Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice

Gil, Carla Igual; Ost, Mario; Kasch, Juliane; Schumann, Sara; Heider, Sarah; Schimrigk, К.

doi:10.1038/s41598-019-56922-w

Cited by 31 publications

(27 citation statements)

References 51 publications

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“…S2a ). Thus, despite that an increase in Gdf15 mRNA in human exercising muscle has been reported 24 , it remains unclear if GDF15 is a relevant myokine 10 , 25 . In contrast to forced treadmill running, voluntary wheel running does not increase circulating GDF15 levels, likely due its lower intensity and/or intermittent nature (Fig.…”

Section: Resultsmentioning

confidence: 93%

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

et al. 2021

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Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.

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Section: Resultsmentioning

confidence: 93%

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

et al. 2021

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“…Moreover, even though its receptor, GDNF family receptor α-like (GFRAL), has not been found expressed in muscle (40) GDF15 is able to induce muscle fiber apoptosis via phosphorylation of STAT3 (13). On the other side, as mentioned, the GDF15 knockout determines the elevation of markers of muscle stress (Atf3, Atf6, and Xbp1s) upon exercise (14). Our data suggest that GDF15 is inversely associated with muscle health, as it is elevated in patients with lower limb mobility impairment and inversely associated with their quadriceps maximal torque.…”

Section: Discussionmentioning

confidence: 99%

“…As it is known that strenuous exercise induces GDF15 expression (20)(21)(22), it has been hypothesized that also skeletal muscle can be a source of this cytokine. Accordingly, GDF15 is expressed in muscles from mouse models of aging and inactivity (12,14). However, this idea has been recently challenged, as the concentrations of GDF15 during a physical exercise resulted similar in arterial and venous blood across the exercised leg (22).…”

Section: Discussionmentioning

confidence: 99%

“…As far as muscle atrophy and sarcopenia, there is debate on whether GDF15 is to be considered protective or detrimental. Recent data from animal models showed that GDF15 is able to induce muscle fiber apoptosis (12,13), but also the ablation of GDF15 resulted in an amplified skeletal muscle post exercise stress response, with a bigger increase of markers of muscle stress (Atf3, Atf6, and Xbp1s) (14). In humans, circulating GDF15 levels are significantly higher in subjects with sarcopenia or muscle atrophy (15)(16)(17) with respect to healthy subjects of comparable age.…”

Section: Introductionmentioning

confidence: 99%

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GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

et al. 2020

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Growth differentiation factor 15 (GDF15) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether GDF15 is beneficial or detrimental. The aim of the study was to analyse the levels of circulating GDF15 in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of GDF15 was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of GDF15 increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating GDF15 is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of GDF15 plasma levels, that after the race are similar to that of patients. Moreover, GDF15 plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that GDF15 is associated with decreased muscle performance and increased inflammation.

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“…According to their nocturnal activity pattern, mice kept under a 12/12 h light/dark schedule show voluntary wheel running activity almost exclusively at night and also consume most of their food (about 75%) during the dark phase [29,30]. The liver as the central metabolic organ and hub of nutrient distribution is particularly affected by the rhythmicity of food intake.…”

Section: Feeding and Exercise As Important Cues For Diurnal Entrainmentmentioning

confidence: 99%

Regulation of diurnal energy balance by mitokines

Schimrigk

Gil

Ost

2021

Cell. Mol. Life Sci.

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The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.

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Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice

Cited by 31 publications

References 51 publications

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

GDF15 Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness

Regulation of diurnal energy balance by mitokines

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