Cytokine Signaling in Skeletal Muscle Wasting

Zhou, Jin; Liu, Bin; Liang, Chun; Li, Yangxin; Song, Yao‐Hua

doi:10.1016/j.tem.2016.03.002

Cited by 150 publications

(112 citation statements)

References 87 publications

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“…Although chronic inflammation is a non‐specific immune response, cytokines are inflammatory mediators that have been implicated in the progression of several diseases and associated co‐morbidities (Deans & Wigmore, ; Fearon, Glass, & Guttridge, ; Lightfoot & Cooper, ; Zhou, Liu, Liang, Li, & Song, ). In addition to tumour growth and development, elevated circulating IL‐6 has been linked to disrupted protein turnover associated with cancer‐induced muscle wasting (Carson & Baltgalvis, ; Cron, Allen, & Febbraio, ; Narsale & Carson, ).…”

Section: Discussionmentioning

confidence: 99%

The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin‐6

VanderVeen

Fix

Montalvo

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Interleukin‐6 has been associated with muscle mass and metabolism in both physiological and pathological conditions. A causal role for interleukin‐6 in the induction of fatigue and disruption of mitochondrial function has not been determined. What is the main finding and its importance?We demonstrate that chronically elevated interleukin‐6 increased skeletal muscle fatigability and disrupted mitochondrial content and function independent of changes in fibre type and mass. Abstract Interleukin‐6 (IL‐6) can initiate intracellular signalling in skeletal muscle by binding to the IL‐6‐receptor and interacting with the transmembrane gp130 protein. Circulating IL‐6 has established effects on skeletal muscle mass and metabolism in both physiological and pathological conditions. However, the effects of circulating IL‐6 on skeletal muscle function are not well understood. The purpose of this study was to determine whether chronically elevated systemic IL‐6 was sufficient to disrupt skeletal muscle force, fatigue and mitochondrial function. Additionally, we examined the role of muscle gp130 signalling during overexpression of IL‐6. Systemic IL‐6 overexpression for 2 weeks was achieved by electroporation of an IL‐6 overexpression plasmid or empty vector into the quadriceps of either C57BL/6 (WT) or skeletal muscle gp130 knockout (KO) male mice. Tibialis anterior muscle in situ functional properties and mitochondrial respiration were determined. Interleukin‐6 accelerated in situ skeletal muscle fatigue in the WT, with a 18.5% reduction in force within 90 s of repeated submaximal contractions and a 7% reduction in maximal tetanic force after 5 min. There was no difference between fatigue in the KO and KO+IL‐6. Interleukin‐6 reduced WT muscle mitochondrial respiratory control ratio by 36% and cytochrome c oxidase activity by 42%. Interleukin‐6 had no effect on either KO respiratory control ratio or cytochrome c oxidase activity. Interleukin‐6 also had no effect on body weight, muscle mass or tetanic force in either genotype. These results provide evidence that 2 weeks of elevated systemic IL‐6 is sufficient to increase skeletal muscle fatigability and decrease muscle mitochondrial content and function, and these effects require muscle gp130 signalling.

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Section: Discussionmentioning

confidence: 99%

The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin‐6

VanderVeen

Fix

Montalvo

et al. 2019

Experimental Physiology

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“…Peripheral muscle wasting has been associated with increased cytokine signaling, especially with TNF-α largely implicated in the process (49, 50). The larger peripheral target muscle morphometry of 24-month-old rats observed in this study, compared to 3-month-old animals could be associated with the reduced levels of peripheral inflammatory cytokines noted.…”

Section: Discussionmentioning

confidence: 99%

Disparate Changes in Plasma and Brainstem Cytokine Levels in Adult and Ageing Rats Associated with Age-Related Changes in Facial Motor Neuron Number, Snout Muscle Morphology, and Exploratory Behavior

et al. 2016

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An overall increase in inflammatory cytokines with age in both the blood and the central nervous system (CNS) has been proposed to explain many aspects of ageing, including decreased motor function and neurodegeneration. This study tests the hypothesis that age-related increases in inflammatory cytokines in the blood and CNS lead to facial motor neuron degeneration. Groups of 3–5 female Sprague-Dawley rats aged 3, 12–18, and 24 months were used. Twelve cytokines interleukin (IL)-1α, IL-β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, tumor necrosis factor-α (TNFα), interferon-γ, and granulocyte macrophage-colony stimulating factor were measured in blood plasma and compared with those in the brainstem after first flushing blood from its vessels. The open-field test was used to measure exploratory behavior, and the morphology of the peripheral target muscle of facial motor neurons quantified. Total numbers of facial motor neurons were determined stereologically in separate groups of 3- and 24-month-old rats. Ageing rats showed a significant 30–42% decrease in blood plasma (peripheral) concentrations of IL-12p70 and TNFα and a significant 43–49% increase in brainstem (central) concentrations of IL-1α, IL-2, IL-4, IL-10, and TNFα. They also showed significant reductions in motor neuron number in the right but not left facial nucleus, reduced exploratory behavior, and increase in peripheral target muscle size. Marginal age-related facial motoneuronal loss occurs in the ageing rat and is characterized by complex changes in the inflammatory signature, rather than a general increase in inflammatory cytokines.

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“…Besides performing contractions to facilitate various physical motions necessary for daily life, skeletal muscles also activate multiple signalling pathways in response to circulating factors to regulate whole body metabolism and maintain general physiological homeostasis . However, threats such as ageing, chronic diseases, inflammation, prolonged inactivity, and inadequate nutrition can lead to progressive loss of skeletal muscle mass and function . In particular, persistent inflammation and increased levels of inflammatory cytokines have been strongly implicated in the ageing‐related loss of skeletal muscle mass, that is, sarcopenia.…”

Section: Introductionmentioning

confidence: 99%

Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention

Shyh‐Chang

et al. 2019

J cachexia sarcopenia muscle

182

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Background Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ageing‐related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons. Methods A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non‐sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty‐two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre‐intensive and post‐intensive lifestyle interventions, were measured. Results The sarcopenic group was significantly older (72.05 ± 6.54 years; P < 0.001), more likely to be inactive and female (57.1% of all sarcopenic patients), and had a higher prevalence of type 2 diabetes (16% higher risk). Compared with non‐sarcopenic subjects, serum interleukin (IL)‐6, IL‐18, tumour necrosis factor‐α (TNF‐α), TNF‐like weak inducer of apoptosis (TWEAK), and leptin were significantly higher, while insulin growth factor 1, insulin, and adiponectin were significantly lower in sarcopenic patients (all P < 0.05). Logistic regression analyses revealed that high levels of TNF‐α (>11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6‐fold and 14.3‐fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4‐fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF‐α, IL‐18, insulin, and adiponectin (all P < 0.05). Conclusions High levels of the inflammatory cytokines TWEAK and TNF‐α are associated with an increased risk of sarcopenia, while the metabolic hormones insulin growth factor 1, insulin, and adiponectin are associated with a decreased risk of sarcopenia in our Chinese patient cohort. Intensive lifestyle interventions could signif...

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Cytokine Signaling in Skeletal Muscle Wasting

Cited by 150 publications

References 87 publications

The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin‐6

The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin‐6

Disparate Changes in Plasma and Brainstem Cytokine Levels in Adult and Ageing Rats Associated with Age-Related Changes in Facial Motor Neuron Number, Snout Muscle Morphology, and Exploratory Behavior

Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention

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