title: Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles.
abstract: 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.
authors.affiliation: Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Emidio E
authors.initials: EE
authors.lastname: Pistilli
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.forename: Fleur
authors.initials: F
authors.lastname: Garton
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Jason P
authors.initials: JP
authors.lastname: Gulbin
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Conner
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Anderson
authors.forename: LeBris S
authors.initials: LS
authors.lastname: Quinn
authors.forename: Kathryn
authors.initials: K
authors.lastname: North
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.forename: Tejvir S
authors.initials: TS
authors.lastname: Khurana
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics*; D007537:Isometric Contraction; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018763:Muscle Fatigue; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D010807:Physical Endurance; D020641:Polymorphism, Single Nucleotide
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D010100:Oxygen; D002118:Calcium