Targeting interleukin-1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis

Background: Ctns-/- mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Inflammatory cytokines such as IL-1 trigger inflammatory cascades and play an important role in the pathogenesis of cachexia. Anakinra is an FDA-approved IL-1 receptor antagonist that blocks IL-1 signaling and may provide targeted novel therapy. Methods: Ctns-/- mice were bred to Il6 -/- and Il1β -/- mice. Ctns-/- mice and wild type control were treated with anakinra (2.5 mg.kg.day, IP) or saline as vehicle for 6 weeks. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning. We measured gastrocnemius weight, total lean mass content, muscle function (grip strength and rotarod activity), muscle fiber size, muscle fatty infiltration and expression of molecules regulating muscle metabolism. We also evaluated the effects of anakinra on the muscle transcriptome. Results: Il-1β deficiency or treatment with anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function in Ctns-/- mice. Anakinra also diminished molecular perturbations of energy homeostasis in adipose tissue and muscle, specifically, aberrant expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26 and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2/Pgf2α, Tlr2, Myd88 and Traf6) in inguinal white adipose tissue in Ctns-/- mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns-/- mice. This was accompanied by correction of the increased muscle wasting signaling pathways (increased protein content of ERK1/2, JNK, p38 MAPK and NF-κB p65 and gene expression of Atrogin-1 and Myostatin) and the decreased myogenesis process (decreased gene expression of MyoD and Myogenin) in gastrocnemius of Ctns-/- mice. Finally, anakinra normalized or attenuated 12 of those top 20 differentially expressed muscle genes in Ctns-/- mice. Conclusions: Anakinra attenuates adipose tissue browning and muscle wasting in Ctns-/- mice. IL-1 receptor blockade may represent a novel targeted treatment for cachexia in patients with infantile nephropathic cystinosis. Key words: infantile nephropathic cystinosis, IL-1, cachexia, adipose tissue browning, muscle wasting