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

Abstract

Background Loss of muscle mass worsens many diseases such as cancer and renal failure, contributes to the frailty syndrome, and is associated with an increased risk of death. Studies conducted on animal models have revealed the preponderant role of muscle proteolysis and in particular the activation of the ubiquitin proteasome system (UPS). Studies conducted in humans remain scarce, especially within renal deficiency. Whether a shared atrophying programme exists independently of the nature of the disease remains to be established. The aim of this work was to identify common modifications at the transcriptomic level or the proteomic level in atrophying skeletal muscles from cancer and renal failure patients. Methods Muscle biopsies were performed during scheduled interventions in early‐stage (no treatment and no detectable muscle loss) lung cancer (LC), chronic haemodialysis (HD), or healthy (CT) patients ( n = 7 per group; 86% male; 69.6 ± 11.4, 67.9 ± 8.6, and 70.2 ± 7.9 years P > 0.9 for the CT, LC, and HD groups, respectively). Gene expression of members of the UPS, autophagy, and apoptotic systems was measured by quantitative real‐time PCR. A global analysis of the soluble muscle proteome was conducted by shotgun proteomics for investigating the processes altered. Results We found an increased expression of several UPS and autophagy‐related enzymes in both LC and HD patients. The E3 ligases MuRF1 (+56 to 78%, P < 0.01), MAFbx (+68 to 84%, P = 0.02), Hdm2 (+37 to 59%, P = 0.02), and MUSA1/Fbxo30 (+47 to 106%, P = 0.01) and the autophagy‐related genes CTPL (+33 to 47%, P = 0.03) and SQSTM1 (+47 to 137%, P < 0.01) were overexpressed. Mass spectrometry identified >1700 proteins, and principal component analysis revealed three differential proteomes that matched to the three groups of patients. Orthogonal partial least square discriminant analysis created a model, which distinguished the muscles of diseased patients (LC or HD) from those of CT subjects. Proteins that most contributed to the model were selected. Functional analysis revealed up to 238 proteins belonging to nine metabolic processes (inflammatory response, proteolysis, cytoskeleton organization, glucose metabolism, muscle contraction, oxidant detoxification, energy metabolism, fatty acid metabolism, and extracellular matrix) involved in and/or altered by the atrophying programme in both LC and HD patients. This was confirmed by a co‐expression network analysis. Conclusions We were able to identify highly similar modifications of several metabolic pathways in patients exhibiting diseases with different aetiologies (early‐stage LC vs. long‐term renal failure). This strongly suggests that a common atrophying programme e...

Signaling Pathways That Control Muscle Mass

“…Interestingly, E3 ligases auto-ubiquitinate, which makes them more susceptible to proteasomal degradation, thus requiring continuous transcriptional replenishment. Two muscle-specific E3 ubiquitin ligases, muscle ring finger1 (MuRF1/Trim63) and muscle atrophy F-box (Atrogin-1/MAFbx), are dramatically upregulated during various types of atrophy [ 68 , 69 , 70 , 71 ]. Moreover, mice deficient in MuRF1 and Atrogin-1 are partially protected against disuse atrophy [ 69 ].…”

“…Additional novel E3 ubiquitin ligases belonging to the Skp1–cullin-1–FBOX E3 ubiquitin ligase complex (SCF) have been identified and found to contribute to muscle loss during fasting, denervation, and cancer cachexia [ 59 , 85 , 86 , 87 ]. MUSA1 ( Fbxo30 ) [ 59 , 71 ], SMART ( Fbxo21 ), and Fbxo31 [ 85 ] are all induced during atrophic conditions and their inhibition materially reduces muscle wasting. Moreover, a recent study found SMART and Fbxo31 to be upregulated in a rodent model of critical illness-induced myopathy, and this upregulation was blunted by passive mechanical loading [ 88 ].…”

Circulating 20S proteasome for assessing protein energy wasting syndrome in hemodialysis patients

“…In animal models of CKD-induced muscle atrophy, studies of muscle biopsies have shown an increase in the 14kDa actin level, a "footprint" of caspase 3 activity [5], increased expression of E3 ligases such as the muscle-specific E3 ligases MuRF1 and MAFbx [9,10], and proteasome subunits [11]. In humans, activation of the UPS is evidenced by an increased expression of several E3 ligases in the muscle of hemodialysis patients [4]. However, it is not possible to perform a muscle biopsy in all patients to detect the activation of UPS.…”

“…The decrease in muscle mass is due to an imbalance in protein synthesis and proteolysis in favor of the latter [ 2 ]. The ubiquitin-proteasome proteolytic system (UPS) is crucial for the atrophying process, notably in chronic kidney disease (CKD) [ 3 , 4 ]. The first step in myofibrillar protein degradation is thought to be activation of caspase 3 [ 5 ].…”

Reduction of stearoyl-CoA desaturase (SCD) contributes muscle atrophy through the excess endoplasmic reticulum stress in chronic kidney disease

“…(6,7) Furthermore, the mRNA levels of ATF4 and CHOP are increased in skeletal muscle in hemodialysis patients. (8) Ectopic accumulation of excess lipids, called lipotoxicity, plays a central role in the pathogenesis of cardio-metabolic diseases. (9) On the other hand, the quality of lipids (lipoquality), which is defined as the functional features of diverse lipid species, has recently been a focus of study in the pathology of metabolic diseases.…”