Research Project: Kas Atrofisi Ve Hipertrofisinin Metabolik Fenotipleme Kafes Sistemi Ile Çalısılması
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Contributors
Funders
ID
TB.00725
Authors
Kır, Serkan
Faculty Member
Publications
Muscle wasting: emerging pathways and potential drug targets
(Elsevier, 2023) Waraich, Aylin Domaniku; Bilgiç, Şevval Nur; Kır, Serkan; Department of Molecular Biology and Genetics; Yes; College of Sciences
Muscle wasting is a serious comorbidity associated with many disorders, including cancer, kidney disease, heart failure, and aging. Progressive loss of skeletal muscle mass negatively influences prognosis and survival, and is often accompanied by frailty and poor quality of life. Clinical trials testing therapeutics against muscle wasting have yielded limited success. Some therapies improved muscle mass in patients without appreciable differences in physical performance. This review article discusses emerging pathways that regulate muscle atrophy, including oncostatin M (OSM) and ectodysplasin A2 (EDA2) receptor (EDA2R) signaling, outcomes of recent clinical trials, and potential drug targets for future therapies.
The Roles of EDA2R in Ageing and Disease
(Wiley, 2025) Kır, Serkan; Farrington, Gemma; Tonge, Lauren; Branagan, Tracy; Sudirman, Sud; Fang, Chao; Luk, Louis; Bolis, Marco; Ahmetov, Ildus I.; Ross, Kehinde; Department of Molecular Biology and Genetics; Yes; College of Sciences
Ageing is a complex biological process driven, in part, by inflammaging. Recent research identifies the ectodysplasin A2 receptor (EDA2R) as a key regulator of inflammaging and a novel biomarker of ageing, with its expression increasing with age across diverse tissues in humans and animal models. Elevated EDA2R gene expression is associated with accelerated ageing, cellular senescence, frailty, obesity, acne, radiation response and increased levels of inflammatory, renal, cardiac and vascular biomarkers. Similarly, elevated EDA2R protein levels, a critical component of the proteomic ageing clock, are associated with a wide range of conditions, including cardiovascular diseases, dementia, Parkinson's disease, mood disorders, post-traumatic stress disorder, various cancers, osteoarthritis, digestive diseases, diabetes, obesity, chronic obstructive pulmonary disease, ear and eye diseases, renal impairment, systemic autoimmune diseases, anaemia, bacterial infections, myositis, frailty, accelerated biological ageing, shorter telomere length, decreased healthspan and longevity, higher all-cause mortality and overall poor health. Beyond serving as a biomarker, EDA2R actively drives ageing, as its overexpression induces inflammation and tissue damage, whereas its inhibition mitigates these effects. Mechanistically, EDA2R activates non-canonical and canonical NF-kappa B signalling, promoting pro-inflammatory and catabolic processes that accelerate ageing phenotypes. Genetic variants of EDA2R are linked to alopecia, facial ageing, lipid profiles and prostate cancer. This review explores the structure and function of the EDA2R gene and protein, its role in tissue-specific ageing, and its therapeutic potential for multiple diseases. Although specific EDA2R antagonists are not yet available, interventions like calorie restriction, physical activity and specific supplements show promise in lowering EDA2R levels.
Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology
(Elsevier, 2024) Kır, Serkan; Özen, Sevgi Döndü; Department of Molecular Biology and Genetics; Yes; College of Sciences
Skeletal muscle is essential in generating mechanical force and regulating energy metabolism and body temperature. Pathologies associated with muscle tissue often lead to impaired physical activity and imbalanced metabolism. Recently, ectodysplasin A2 receptor (EDA2R) signaling has been shown to promote muscle loss and glucose intolerance. Upregulated EDA2R expression in muscle tissue was associated with aging, denervation, cancer cachexia, and muscular dystrophies. Here, we describe the roles of EDA2R signaling in muscle pathophysiology, including muscle atrophy, insulin resistance, and aging-related sarcopenia. We also discuss the EDA2R pathway, which involves EDA-A2 as the ligand and nuclear factor (NF)κB-inducing kinase (NIK) as a downstream mediator, and the therapeutic potential of targeting these proteins in the treatment of muscle wasting and metabolic dysfunction.
Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism
(Wiley, 2024) Ağca, Samet; Bilgiç, Şevval Nur; Kır, Serkan; Sucuoğlu, Melis; Waraich, Aylin Domaniku; Dag, Meric; Dogan, Sukru Anil; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; Yes; College of Sciences; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
Background Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.MethodsLewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.Results Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.ConclusionsThis study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.
