Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis‐associated cachexia

Abstract

Background Ctns−/− mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns−/− mice are 25(OH)D3 and 1,25(OH)2D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns−/− mice. Methods Twelve‐month‐old Ctns−/− mice and wild‐type controls were treated with 25(OH)D3 and 1,25(OH)2D3 (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns−/− mice using RNAseq. Results Supplementation of 25(OH)D3 and 1,25(OH)2D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2D3 in Ctns−/− mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns−/− mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP‐1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF‐κB pathway) in inguinal white adipose tissue in Ctns−/− mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns−/− mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL‐1β, IL‐6, and TNF‐α as well as an increased gene expression of Murf‐2, atrogin‐1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns−/− mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns−/− mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2D3 normalized the top 20 differentially expressed genes in Ctns−/− mice. Conclusions We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns−/− mice via multiple cellular and molecular mechanisms.

Nutrition in the spotlight in cachexia, sarcopenia and muscle: avoiding the wildfire

“…We selected articles investigating nutrition interventions, macronutrient intake below recommended, and micronutrient deficiency. We found 26 articles: 10 clinical trials, 3,25–33 five cross‐sectional studies, 34–38 three experimental animal studies 39–41 (one of which also included a human cross‐sectional analysis 38 ), three narrative reviews, 6,42,43 two retrospective studies, 44,45 two systematic reviews or meta‐analyses, 46,47 and one questionnaire survey 48 . Within the 320 original and review articles published in 2018, 2019, and 2020 in JCSM , the 26 articles on nutrition that we found comprise approximately 8%.…”

“…Of the nutrition studies that we found, one explored the role of protein, 31 three explored the role of vitamin D, 26,38,39 two explored the role of several nutrients, 3,41 and one explored the role of natural product (astaxanthin) supplements 40 . Seven studies 25,27–30,32,33 investigated the effects of multimodal interventions (defined as two or more approaches) on muscle mass.…”

Vitamin D ameliorates adipose browning in chronic kidney disease cachexia

“…We and others have demonstrated the presence of WAT browning in CKD mice 5 amongst other animal disease models of cachexia as well as in patients with cachexia 6 – 9 . We also demonstrated WAT browning in a mouse model of cystinosis, a genetic cause of CKD 10 , 11 .…”

A Pilot Study on the Whole Exome Sequencing of Prostate Cancer in the Indian Phenotype Reveals Distinct Polymorphisms

“…We also observed that CTNS (17p13), a gene that causes cystinosis, is associated with multisystem genetic disorder, wherein cysteine is accumulated in different tissues including the adipose and prostate. Strikingly, it is known that vitamin D repletion could be associated with CTNS knockout or mutated mice indicating vitamin D as a key-player in the pathogenesis of PCa ( Cheung et al, 2019 ).…”