Introduction Muscle atrophy is frequently encountered in diseased patients. It contributes to patient’s frailty and is associated with an increased risk of death. Studies using animal models suggest the involvement of the Ubiquitin Proteasome System (UPS) in renal failure-induced muscle atrophy. However, this remains to be established in humans. Another important goal is to detect markers that may help fighting against muscle atrophy through nutritional or pharmacological strategies. Indeed, it is very difficult to counteract the increased proteolysis when it is established. 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. Methods Muscle biopsies (n = 7 per group) were obtained upon programmed surgery. mRNA and protein levels were determined using qRT-PCR, immunoblotting and proteomic approaches. Results We found that the UPS and autophagy were activated in both HD and LC patients. Mass spectrometry analysis identified > 1700 proteins. Main component analysis revealed 3 distinct protein expression profiles corresponding to the 3 groups studied. We identified 106 proteins that were significantly modified (decreased or increased) in both HD and LC patients compared to controls (CT). Hierarchical cluster analysis showed that expression levels of these proteins distinguished diseased (HD or LC) vs. CT patients. Orthogonal partial least square discriminant analysis confirmed these results. Conclusion We demonstrated that the UPS and autophagy were activated during long-term disease in humans. We also found a set of proteins whose expression levels may be specific of the atrophying process. These proteins constitute potential biomarkers witnessing the activation of muscle atrophy and/or potential therapeutic targets