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 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.

Mitochondrial ultrastructural adaptations in fast muscles of mice lacking IL15RA

“…Previous studies focusing on the functional effects of lack of IL15RA in isolated muscle mitochondria fractions suggested that Il15ra −/− mitochondria are capable of a higher state 3 respiration (ADP-stimulated in presence of excess substrate), but also are in a partially uncoupled state (O'Connell et al, 2015). In addition, enhanced contraction-induced AMPK and ACC phosphorylation promotes mitochondrial uptake and oxidation of fatty acids in Il15ra −/− muscles (Loro et al, 2015).…”

“…Fast muscles of mice lacking IL15RA (Il15ra −/− ) are fatigue resistant (Pistilli et al, 2011) and their mitochondria more efficiently oxidize fatty acids as primary energy fuel (Loro et al, 2015). Polarographic analysis of isolated SS and IMF Il15ra −/− muscle mitochondria showed higher state 3 respiration and a tendency towards uncoupled oxygen consumption, especially in the IMF fraction (O'Connell et al, 2015).…”

Skeletal muscle IL‐15/IL‐15Rα and myofibrillar protein synthesis after resistance exercise

“…Although part of the effects of IL‐15 is mediated by its binding to IL‐15Rα, this alpha‐receptor may also exert functions independent from IL‐15 in skeletal muscle. IL‐15Rα may have a role in determining the phenotype and fatigability of muscle fibers, and mitochondrial fuel utilization . In addition, human studies indicate that IL‐15Rα may be involved in muscle hypertrophy and strength gains after resistance training .…”

Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype

“…PDOX-bearing animals were euthanized approximately 30 days after reaching a tumor volume of tumor-bearing animals and tissues were processed identically in both groups. Immediately after death, both quadriceps muscles from each mouse were quickly removed and interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria were isolated separately according to previously described methods [39][40][41][42] Luminescence intensity values were blank-corrected and normalized to account for differing protein concentrations, which were quantified using the DC™ Protein Assay (Bio-Rad, California, USA).…”