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Poster De Conférence Année : 2018

Muscle wasting in patients with end-stage renal disease or early-stage lung cancer: Common mechanisms at work

Résumé

Loss of muscle mass aggravates many diseases such as cancer and renal failure, contributes to the frailty syndrome and is associated with an increased risk of death (1, 2). Studies conducted on animal models have revealed the preponderant role of muscle proteolysis and in particular the activation of the ubiquitin proteasome system (UPS) (3, 4). However, studies conducted in humans remain scarce, especially within renal deficiency. In addition, whether a common/similar atrophying programme exists independently of the nature of the disease remains to be established. The aim of this work was therefore to identify common modifications at the transcriptomic or the proteomic levels in atrophying skeletal muscles from cancer and renal failure patients Our objectives were (i) to identify the proteolytic systems activated in chronic hemodialysis (HD) or lung cancer (LC) patients, i.e. pathologies having a different etiology and (ii) to identify markers specific to the activation of muscle atrophy processes independently of the pathology per se. Muscle biopsies were performed during scheduled interventions in early stage (no treatment, no detectable muscle loss) lung cancer (LC), chronic hemodialysis (HD) or healthy (CT) patients (n = 7 per group). Proteolysis was addressed by quantitation of gene expression of members of the UPS, autophagy and apoptosis systems by quantitative RT-PCR. A global analysis of the soluble muscle proteome was conducted by shotgun proteomic for investigating the common metabolic processes altered. We found an increased expression of several UPS and autophagy-related enzymes in both LC and HD groups, suggesting that proteolytic systems were activated in both early stage and long lasting diseases. Mass spectrometry identified more than 1700 proteins and principal Component Analysis (PCA) revealed 3 differential proteomes that matched to the 3 groups of patients. Orthogonal Partial Least Square Discriminant Analysis (O-PLS-DA) was used to create a model, which distinguished the muscles of diseased patients (LC or HD) from those of healthy subjects. Proteins that most contributed to the model were selected. Functional analysis revealed up to 9 metabolic processes (including proteolysis and muscle contraction) involved in and/or altered by the atrophying programme in both LC and HD patients, which was confirmed by a co-expression network analysis. In conclusion, We were able to identify highly similar modifications of several metabolic pathways in patients exhibiting diseases with highly different etiologies (early-stage lung cancer vs. long term renal failure). This strongly suggests that a common atrophying program exists independently of the disease. The mechanisms at stake are as many avenues for the development of treatments for preventing muscle wasting Reference(s) (1) von Haehling, S., Anker, M.S. & Anker, S.D. Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016. J Cachexia Sarcopenia Muscle 2016; 7:507-509. (2) Kalantar-Zadeh, K., et al. Why cachexia kills: examining the causality of poor outcomes in wasting conditions. J Cachexia Sarcopenia Muscle 2013; 4:89-94. (3) Aniort, J., et al. Upregulation of MuRF1 and MAFbx participates to muscle wasting upon gentamicin-induced acute kidney injury. Int. J. Biochem. Cell Biol. 2016; 79:505-516. (4) Lecker, S.H., et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 2004; 18:39-51.
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Dates et versions

hal-01882339 , version 1 (26-09-2018)

Identifiants

  • HAL Id : hal-01882339 , version 1
  • PRODINRA : 446574

Citer

Julien Aniort, Cécile Polge, Agnes Claustre, Lydie Combaret, Daniel Béchet, et al.. Muscle wasting in patients with end-stage renal disease or early-stage lung cancer: Common mechanisms at work. 8. Colloque Protéolyse Cellulaire, Oct 2018, La Grande Motte, France. 2018. ⟨hal-01882339⟩
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