IL-15 is required for postexercise induction of the pro-oxidative mediators PPARδ and SIRT1 in male mice
Open accessAbstract
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.
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IL-15 augments PPARδ and PGC-1α activity, favoring mitochondrial biogenesis and fatty acid oxidation.
“and augments PPARδ and PGC-1α activity, favoring mitochondrial biogenesis and FAO [84,91,126]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [126]
The Discussion reports that IL-15 induces muscle PPARδ expression and suggests that this could lead to PGC-1α mRNA expression; it also links IL-15 overexpression with increased lipid oxidation. But the Results and Discussion say IL-15 was not required for postexercise PGC-1α protein induction. The paper does not establish increased PGC-1α activity or mitochondrial biogenesis as effects of IL-15. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExercise-inducible myokines irisin, IL-6, IL-15, BAIBA, and METRNL, as well as osteokine OCN, directly stimulate oxidative metabolism in autocrine and endocrine ways.
“Exercise-inducible myokines, such as irisin [62,63], IL-6 [76,77], IL-15 [91,126], BAIBA [111], and METRNL [100], as well as the osteokine OCN [71] have been shown to directly stimulate oxidative metabolism in autocrine and endocrine ways, respectively (1).”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [126]
The Abstract and Discussion report that exercise increases circulating IL-15 and that IL-15 is necessary and sufficient for upregulation of the pro-oxidative regulator PPARδ in mouse skeletal muscle. But the Discussion says the study did not establish that exercising muscle released the IL-15 and could not rule out indirect effects. It therefore does not establish the cited claim that IL-15 directly stimulates oxidative metabolism through autocrine or endocrine action. (LLM, conf=0.88)
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Obesity, Myokines, and Metabolic Health
Malandrino, N., & Ahima, R. S. (2023) · Springer eBooks · doi:10.1007/978-3-319-12125-3_56-1
Hyödynmaa, J. (2015) · Jyväskylä University Digital Archive (University of Jyväskylä)
- Authors
- Quinn, L. S., Anderson, B. G., Conner, J. D., Wolden-Hanson, T., & Marcell, T. J.
- Affiliations
- University of Washington (US)
- VA Puget Sound Health Care System (US)
- Research Service (L.S.Q., J.D.C., T.W.-H.), VA Puget Sound Health Care System, Seattle, Washington 98108
- California State University, Stanislaus (US)
- Corresponding author
- Quinn, LeBris S.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2014-01-01
- Volume
- 155
- Issue
- 1
- Pages
- 143-155
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC5378429
- OpenAlex
- W2009231761
- Semantic Scholar
- 6c7f4da9f7d9a07200a9770e19540609dd873b8a
- Cited by
- 40
- References
- 48
- Citations by year
- 2024: 5 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 7 · 2014: 4
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001026)
- National Institute on Aging (P30AG013280)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK 17047, P30DK017047)
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- IL-15, PPARδ, SIRT1, PGC-1α, PGC-1β, skeletal muscle, physical activity, oxidative stress, IL-15 receptor alpha, treadmill running, exercise-induced gene expression
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Body Composition, Gene Expression Regulation, Male, Oxygen, Physical Conditioning, Animal, RNA, Messenger, Transcription Factors, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Muscle, Skeletal, Interleukin-15, Mice, Sirtuin 1, Real-Time Polymerase Chain Reaction
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