The regulation of interleukin‐6 implicates skeletal muscle as an integrative stress sensor and endocrine organ

Abstract

Skeletal muscle has been identified as an endocrine organ owing to its capacity to produce and secrete a variety of cytokines (myokines) and other proteins. To date, myokines have primarily been studied in response to exercise or metabolic challenges; however, numerous observations suggest that skeletal muscle may also release myokines in response to certain categories of internal or external stress exposure. Internal stress signals include oxidative or nitrosative stress, damaged or unfolded proteins, hyperthermia or energy imbalance. External stress signals, which act as indicators of organismal stress or injury in other cells, employ mediators such as catecholamines, endotoxin, alarmins, ATP and pro-inflammatory cytokines, such as tumour necrosis factor-α and interleukin-1β. External stress signals generally induce cellular responses through membrane receptor systems. In this review, we focus on the regulation of interleukin-6 (IL-6) as a prototypical stress response myokine and highlight evidence that IL-6 gene regulation in muscle is inherently organized to respond to a wide variety of internal and external stressors. Given that IL-6 can initiate protective, anti-inflammatory or restorative processes throughout the organism during life-threatening conditions, we present the argument that skeletal muscle has a physiological function as a sensor and responder to stress. Furthermore, we hypothesize that it may comprise a fundamental component of the organism’s acute stress response.

Hot water immersion induces an acute cytokine response in cervical spinal cord injury

“…Heat shock factors contribute to the activation of IL-6 synthesis during hyperthermia: As cell temperature rises, protein denaturation results in an increased concentration of heat shock factors, inducing enhanced transcription of IL-6 protein (Welc and Clanton 2013). Increases in IL-6 mRNA exhibit a doseresponse relationship: temperatures of 40.5 ºC do not increase mouse myotube IL-6 mRNA, whereas temperatures of 41 ºC induce 2.5 fold elevations (Welc et al 2012).…”

“…Such interventions also impact on immunity and increase immune cell counts and cytokine secretion (Laing et al 2008). This has been attributed to heat shock factors (Welc and Clanton 2013) and the core-temperature related increases of stress hormones acting on adrenergic receptors on immune cells (Kappel et al 1991), even though these increases are more modest when at rest than during exercise.…”

“…It has been suggested that with repeated moderate-vigorous exercise, the recurrent and longer lasting antiinflammatory response reduces levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6), at rest (Gleeson et al 2011). The cytokine response -in the specific case of IL-6 -is governed by muscle-contraction dependent and sympathetic nervous system mediated signalling pathways (Welc and Clanton 2013). This may explain the blunted cytokine response to acute exercise in CSCI, given their reduced muscle mass and sympathetic dysfunction (Kouda et al 2012;Paulson et al 2013)., and Iin turn, this may contribute to higher concentrations of pro-inflammatory markers found in CSCI at rest (Davies et al 2007;Kouda et al 2012;Segal et al 1997).…”

Inflammation-mediating cytokine response to acute handcycling exercise with/without functional electrical stimulation-evoked lower-limb cycling

“…The production and release of IL-6 is regulated by a synergy of signaling pathways responsive to mechanical stimuli, intramuscular calcium concentrations, muscle glycogen stores, and the sympathetic nervous system (SNS) [3,12,21]. In support of previous findings, 30 min of moderate intensity upper-limb exercise alone resulted in a significant increase in SNS-mediated plasma adrenaline concentrations [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Despite this SNS response, the 0.5-fold increase in plasma IL-6 observed during HC was smaller than the IL-6 response previously reported by Kouda et al in a group of non-spinal injured controls during 20 min arm-crank ergometry at the same relative intensity [9].…”

“…It is unknown whether the deterioration in skeletal muscle size [19] and alterations in skeletal muscle metabolism [20] observed following lower-limb paralysis will affect the release of IL-6 and the subsequent anti-inflammatory cascade. Similarly, it is unknown whether involuntary FES-evoked contractions can activate intracellular signaling mechanisms responsible for the production and release of the myokine IL-6 during acute exercise [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”