IL-15Rα deficiency leads to mitochondrial and myofiber differences in fast mouse muscles

Pistilli, Emidio E.; Guo, Guijie; Stauber, William T.

doi:10.1016/j.cyto.2012.09.025

Cited by 18 publications

(31 citation statements)

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“…Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic signaling and changing the oxidative properties of muscle (28,29,33,34,36,40). IL-15 levels increase in muscles of endurance-trained individuals (44).…”

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confidence: 99%

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Loro

Seifert

Moffat

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15R␣ take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R␣ promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15R␣ on metabolism and obesity are currently unknown. We report that mice lacking IL-15R␣ (IL-15R␣ Ϫ/Ϫ ) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R␣ Ϫ/Ϫ mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15R␣ Ϫ/Ϫ are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R␣ in metabolism and obesity.interleukin-15 receptor alpha; diet-induced obesity; muscle; fatty acid oxidation; fatigue recovery; glucose homeostasis ACCUMULATION OF EXCESSIVE body fat is a physiological consequence of unnecessary caloric intake. With greater worldwide food production, often the caloric intake largely exceeds the physiological energy requirements, and as a result, the obesity pandemic is growing at alarming rates in both developed and developing countries (21,47). Apart from the role of environmental factors, particularly an energy-dense diet and sedentary lifestyle, obesity also has important genetic determinants that have been conserved across species. Identifying the molecular mechanisms regulating metabolic efficiency (the capacity to convert energy intake into storable energy forms) is of great interest because of the low success in using caloric restriction as a means to manage obesity. Indeed, a number of pathways have been recently identified that reduce the extent of dietinduced obesity (DIO) by decreasing metabolic efficiency rather than energy input (8,10,11,43,56,59,60). Targeting these pathways with pharmacological approaches may also have the advantage of reproducing some of the benefits normally associated with physical exercise. Together with caloric restriction, exercise is a mainstay of a healthy life style and contributes to the control of metabolic efficiency. In addition to converting energy into movement, exercise increases the rates of lipolysis and fat oxidation, promotes heat dissipation (49, 53), and causes long-term changes in the expression of numerous genes, including IL-15R␣/IL-15 (55).IL-15 and its primary binding partner IL-15R␣ have emerged as important regulators of cell functions in both lymphoid and nonlymphoid tissues. Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic...

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mentioning

confidence: 99%

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

Loro

Seifert

Moffat

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Specifically, mitochondria from the skeletal muscles of IL15RαKO mice present a swollen phenotype with sparse cristae. In support of this visual observation, mitochondrial internal complexity, a flow cytometric measure of cristae structure, is lower compared to mitochondria isolated from control muscles (40). It remains unclear whether these structural alterations which are observed with IL-15Rα deficiency impact mitochondrial function.…”

Section: Introductionmentioning

confidence: 56%

“…Standard rodent chow and water were provided ab libitum. Experimental procedures were performed using mice between 9 and 11 weeks of age, to maintain consistency with our previously published data (39, 40). All experimental procedures were submitted to and approved by the West Virginia University Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, there is evidence of a shift towards an oxidative muscle phenotype driven by alterations to the mitochondrial network. Muscles from the IL15RαKO mouse display a greater mitochondrial density, an observation supported by greater transcriptional activity of genes associated with mitochondrial biogenesis such as peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and peroxisome proliferator-activated receptor delta (PPARδ) (39, 40). Interestingly, a separate transgenic mouse model bred to over-express a highly secretable form of IL-15 within skeletal muscle also displays greater circulating levels of IL-15, increases in exercise capacity and similar molecular markers indicative of an oxidative shift (42).…”

Section: Introductionmentioning

confidence: 99%

“…interfibrillar mitochondria; IFM). Based on the phenotypic changes observed at the whole muscle level in the IL15RαKO mouse (39), as well as the alterations in mitochondrial density and morphology (40), we hypothesized that the respiratory capacity of the IFM mitochondrial subpopulation isolated from muscle of IL15RαKO mice would be greater compared to the IFM isolated from muscles of control mice, and that proteomic and genomic analyses would highlight markers in support of this respiratory phenotype. Polarography experiments revealed differences in several respiratory parameters measured in mitochondrial subpopulations isolated form muscles of IL15RαKO mice and controls, and multi-dimensional protein identification suggested that these changes are associated with altered expression of mitochondrial-associated proteins.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Interleukin-15 receptor alpha knockout (IL15RαKO) mice exhibit a greater skeletal muscle mitochondrial density with an altered mitochondrial morphology. However, the mechanism and functional impact of these changes have not been determined. In this study, we characterized the functional, proteomic, and genomic alterations in mitochondrial subpopulations isolated from the skeletal muscles of IL15RαKO mice and B6129 background control mice. State 3 respiration was greater in interfibrillar mitochondria and whole muscle ATP levels were greater in IL15RαKO mice supporting the increases in respiration rate. However, the state 3/state 4 ratio was lower, suggesting some degree of respiratory uncoupling. Proteomic analyses identified several markers independently in mitochondrial subpopulations that are associated with these functional alterations. Next Generation Sequencing of mtDNA revealed a high degree of similarity between the mitochondrial genomes of IL15RαKO mice and controls in terms of copy number, consensus coding and the presence of minor alleles, suggesting that the functional and proteomic alterations we observed occur independent of alterations to the mitochondrial genome. These data provide additional evidence to implicate IL-15Rα as a regulator of skeletal muscle phenotypes through effects on the mitochondrion, and suggest these effects are driven by alterations to the mitochondrial proteome.

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Obesity, Myokines, and Metabolic Health

Malandrino,

Ahima

2023

Metabolic Syndrome

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IL-15Rα deficiency leads to mitochondrial and myofiber differences in fast mouse muscles

Cited by 18 publications

References 17 publications

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

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

Obesity, Myokines, and Metabolic Health

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