Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy

Pistilli, Emidio E.; Siu, Parco M.; Alway, Stephen E.

doi:10.1152/ajpcell.00496.2006

Cited by 67 publications

(59 citation statements)

References 45 publications

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“…Our laboratory has previously suggested that skeletal muscle increases IL-15 mRNA concentrations in response to atrophic stimuli, as a molecular attempt to counter muscle loss [3]. In this study, we tested the hypothesis that IL-15 would attenuate apoptosis within aged skeletal muscles by increasing circulating levels of IL-15 protein in aged rats.…”

Section: Discussionmentioning

confidence: 97%

“…Skeletal muscle expresses mRNAs for both IL-15 [2] and the three components of the IL-15 receptor (IL-15R: IL-15Rα, IL-2R/IL-15Rβ, γc) [3]. While conditions that promote muscle atrophy (i.e.-aging, disuse) have been shown to alter IL-15 mRNA concentrations within skeletal muscle [3], the role that the IL-15/IL-15R axis plays in skeletal muscle remains not fully elucidated. Production of mature IL-15 protein is tightly regulated at the levels of protein translation and vesicle trafficking, explaining in part, why mature IL-15 protein has been difficult to measure in biological fluids [4].…”

Section: Introductionmentioning

confidence: 99%

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Systemic elevation of interleukin-15 in vivo promotes apoptosis in skeletal muscles of young adult and aged rats

Pistilli

2008

Biochemical and Biophysical Research Communications

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In this study, we tested the hypothesis that systemic elevation of IL-15 would attenuate apoptosis in skeletal muscles of aged rats. IL-15 was administered to young adult (n=6) and aged (n=6) rats for 14 days. Apoptosis was quantified using an ELISA assay and verified through TUNEL staining of muscle sections. As expected, apoptosis was greater in muscles from aged control rats, compared to age-matched control. Apoptosis was also greater in the muscles from young adult and aged rats treated with IL-15. These increases in apoptosis were associated with decreases in muscle mass of IL-15 treated rats. These data do not support our initial hypothesis and suggest that systemic elevation of IL-15 promotes apoptosis in skeletal muscle. The proposed anti-apoptotic property of IL-15 may be specific to cell-type and/or the degree of muscle pathology present; however, additional research is required to more clearly decipher its role in skeletal muscle.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Systemic elevation of interleukin-15 in vivo promotes apoptosis in skeletal muscles of young adult and aged rats

Pistilli

2008

Biochemical and Biophysical Research Communications

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“…Total RNA was isolated from gastrocnemius muscles, spleen, and kidney of IL-15Rα-KO mice and B6129 control mice as previously described (4). RNA quantity and integrity were assessed using a Nano-Drop 2000 Spectrophotometer (Thermo Scientific); the 260/280 ratio for all samples used was between 1.9 and 2.1.…”

Section: Taqman Qpcrmentioning

confidence: 99%

“…The plasma membrane receptor for IL-15 was initially characterized as trimeric in structure, composed of IL-2 receptor β (IL-2Rβ), the common gamma chain (γc), and a specific IL-15Rα chain (2,3). Transcripts for IL-15 and IL-15Rα have a wide tissue distribution, and skeletal muscle tissue contains an abundance of IL15 and IL15RA mRNAs (1,2) that are responsive to atrophic stimuli (4), muscle contraction (5), and aging (4,6,7). In vitro experiments in myogenic cells initially suggested that IL-15 was an anabolic factor for skeletal muscle, able to stimulate the accumulation of contractile protein in differentiated myotubes (8)(9)(10).…”

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confidence: 99%

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

Pistilli¹,

Bogdanovich²,

Garton³

et al. 2011

J. Clin. Invest.

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128

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IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15Rα-knockout (IL-15Rα-KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15Rα has a role in defining the phenotype of fast skeletal muscles in vivo.

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“…43 RNA quantity and integrity was accessed using a NanoDrop spectrophotometer (Thermo Scientific, Wilmington, DE); the 260/280 ratio for all samples used was between 1.9 and 2.1. Two micrograms of total RNA was reverse transcribed to make cDNA using a high-capacity cDNA reverse transcription kit according to the manufacturer's instructions (Applied Biosystems, Foster City, CA).…”

Section: Qpcr Gene Expression Analysismentioning

confidence: 99%

Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy

Pistilli

Bogdanovich

Goncalves

et al. 2011

The American Journal of Pathology

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The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-␤ superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg ؊1 body weight. After 12 weeks of treatment, the 10.0 mg/kg ؊1 dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg ؊1 ), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.

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Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy

Abstract: Pistilli EE, Siu PM, Alway SE. Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy.

Cited by 67 publications

References 45 publications

Systemic elevation of interleukin-15 in vivo promotes apoptosis in skeletal muscles of young adult and aged rats

Systemic elevation of interleukin-15 in vivo promotes apoptosis in skeletal muscles of young adult and aged rats

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy

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