bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.02.05.429989

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

Cheung, W. W.·Hao, S.·Zheng, R.·Wang, Z.·Gonzalez, A.·Zhou, P.·Hoffman, H. M.·Mak, R. H.
View original source ↗Export metadata ↓

Abstract

BackgroundCtns-/- 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. MethodsCtns-/- mice were bred to Il6 -/- and Il1{beta} -/- 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. ResultsIl-1{beta} 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/Pgf2, 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-{kappa}B 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. ConclusionsAnakinra 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.

Source connections

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Cheung, W. W., Hao, S., Zheng, R., Wang, Z., Gonzalez, A., Zhou, P., Hoffman, H. M., Mak, R. H.. 2021-02-07. Targeting interleukin-1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis. https://doi.org/10.1101/2021.02.05.429989

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Epigenetic Rescue of Disuse Muscle Atrophy by Histone Deacetylase Inhibitor Trichostatin A

Mechanical unloading rapidly induces skeletal muscle atrophy and functional deterioration, yet how the loss of mechanical input influences nuclear architecture, chromatin organization, and associated transcriptional programs remains poorly understood. Here, we investigated whether pharmacological inhibition of histone deacetylases (HDACs) using Trichostatin A (TSA) could attenuate the consequences of continued mechanical unloading in a murine hindlimb suspension model. Following 14 days of unloading, mice exhibited impaired locomotor activity, altered muscle architecture, and widespread transcriptional reprogramming characterized by increased expression of atrophy associated genes, inflammatory mediators, and extracellular matrix remodeling pathways, alongside suppression of mitochondrial metabolic programs. Super resolution imaging further revealed irregular Lamin A/C organization and disruption of discrete H3K9me3 associated heterochromatin foci. Systemic TSA treatment significantly attenuated the decline in locomotor activity, accompanied by trends toward reduced body weight loss, and preservation of muscle morphology. Transcriptomic analysis demonstrated a substantial shift toward the baseline expression profile, with high-dose TSA attenuating FOXO associated catabolic programs, inflammatory, and extracellular matrix-related signatures, while enhancing mitochondrial oxidative phosphorylation pathways. Quantitative gene level and pathway analyses further revealed dose dependent and selective reversal of unloading associated transcriptional changes. Notably, TSA treatment also partially preserved nuclear lamina organization and the focal distribution of H3K9me3 associated heterochromatin. Despite these muscle specific benefits, TSA did not prevent trabecular bone loss over the 14-day unloading period, although several muscle-expressed genes potentially involved in muscle to bone communication were altered by treatment. Together, these findings demonstrate that HDAC inhibition counteracts multiple functional and molecular consequences of skeletal muscle unloading and is associated with partial preservation of nuclear and heterochromatin organization. This study supports a link between mechanical unloading, nuclear architectural remodeling, and HDAC sensitive transcriptional regulation, providing a foundation for epigenetic strategies to counter disuse induced muscle deterioration.

physiology↗
bioRxiv2026

Residual Hearing Loss After Chronic Cochlear Implantation in Guinea Pigs is Primarily Conductive

It is desirous to preserve residual low-frequency hearing in cochlear implant recipients, as dual stimulation using electrical and acoustic signals results in superior speech-in-noise processing and musicality. However, cochlear implant recipients commonly lose their residual acoustic hearing gradually following surgical placement of the array. The governing mechanism is not understood and is likely due to multiple factors including surgical trauma, inflammation, and the foreign body induced immune response to the array, including formation of intracochlear fibrosis. Normal mechanical function of the cochlea is expected to underpin residual hearing but has not been directly studied. This function includes efficient transmission of sound to the cochlea via the middle ear, sound propagation via the basilar membrane travelling wave, mechanical tuning characteristics, and the non-linear cochlear amplification of responses to low-frequency stimulation. Here, we examined these features in cochleae and middle ears of unimplanted, acutely and chronically implanted guinea pigs using our minimally invasive preparation and optical coherence tomography vibrometry. We observed that mechanical tuning and amplification is not significantly altered by either acute or chronic implant. However, the response threshold was raised and proportional to middle ear responses. Additionally, the organ of Corti phase, and its sound intensity dependent changes, are unaltered by CI. Finally, a cluster analysis revealed sensitivity loss in chronically implanted animals is caused by middle ear dysfunction. Hence, in the guinea pig model, the dominant etiology of residual hearing loss is conductive. More research is required to establish whether residual hearing loss in humans similarly shares conductive elements.

physiology↗
bioRxiv2026

Satellite cell glucocorticoid receptor restrains myogenic commitment without mediating the effects of therapeutic glucocorticoids on muscle repair

Glucocorticoids (GCs) exert profound effects on skeletal muscle, but the contribution of satellite cell (SatC) glucocorticoid receptor (GR) signaling to muscle regeneration remains poorly understood. Here, we investigated the role of GR in SatC homeostasis and assessed whether SatC GR mediates the effects of therapeutic GCs on muscle repair. Conditional deletion of GR in SatC reduced the number of PAX7-positive cells during regeneration in young mice, but did not substantially impair muscle repair in either young or aged animals. Transcriptomic and chromatin profiling revealed that GR occupies genes involved in stem cell fate and developmental signaling, with extensive GR binding already established in quiescent SatC. GR-deficient quiescent SatC showed reduced expression of Yap1, Runx1 and Foxo1, together with increased Myog expression. Similarly, GR silencing in human myoblasts induced early myogenic differentiation markers without affecting proliferation, supporting a conserved role for GR in restraining myogenic commitment. We next examined the effects of two therapeutic GCs on muscle regeneration. Chronic prednisone treatment altered the transcriptional landscape of regenerating muscle in an age-dependent manner, without substantially affecting histological repair. In contrast, dexamethasone administration during the early inflammatory phase delayed regeneration, with persistent necrosis and increased collagen deposition. These effects were comparable in control and SatC-specific GR-deficient mice, indicating that they do not require GR in SatC. Together, these findings identify GR as a regulator of the quiescent, undifferentiated state of SatC, while showing that the effects of therapeutic GCs on muscle repair are largely independent of SatC GR. They further highlight the importance of treatment regimen and physiological context in determining the effects of GCs on skeletal muscle regeneration.

physiology↗