Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise

Gudiksen, Anders; Schwartz, Camilla Victoria Lindgren; Bertholdt, Lærke; Joensen, Ella; Knudsen, Janne Lehmann; Pilegaard, Henriette

doi:10.1371/journal.pone.0156460

Cited by 32 publications

(50 citation statements)

References 53 publications

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“…While we were writing this manuscript the Pilegaard laboratory reported an RER increase in muscle-specific IL-6 KO males during 120 min of treadmill exercise [32]. They also observed a higher pyruvate dehydrogenase activity (PDH) at rest and after 60 min of exercise, and suggested that muscle IL-6 exerts an inhibitory action on skeletal muscle PDH and therefore on carbohydrate utilization, supporting the RER results.…”

Section: Discussionmentioning

confidence: 57%

Role of muscle IL-6 in gender-specific metabolism in mice

et al. 2017

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The aim of the present work was to further explore the physiological roles of muscle-derived IL-6. Adult-floxed and conditional skeletal muscle IL-6 knock out male and female mice were used to study energy expenditure (indirect calorimetry at rest and during treadmill exercise, and body temperature cycle during the light phase) and energy intake (response to fast/refeeding). We also evaluated the responses to leptin and the activity of the insulin signalling pathway in skeletal muscle and liver by phosphorylation of Akt at Ser 473. The stress response was also studied. Results indicate a relevant role of muscle IL-6 in maintaining energy homeostasis, especially in males. Absence of muscle IL-6 in male mice results in lower core body temperature in the light phase, increased respiratory exchange ratio (RER) both at rest and during exercise, increased expression of TCA cycle marked gene, citrate synthase in muscle, reduced fat storage and decreased body weight and food consumption in response to leptin. In females, muscle IL-6 deficiency increases VO2 and CO2 levels similarly. Also in contrast to males, energy expenditure (EE) measured over 48h reveals a significant elevation in female mice with muscle IL-6 deficiency; moreover, they show a modified response to fasting-refeeding and to restraint stress. The present results contribute to the understanding of the role of muscle IL-6 in male and female mouse metabolism, not only during exercise but also in the basal state and in situations where energy balance is altered.

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Section: Discussionmentioning

confidence: 57%

Role of muscle IL-6 in gender-specific metabolism in mice

et al. 2017

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“…Although several intracellular pathways can be activated by gp130 signaling, STAT3 activation is often regarded as the canonical pathway (13). Plasma IL-6 has been associated with muscle oxidative metabolism alterations that occur with disease and exercise (17,65). Chronically elevated plasma IL-6 in tumor-bearing mice can negatively regulate muscle mass and oxidative metabolism (3,65).…”

Section: Introductionmentioning

confidence: 99%

“…Chronically elevated plasma IL-6 in tumor-bearing mice can negatively regulate muscle mass and oxidative metabolism (3,65). Alternatively, exercise-induced increases in plasma IL-6 have been implicated in the acute metabolic response to exercise (17), and contracting muscles are a major producer of IL-6 (14,15). Although exercise can alter systemic and local intracellular signaling that regulates muscle metabolic homeostasis (11,22,48,70), our understanding of the importance of IL-6 signaling for exercise-induced mitochondrial adaptations has proven to be challenging.…”

Section: Introductionmentioning

confidence: 99%

Role of gp130 in basal and exercise-trained skeletal muscle mitochondrial quality control

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Hardee

Gao

et al. 2018

Journal of Applied Physiology

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The IL-6 cytokine family activates intracellular signaling pathways through glycoprotein-130 (gp130), and this signaling has established regulatory roles in muscle glucose metabolism and proteostasis. Although the IL-6 family has been implicated as myokines regulating the muscles' metabolic response to exercise, gp130's role in mitochondrial quality control involving fission, fusion, mitophagy, and biogenesis is not well understood. Therefore, we examined gp130's role in basal and exercise-trained muscle mitochondrial quality control. Muscles from C57BL/6, skeletal muscle-specific gp130 knockout (KO) mice, and CC myotubes, were examined. KO did not alter treadmill run-to-fatigue or indices of mitochondrial content [cytochrome- c oxidase (COX) activity] or biogenesis (AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor A, and COX IV). KO increased mitochondrial fission 1 protein (FIS-1) while suppressing mitofusin-1 (MFN-1), which was recapitulated in myotubes after gp130 knockdown. KO induced ubiquitin-binding protein p62, Parkin, and ubiquitin in isolated mitochondria from gastrocnemius muscles. Knockdown of gp130 in myotubes suppressed STAT3 and induced accumulation of microtubule-associated protein-1 light chain 3B (LC3)-II relative to LC3-I. Suppression of myotube STAT3 did not alter FIS-1 or MFN-1. Exercise training increased muscle gp130 and suppressed STAT3. KO did not alter the exercise-training induction of COX activity, biogenesis, FIS-1, or Beclin-1. KO increased MFN-1 and suppressed 4-hydroxynonenal after exercise training. These findings suggest a role for gp130 in the modulation of mitochondrial dynamics and autophagic processes. NEW & NOTEWORTHY Although the IL-6 family of cytokines has been implicated in the regulation of skeletal muscle protein turnover and metabolism, less is understood about its role in mitochondrial quality control. We examined the glycoprotein-130 receptor in the regulation of skeletal muscle mitochondria quality control in the basal and exercise-trained states. We report that the muscle glycoprotein-130 receptor modulates basal mitochondrial dynamics and autophagic processes and is not necessary for exercise-training mitochondrial adaptations to quality control.

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“…Moreover, exercise training-induced increases in UCP-1 in inguinal white AT are absent in whole body IL-6 deficient mice (Knudsen et al 2014). While these findings hint at the possibility of a muscle-IL-6-AT signaling axis recent work has shown intact exercise-induced increases in circulating IL-6 from muscle specific IL-6 knockout mice (Gudiksen et al 2016) providing evidence that muscle is not the sole producer of IL-6 during exercise and/or the recovery from it.…”

Section: Catecholamines Il-6 and Other Potential Mediatorsmentioning

confidence: 96%

“…While these findings hint at the possibility of a muscle‐IL‐6‐AT signaling axis recent work has shown intact exercise‐induced increases in circulating IL‐6 from muscle specific IL‐6 knockout mice (Gudiksen et al. ) providing evidence that muscle is not the sole producer of IL‐6 during exercise and/or the recovery from it.…”

Section: Catecholamines Il‐6 and Other Potential Mediatorsmentioning

confidence: 97%

Cycling our way to fit fat

2017

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Adipose tissue is increasingly being recognized as a key regulator of whole body carbohydrate and lipid metabolism. In conditions of obesity and insulin resistance mitochondrial content in this tissue is reduced, while treatment with insulin sensitizing drugs such as thiazolidinediones (TZDs) increase mitochondrial content. It has been known for decades that exercise increases mitochondrial content in skeletal muscle and now several laboratories have shown similar effects in adipose tissue. To date the specific mechanisms mediating this effect have not been fully identified. In this review we highlight recent work suggesting that increases in lipolysis and subsequently fatty acid re‐esterification trigger the activation of 5' AMP‐activated protein kinase (AMP) activated protein kinase and ultimately the induction of mitochondrial biogenesis. It is our current view that this pathway could be a unifying mechanism linking numerous systemic factors (catecholamines, interleukin‐6, meteorin‐like) to induction of mitochondrial biogenesis following exercise.

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Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise

Cited by 32 publications

References 53 publications

Role of muscle IL-6 in gender-specific metabolism in mice

Role of muscle IL-6 in gender-specific metabolism in mice

Role of gp130 in basal and exercise-trained skeletal muscle mitochondrial quality control

Cycling our way to fit fat

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