role of the GDF15/GFRAL axis in one important component of chemotherapy-induced fatigue.

GDF15 has already been found to decrease physical exercise measured by voluntary wheel running in mice (Klein et al. 2021). This effect was obtained in response to a pharmacological dose of recombinant human GDF15 and it was mediated by GFRAL as it was no longer apparent in mice deficient for Gfral. However, the negative effects of GDF15 on voluntary wheel running activity were in stark contrast to the physiological increase in GDF15 that had already been shown to be induced by physical exercise in both humans and mice. Short-term endurance exercise and resistance exercise moderately increased circulating levels of GDF15 whereas long-term endurance exercise had more potent effects, resulting in levels of GDF15 that were 4 to 5 times higher than normal (Klein et al. 2022). However, the effects of physical exercise on circulating GDF15 were transient in contrast to those resulting from mitochondrial dysfunction (Klein et al. 2022). More important for the interpretation of the results of the present experiments on mGDF15-fc induced decrease in wheel running, the pharmacological effects of recombinant human GDF15 on wheel running were not due to decreased fitness as mice treated with recombinant human GDF15 were still able to run to exhaustion in a treadmill running task. In addition, the effects of GDF15 on wheel running were not positively related to the anorexic activity of this mitokine as repeated daily injections of recombinant human GDF15 led to tolerance to the anorexia but not to the fatigue-inducing effects of GDF15 (Klein et al. 2021). It is important to consider the potential confounds that arise from using voluntary wheel running as our metric for fatigue. There could be alterations in food intake, fat mass, or lean tissue mass that accentuate (or mask) our results. Long-term running wheel access alters several metabolic parameters, but at least two studies have demonstrated that circulating GDF15 is not increased by voluntary wheel running (Gil et al. 2019; Klein et al. 2021). Though this does not assuage concerns that running wheel access is changing the physiology of the mice studied in the present experiment, it does indicate that the changes are not mediated by GDF15. The findings obtained in the present study confirm the effects of GDF15 on wheel running but they add an important dimension to this effect by showing that high levels of endogenous GDF15 induced by cisplatin-dependent mitochondrial dysfunction mediate the GFRAL-dependent decrease in wheel running induced by this treatment condition.

In terms of neuronal circuits, it is not yet known whether the neuronal network that mediates the effects of GDF15 on wheel running is the same as the one that is involved in the anorectic and nausea-inducing effect of this mitokine even if the dissociation observed between the effects of GDF15 on wheel running and on food intake during repeated administration of this mitokine casts some doubt on this possibility (Klein et al. 2021). In contrast to the wide range of metabolic effects of GDF15, its only known receptor, GFRAL, is located exclusively in the area postrema and nucleus tractus solitarius and it is present on neurons that express mainly cholecystokinin (CCK) and to a lesser extent tyrosine hydroxylase (TH). Blocking CCK signaling by various means including pharmacological antagonism of CCK receptors and deletion of CCK neurons in the area postrema and nucleus tractus solitarius by specific overexpression of caspase in these neurons attenuated the anorexia caused by GDF15 (Worth et al. 2020). Whether the same neurons mediate the effect of cisplatin on wheel running is not yet known. The possibility of alternative receptor mechanisms should not be dismissed. As binding of GDF15 to GFRAL activates RET signaling, which is more ubiquitous than GFRAL, there is always the possibility that a soluble form of GFRAL is released and by binding to GDF15 it activates RET signaling in cells other than hindbrain-located neurons (Tsai et al. 2018).

We have limited our investigation to cisplatin as a chemotherapeutic agent because of its well-known ability to induce mitochondrial dysfunction. Still, we do not know yet whether other neurotoxic effects of cisplatin that are dependent on its ability to induce mitochondrial dysfunction and include peripheral neuropathy and cognitive impairment (Lomeli et al. 2017; Trecarichi & Flatters 2019) are mediated by GDF15. In addition, other pathological conditions leading to mitochondrial dysfunction and production of elevated levels of circulating GDF15 such as tumor growth and dissemination and other forms of cancer therapy (Weinberg & Chandel 2015; Assadi et al 2020; Myojin et al. 2021) still need to be investigated. Finally, due to the complex nature of fatigue, it is worth reiterating that any generalization of these findings to the full spectrum of cancer-related fatigue would be premature. We have only demonstrated a role for GDF15 in cisplatin-induced decreases in wheel running which is considered as a proxy for physical fatigue (Grossberg et al 2018; Grossberg et al 2020). Additional work is necessary to claim anything beyond that. Despite these limitations, the results of the present series of experiments provide proof of principle for a role of endogenous GDF15 in the fatigue inducing effects of chemotherapy and position the GDF15/GFRAL axis as a potential target for the development of new therapies for treating cancer-related fatigue.

Highlights.

  • Cisplatin increases circulating levels of the mitokine GDF15

  • Administration of exogenous GDF15 induces behavioral fatigue measured by decreased wheel running and exacerbates cisplatin-induced behavioral fatigue

  • Immunoneutralization of GFRAL prevents cisplatin-induced wheel running decrements

Acknowledgements

We would like to thank Dr. Paul Emmerson (Eli Lilly, Indianapolis, IN) and Dr. Harding Luan (NGM Bio, San Franciso, CA) for the provision of reagents and their scientific insights on the results of the present experiments.

Funding supported by the National Institute of Health (R01 CA193522, R01 NS073939, R21 NS130712). Additional support came from the University of Texas MD Anderson Cancer Center and the NIH MD Anderson Cancer Center Support Grant [P30 CA016672].

Conflict of Interest

RD receives honorarium from Good Cap (Toronto, Canada) for consultancy work not related to the present research

References

  1. Alexander JF, Seua AV, Arroyo LD, Ray PR, Wangzhou A, Heiβ-Lückemann L, Schedlowski M, Price TJ, Kavelaars A, & Heijnen CJ (2021). Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics, 11(7), 3109–3130. 10.7150/thno.53474 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alexander JF, Mahalingam R, Seua AV, Wu S, Arroyo LD, Hörbelt T, Schedlowski M, Blanco E, Kavelaars A, & Heijnen CJ (2022). Targeting the Meningeal Compartment to Resolve Chemobrain and Neuropathy via Nasal Delivery of Functionalized Mitochondria. Advanced healthcare materials, 11(8), e2102153. 10.1002/adhm.202102153 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Assadi A, Zahabi A, & Hart RA (2020). GDF15, an update of the physiological and pathological roles it plays: a review. Pflugers Archiv : European journal of physiology, 472(11), 1535–1546. 10.1007/s00424-020-02459-1 [DOI] [PubMed] [Google Scholar]
  4. Averbeck D, & Rodriguez-Lafrasse C (2021). Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts. International journal of molecular sciences, 22(20), 11047. 10.3390/ijms222011047 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baek SJ, & Eling T (2019). Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases. Pharmacology & therapeutics, 198, 46–58. 10.1016/j.pharmthera.2019.02.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berger AM, et al. (2015). “Cancer-Related Fatigue, Version 2.2015.” J Natl Compr Canc Netw 13(8): 1012–1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, & Breit SN (1997). MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proceedings of the National Academy of Sciences of the United States of America, 94(21), 11514–11519. 10.1073/pnas.94.21.11514 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bower JE, Ganz PA, Desmond KA, Bernaards C, Rowland JH, Meyerowitz BE, & Belin TR (2006). Fatigue in long-term breast carcinoma survivors: a longitudinal investigation. Cancer, 106(4), 751–758. 10.1002/cncr.21671 [DOI] [PubMed] [Google Scholar]
  9. Bower JE (2014). Cancer-related fatigue--mechanisms, risk factors, and treatments. Nature reviews. Clinical oncology, 11(10), 597–609. 10.1038/nrclinonc.2014.127 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Breen DM, Kim H, Bennett D, Calle RA, Collins S, Esquejo RM, He T, Joaquim S, Joyce A, Lambert M, Lin L, Pettersen B, Qiao S, Rossulek M, Weber G, Wu Z, Zhang BB, & Birnbaum MJ (2020). GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates. Cell metabolism, 32(6), 938–950.e6. 10.1016/j.cmet.2020.10.023 [DOI] [PubMed] [Google Scholar]
  11. Breit SN, Brown DA, & Tsai VW (2021). The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe?. Annual review of physiology, 83, 127–151. 10.1146/annurev-physiol-022020-045449 [DOI] [PubMed] [Google Scholar]
  12. Chiu GS, Maj MA, Rizvi S, Dantzer R, Vichaya EG, Laumet G, Kavelaars A, & Heijnen CJ (2017). Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function. Cancer research, 77(3), 742–752. 10.1158/0008-5472.CAN-16-1817 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cimino I, Kim H, Tung Y, Pedersen K, Rimmington D, Tadross JA, Kohnke SN, Neves-Costa A, Barros A, Joaquim S, Bennett D, Melvin A, Lockhart SM, Rostron AJ, Scott J, Liu H, Burling K, Barker P, Clatworthy MR, Lee EC, … O’Rahilly S (2021). Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15. Proceedings of the National Academy of Sciences of the United States of America, 118(27), e2106868118. 10.1073/pnas.2106868118 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cohen RA, Gullett JM, Woods AJ, Porges EC, Starkweather A, Jackson-Cook CK, Lynch-Kelly DL, & Lyon DE (2019). Cytokine-associated fatigue prior to, during, and post-chemotherapy for breast cancer. Journal of neuroimmunology, 334, 577001. 10.1016/j.jneuroim.2019.577001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Emmerson PJ, Wang F, Du Y, Liu Q, Pickard RT, Gonciarz MD, Coskun T, Hamang MJ, Sindelar DK, Ballman KK, Foltz LA, Muppidi A, Alsina-Fernandez J, Barnard GC, Tang JX, Liu X, Mao X, Siegel R, Sloan JH, Mitchell PJ, … Wu X (2017). The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nature medicine, 23(10), 1215–1219. 10.1038/nm.4393 [DOI] [PubMed] [Google Scholar]
  16. Gil CI, Ost M, Kasch J, Schumann S, Heider S, & Klaus S (2019). Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice. Scientific reports, 9(1), 20120. 10.1038/s41598-019-56922-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goedendorp MM, et al. (2008). “Severe fatigue and related factors in cancer patients before the initiation of treatment.” Br J Cancer 99(9): 1408–1414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Grossberg AJ, Vichaya EG, Christian DL, Molkentine JM, Vermeer DW, Gross PS, Vermeer PD, Lee JH, & Dantzer R (2018). Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling. Cancer research, 78(3), 695–705. 10.1158/0008-5472.CAN-17-2168 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Grossberg AJ, Vichaya EG, Gross PS, Ford BG, Scott KA, Estrada D, Vermeer DW, Vermeer P, & Dantzer R (2020). Interleukin 6-independent metabolic reprogramming as a driver of cancer-related fatigue. Brain, behavior, and immunity, 88, 230–241. 10.1016/j.bbi.2020.05.043 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hanna EY, et al. (2015). “The symptom burden of treatment-naive patients with head and neck cancer.” Cancer 121(5): 766–773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hofman M, et al. (2004). “Cancer patients’ expectations of experiencing treatment-related side effects: a University of Rochester Cancer Center--Community Clinical Oncology Program study of 938 patients from community practices.” Cancer 101(4): 851–857. [DOI] [PubMed] [Google Scholar]
  22. Izaguirre DI, Ng CW, Kwan SY, Kun EH, Tsang Y, Gershenson DM, & Wong KK (2020). The Role of GDF15 in Regulating the Canonical Pathways of the Tumor Microenvironment in Wild-Type p53 Ovarian Tumor and Its Response to Chemotherapy. Cancers, 12(10), 3043. 10.3390/cancers12103043 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Klein AB, Kleinert M, Richter EA, & Clemmensen C (2022). GDF15 in Appetite and Exercise: Essential Player or Coincidental Bystander?. Endocrinology, 163(1), bqab242. 10.1210/endocr/bqab242 [DOI] [PubMed] [Google Scholar]
  24. Klein AB, Nicolaisen TS, Ørtenblad N, Gejl KD, Jensen R, Fritzen AM, Larsen EL, Karstoft K, Poulsen HE, Morville T, Sahl RE, Helge JW, Lund J, Falk S, Lyngbæk M, Ellingsgaard H, Pedersen BK, Lu W, Finan B, Jørgensen SB, … Clemmensen C (2021). Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. Nature communications, 12(1), 1041. 10.1038/s41467-021-21309-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lajer M, Jorsal A, Tarnow L, Parving HH, & Rossing P (2010). Plasma growth differentiation factor-15 independently predicts all-cause and cardiovascular mortality as well as deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetes care, 33(7), 1567–1572. 10.2337/dc09-2174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Laumet G, Edralin JD, Dantzer R, Heijnen CJ, & Kavelaars A (2019). Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice. Pain, 160(6), 1459–1468. 10.1097/j.pain.0000000000001512 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lawton LN, Bonaldo MF, Jelenc PC, Qiu L, Baumes SA, Marcelino RA, de Jesus GM, Wellington S, Knowles JA, Warburton D, Brown S, & Soares MB (1997). Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta. Gene, 203(1), 17–26. 10.1016/s0378-1119(97)00485-x [DOI] [PubMed] [Google Scholar]
  28. Lomeli N, Di K, Czerniawski J, Guzowski JF, & Bota DA (2017). Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free radical biology & medicine, 102, 274–286. 10.1016/j.freeradbiomed.2016.11.046 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Luan HH, Wang A, Hilliard BK, Carvalho F, Rosen CE, Ahasic AM, Herzog EL, Kang I, Pisani MA, Yu S, Zhang C, Ring AM, Young LH, & Medzhitov R (2019). GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance. Cell, 178(5), 1231–1244.e11. 10.1016/j.cell.2019.07.033 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ma J, Kavelaars A, Dougherty PM, & Heijnen CJ (2018). Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer, 124(11), 2289–2298. 10.1002/cncr.31248 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Macia L, Tsai VW, Nguyen AD, Johnen H, Kuffner T, Shi YC, Lin S, Herzog H, Brown DA, Breit SN, & Sainsbury A (2012). Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets. PloS one, 7(4), e34868. 10.1371/journal.pone.0034868 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Moore AG, Brown DA, Fairlie WD, Bauskin AR, Brown PK, Munier ML, Russell PK, Salamonsen LA, Wallace EM, & Breit SN (2000). The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. The Journal of clinical endocrinology and metabolism, 85(12), 4781–4788. 10.1210/jcem.85.12.7007 [DOI] [PubMed] [Google Scholar]
  33. Myojin Y, Hikita H, Sugiyama M, Sasaki Y, Fukumoto K, Sakane S, Makino Y, Takemura N, Yamada R, Shigekawa M, Kodama T, Sakamori R, Kobayashi S, Tatsumi T, Suemizu H, Eguchi H, Kokudo N, Mizokami M, & Takehara T (2021). Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production. Gastroenterology, 160(5), 1741–1754.e16. 10.1053/j.gastro.2020.12.015 [DOI] [PubMed] [Google Scholar]
  34. Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA, & Thompson DD (1998). Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. The Journal of biological chemistry, 273(22), 13760–13767. 10.1074/jbc.273.22.13760 [DOI] [PubMed] [Google Scholar]
  35. Patel AR, Frikke-Schmidt H, Bezy O, Sabatini PV, Rittig N, Jessen N, Myers MG Jr, & Seeley RJ (2022). LPS induces rapid increase in GDF15 levels in mice, rats, and humans but is not required for anorexia in mice. American journal of physiology. Gastrointestinal and liver physiology, 322(2), G247–G255. 10.1152/ajpgi.00146.2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pavlova NN, & Thompson CB (2016). The Emerging Hallmarks of Cancer Metabolism. Cell metabolism, 23(1), 27–47. 10.1016/j.cmet.2015.12.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. R Core Team (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. [Google Scholar]
  38. Scott K, Phan TT, Boukelmoune N, Heijnen CJ, & Dantzer R (2023). Chronic restraint stress impairs voluntary wheel running but has no effect on food-motivated behavior in mice. Brain Behavior and Immunity, 107(1), 319–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Servaes P, et al. (2002). “Fatigue in cancer patients during and after treatment: prevalence, correlates and interventions.” Eur J Cancer 38(1): 27–43. [DOI] [PubMed] [Google Scholar]
  40. Servaes P, Gielissen MF, Verhagen S, & Bleijenberg G (2007). The course of severe fatigue in disease-free breast cancer patients: a longitudinal study. Psycho-oncology, 16(9), 787–795. 10.1002/pon.1120 [DOI] [PubMed] [Google Scholar]
  41. Spanopoulou A, & Gkretsi V (2020). Growth differentiation factor 15 (GDF15) in cancer cell metastasis: from the cells to the patients. Clinical & experimental metastasis, 37(4), 451–464. 10.1007/s10585-020-10041-3 [DOI] [PubMed] [Google Scholar]
  42. Suriben R, Chen M, Higbee J, Oeffinger J, Ventura R, Li B, Mondal K, Gao Z, Ayupova D, Taskar P, Li D, Starck SR, Chen HH, McEntee M, Katewa SD, Phung V, Wang M, Kekatpure A, Lakshminarasimhan D, White A, … Allan BB (2020). Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Nature medicine, 26(8), 1264–1270. 10.1038/s41591-020-0945-x [DOI] [PubMed] [Google Scholar]
  43. Thong M, van Noorden C, Steindorf K, & Arndt V (2020). Cancer-Related Fatigue: Causes and Current Treatment Options. Current treatment options in oncology, 21(2), 17. 10.1007/s11864-020-0707-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Trecarichi A, & Flatters S (2019). Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced peripheral neuropathy. International review of neurobiology, 145, 83–126. 10.1016/bs.irn.2019.05.001 [DOI] [PubMed] [Google Scholar]
  45. Tsai V, Husaini Y, Sainsbury A, Brown DA, & Breit SN (2018). The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases. Cell metabolism, 28(3), 353–368. 10.1016/j.cmet.2018.07.018 [DOI] [PubMed] [Google Scholar]
  46. Vichaya EG, Chiu GS, Krukowski K, Lacourt TE, Kavelaars A, Dantzer R, Heijnen CJ, & Walker AK (2015). Mechanisms of chemotherapy-induced behavioral toxicities. Frontiers in neuroscience, 9, 131. 10.3389/fnins.2015.00131 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Vichaya EG, Ford BG, Quave CB, Rishi MR, Grossberg AJ, & Dantzer R (2020). Toll-like receptor 4 mediates the development of fatigue in the murine Lewis Lung Carcinoma model independently of activation of macrophages and microglia. Psychoneuroendocrinology, 122, 104874. 10.1016/j.psyneuen.2020.104874 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, & Steinberg GR (2021). GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nature reviews. Endocrinology, 17(10), 592–607. 10.1038/s41574-021-00529-7 [DOI] [PubMed] [Google Scholar]
  49. Wang Q, & Hutt KJ (2021). Evaluation of mitochondria in mouse oocytes following cisplatin exposure. Journal of ovarian research, 14(1), 65. 10.1186/s13048-021-00817-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Weinberg SE, & Chandel NS (2015). Targeting mitochondria metabolism for cancer therapy. Nature chemical biology, 11(1), 9–15. 10.1038/nchembio.1712 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Welsh JB, Sapinoso LM, Kern SG, Brown DA, Liu T, Bauskin AR, Ward RL, Hawkins NJ, Quinn DI, Russell PJ, Sutherland RL, Breit SN, Moskaluk CA, Frierson HF Jr, & Hampton GM (2003). Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proceedings of the National Academy of Sciences of the United States of America, 100(6), 3410–3415. 10.1073/pnas.0530278100 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Worth AA, Shoop R, Tye K, Feetham CH, D’Agostino G, Dodd GT, Reimann F, Gribble FM, Beebe EC, Dunbar JD, Alexander-Chacko JT, Sindelar DK, Coskun T, Emmerson PJ, & Luckman SM (2020). The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling. eLife, 9, e55164. 10.7554/eLife.55164 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Yang S, Chu S, Gao Y, Ai Q, Liu Y, Li X, & Chen N (2019). A Narrative Review of Cancer-Related Fatigue (CRF) and Its Possible Pathogenesis. Cells, 8(7), 738. 10.3390/cells8070738 [DOI] [PMC free article] [PubMed] [Google Scholar]

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