Muscle-specific deletion of exons 2 and 3 of theIL15RAgene in mice: effects on contractile properties of fast and slow muscles

Abstract

Interleukin-15 (IL-15) is a putative myokine hypothesized to induce an oxidative skeletal muscle phenotype. The specific IL-15 receptor alpha subunit (IL-15Rα) has also been implicated in specifying this contractile phenotype. The purposes of this study were to determine the muscle-specific effects of IL-15Rα functional deficiency on skeletal muscle isometric contractile properties, fatigue characteristics, spontaneous cage activity, and circulating IL-15 levels in male and female mice. Muscle creatine kinase (MCK)-driven IL-15Rα knockout mice ( mIl15rafl/fl/Cre+) were generated using the Cre-loxP system. We tested the hypothesis that IL-15Rα functional deficiency in skeletal muscle would increase resistance to contraction-induced fatigue, cage activity, and circulating IL-15 levels. There was a significant effect of genotype on the fatigue curves obtained in extensor digitorum longus (EDL) muscles from female mIl15rafl/fl/Cre+mice, such that force output was greater during the repeated contraction protocol compared with mIl15rafl/fl/Cre−control mice. Muscles from female mIl15rafl/fl/Cre+mice also had a twofold greater amount of the mitochondrial genome-specific COXII gene compared with muscles from mIl15rafl/fl/Cre−control mice, indicating a greater mitochondrial density in these skeletal muscles. There was a significant effect of genotype on the twitch:tetanus ratio in EDL and soleus muscles from mIl15rafl/fl/Cre+mice, such that the ratio was lower in these muscles compared with mIl15rafl/fl/Cre−control mice, indicating a pro-oxidative shift in muscle phenotype. However, spontaneous cage activity was not different and IL-15 protein levels were lower in male and female mIl15rafl/fl/Cre+mice compared with control. Collectively, these data support a direct effect of muscle IL-15Rα deficiency in altering contractile properties and fatigue characteristics in skeletal muscles.