IL-15 Is Required for Postexercise Induction of the Pro-Oxidative Mediators PPARδ and SIRT1 in Male Mice

Abstract

Physical exercise induces transient upregulation of the pro-oxidative mediators peroxisome proliferator-activated receptor-δ (PPARδ), silent information regulator of transcription (sirtuin)-1 (SIRT1), PPARγ coactivator 1α (PGC-1α), and PGC-1β in skeletal muscle. To determine the role of the cytokine IL-15 in acute postexercise induction of these molecules, expression of these factors after a bout of exhaustive treadmill running was examined in the gastrocnemius muscle of untrained control and IL-15-knockout (KO) mice. Circulating IL-15 levels increased transiently in control mice after exercise. Control mice, but not IL-15-KO mice, upregulated muscle PPARδ and SIRT1 protein after exercise, accompanied by a complex pattern of mRNA expression for these factors. However, in exhaustive exercise, control mice ran significantly longer than IL-15-KO mice. Therefore, in a second experiment, mice were limited to a 20-minute run, after which a similar pattern of induction of muscle PPARδ and SIRT1 protein by control mice only was observed. In a separate experiment, IL-15-KO mice injected systemically with recombinant IL-15 upregulated muscle PPARδ and SIRT1 mRNA within 30 minutes and also exhibited increased muscle PPARδ protein levels by 3 hours. After exercise, both control and IL-15-KO mice downregulated IL-15 receptor-α (IL-15Rα) mRNA, whereas IL-15Rα-deficient mice exhibited constitutively elevated circulating IL-15 levels. These observations indicate IL-15 release after exercise is necessary for induction of PPARδ and SIRT1 at the protein level in muscle tissue and suggest that exercise releases IL-15 normally sequestered by the IL-15Rα in the resting state. These findings could be used to develop an IL-15-based strategy to induce many of the metabolic benefits of physical exercise.

Dysregulation of metabolic‐associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin‐15 targeting fatigue

“…IL‐15 is critical for the maintenance of NK cell and CD8 T cell number and function (see reviews Waldmann and Tagaya and Fehniger and Caligiuri). Our laboratory and others have shown that IL‐15 is also associated with enhancing the oxidative capacity of skeletal muscle . Specifically, mice genetically modified to have greater circulating levels of IL‐15 have a greater mitochondrial density in skeletal muscle, a greater resistance to contraction induced fatigue, and can perform longer on a motorized treadmill .…”

IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

“…Nevertheless, once released into circulation the IL-15/IL-15Rα complex binds, or IL-15 acting alone, to the IL-2Rβ/γ chains on its target tissue (Giri et al, 1995). It has repeatedly been shown that IL-15 induces mitochondrial associated factors in various tissues, such as adipose and SKM (Almendro et al, 2006; Quinn et al, 2012, 2013; Barra et al, 2014; O'Connell and Pistilli, 2015). With this in mind, we examined the role of IL-15 signaling in mediating increases in substrate availability through modulation of transport proteins.…”

“…Increased circulating levels of IL-15 have been implicated in stimulating expression of mitochondrial associated factors, such as PPARs and SIRT1, in mouse SKM (Almendro et al, 2008; Quinn et al, 2012, 2013; O'Connell and Pistilli, 2015). Additionally, IL-15 has the ability to stimulate both glucose uptake and fatty acid oxidation in SKM cells (Busquets et al, 2006).…”

IL-15Rα deficiency in skeletal muscle alters respiratory function and the proteome of mitochondrial subpopulations independent of changes to the mitochondrial genome

“…Despite widespread tissue expression of IL-15, its receptor complex, and IL-15Rα, the functions of IL-15 in non-immune tissues have only recently begun to be recognized. Evidence is accumulating which suggests that IL-15 plays a role as a myokine associated with oxidative skeletal muscle phenotypes (39, 41-43). …”

“…In the absence of the regulatory action of IL-15Rα, global tissue IL-15Rα knockout (IL15RαKO) mice display greater circulating levels of IL-15 (20, 43). Phenotypically, these mice display an increased capacity for exercise and ex vivo studies of muscle function have shown that fast muscles from IL15RαKO mice are resistant to fatigue (20, 39).…”