scholarly journals Targeting interleukin‐1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis

2021 ◽  
Author(s):  
Wai W. Cheung ◽  
Sheng Hao ◽  
Ronghao Zheng ◽  
Zhen Wang ◽  
Alex Gonzalez ◽  
...  
Keyword(s):  
Muscle Wasting ◽  
Interleukin 1 ◽  
Nephropathic Cystinosis

scholarly journals Muscle and Bone Impairment in Infantile Nephropathic Cystinosis: New Concepts

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 170
Author(s):  
Dieter Haffner ◽  
Maren Leifheit-Nestler ◽  
Candide Alioli ◽  
Justine Bacchetta
Keyword(s):  
Muscle Wasting ◽  
Bone Cells ◽  
Interleukin 1 ◽  
Bone Defects ◽  
Hypophosphatemic Rickets ◽  
Nephropathic Cystinosis ◽  
Renal Fanconi Syndrome ◽  
Metabolic Bone ◽  
Cellular Bone

Cystinosis Metabolic Bone Disease (CMBD) has emerged during the last decade as a well-recognized, long-term complication in patients suffering from infantile nephropathic cystinosis (INC), resulting in significant morbidity and impaired quality of life in teenagers and adults with INC. Its underlying pathophysiology is complex and multifactorial, associating complementary, albeit distinct entities, in addition to ordinary mineral and bone disorders observed in other types of chronic kidney disease. Amongst these long-term consequences are renal Fanconi syndrome, hypophosphatemic rickets, malnutrition, hormonal abnormalities, muscular impairment, and intrinsic cellular bone defects in bone cells, due to CTNS mutations. Recent research data in the field have demonstrated abnormal mineral regulation, intrinsic bone defects, cysteamine toxicity, muscle wasting and, likely interleukin-1-driven inflammation in the setting of CMBD. Here we summarize these new pathophysiological deregulations and discuss the crucial interplay between bone and muscle in INC. In future, vitamin D and/or biotherapies targeting the IL1β pathway may improve muscle wasting and subsequently CMBD, but this remains to be proven.

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

2019 ◽  
Vol 11 (1) ◽  
pp. 120-134 ◽  
Author(s):  
Wai W. Cheung ◽  
Sheng Hao ◽  
Zhen Wang ◽  
Wei Ding ◽  
Ronghao Zheng ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Muscle Wasting ◽  
Nephropathic Cystinosis ◽  
Tissue Browning

scholarly journals A Leptin Receptor Antagonist Attenuates Adipose Tissue Browning and Muscle Wasting in Infantile Nephropathic Cystinosis-Associated Cachexia

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1954
Author(s):  
Alex Gonzalez ◽  
Wai W. Cheung ◽  
Elliot A. Perens ◽  
Eduardo A. Oliveira ◽  
Arieh Gertler ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Receptor Antagonist ◽  
Energy Homeostasis ◽  
Muscle Wasting ◽  
Leptin Receptor ◽  
Nephropathic Cystinosis ◽  
Muscle Genes ◽  
Muscle Fat Infiltration ◽  
And Control ◽  
Tissue Browning

Mice lacking the functional cystinosin gene (Ctns−/−), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in Ctns−/− mice. We treated 12-month-old Ctns−/− mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in Ctns−/− mice. PLA attenuated adipose tissue browning in Ctns−/− mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns−/− mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of Ctns−/− mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in Ctns−/− mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC.

scholarly journals Muscle wasting and adipose tissue browning in infantile nephropathic cystinosis

2015 ◽  
Vol 7 (2) ◽  
pp. 152-164 ◽  
Author(s):  
Wai W. Cheung ◽  
Stephanie Cherqui ◽  
Wei Ding ◽  
Mary Esparza ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Muscle Wasting ◽  
Nephropathic Cystinosis ◽  
Tissue Browning

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

2021 ◽  
Author(s):  
Wai W Cheung ◽  
Sheng Hao ◽  
Ronghao Zheng ◽  
Zhen Wang ◽  
Alex Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Lean Mass ◽  
Muscle Function ◽  
Muscle Wasting ◽  
Nephropathic Cystinosis ◽  
Mass Content ◽  
Aberrant Expression ◽  
Fiber Size ◽  
Tissue Browning

ABSTRACTBackgroundCtns−/− 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 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.ResultsIl-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.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.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 ◽  
pp. 173-186 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Proteolytic Enzymes ◽  
Cathepsin L ◽  
Ubiquitin Proteasome System ◽  
Complete Breakdown ◽  
Skeletal Muscle Proteins ◽  
Ubiquitin Proteasome ◽  
Tripeptidyl Peptidase Ii ◽  
F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 (1) ◽  
pp. 173 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome
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