title: IL-15Rα deficiency in skeletal muscle alters respiratory function and the proteome of mitochondrial subpopulations independent of changes to the mitochondrial genome.
abstract: 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 occurred 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.
authors.affiliation: Division of Exercise Physiology, United States.
authors.forename: Grant C
authors.initials: GC
authors.lastname: O'Connell
authors.affiliation: Division of Exercise Physiology, United States.
authors.forename: Cody
authors.initials: C
authors.lastname: Nichols
authors.affiliation: Division of Exercise Physiology, United States.
authors.forename: Ge
authors.initials: G
authors.lastname: Guo
authors.affiliation: Division of Exercise Physiology, United States.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Croston
authors.affiliation: Division of Exercise Physiology, United States.
authors.forename: Dharendra
authors.initials: D
authors.lastname: Thapa
authors.affiliation: Division of Exercise Physiology, United States; Center for Cardiovascular and Respiratory Sciences, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Hollander
authors.affiliation: Division of Exercise Physiology, United States; Center for Cardiovascular and Respiratory Sciences, United States; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, United States. Electronic address: epistilli2@hsc.wvu.edu.
authors.forename: Emidio E
authors.initials: EE
authors.lastname: Pistilli
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D019069:Cell Respiration; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D053720:Interleukin-15 Receptor alpha Subunit / Q000172:deficiency*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D020543:Proteome / Q000032:analysis*
chemical_list: D004272:DNA, Mitochondrial; D053720:Interleukin-15 Receptor alpha Subunit; D020543:Proteome; D000255:Adenosine Triphosphate
keywords: IL-15Rα; Il-15; Mitochondrial genome; Mitochondrial subpopulations; Myokine; NGS