The double‐edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbation

Jheng, J.R.; Chen, Yuan Siao; Ao, Un Iong; Chan, Ding‐Cheng; Huang, Jenq‐Wen; Hung, Kuan‐Yu; Tarng, Der Cheng; Chiang, Chih‐Kang

doi:10.1002/jcsm.12288

Cited by 36 publications

(32 citation statements)

References 68 publications

(142 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ER stress response can be activated by several stress factors (nutrient deprivation, reactive oxygen species, etc.) and more recently in mice injected with indoxyl sulfate, a uraemic toxin . However, it is the first time that an ER stress is detected in HD patients.…”

Section: Discussionmentioning

confidence: 99%

“…and more recently in mice injected with indoxyl sulfate, a uraemic toxin. 53 However, it is the first time that an ER stress is detected in HD patients. The ER stress response involves in particular the PERK/ATF4/CHOP signalling pathway that decreases overall protein translation, triggers the specific expression of chaperones, activates the UPS and autophagy proteolytic systems, and may ultimately lead to apoptosis.…”

Section: Increased Expressionmentioning

confidence: 99%

See 1 more Smart Citation

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

Aniort

Stella

Philipponnet

et al. 2019

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Increased Expressionmentioning

confidence: 99%

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

Aniort

Stella

Philipponnet

et al. 2019

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

show abstract

“…Most importantly, our motif analysis revealed transcription factors that have not yet been reported or identified previously in cancer cachexia. These factors are related to cell cycle and myogenesis (E2f3, Yy1, and Creb3) [62][63][64], unfolding protein response (Xbp1) [65], and muscle fiber metabolism (ESRRA) [66]. Also, we identified an increased expression of the myogenic regulatory factors Myf6 and Myog.…”

Section: Discussionmentioning

confidence: 75%

MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia

Fernández¹,

Ferreira²,

Vechetti³

et al. 2019

Preprint

View full text Add to dashboard Cite

Cachexia is a complex metabolic syndrome characterized by loss of skeletal muscle, leading to a significant weight loss that impacts patient morbidity and mortality. Given the complexity of gene regulatory networks that control gene expression, our objective was to perform an integrative mRNA and miRNA profiling to identify genetic programs that capture essential mechanistic details that promote muscle atrophy in cancer cachexia. Here, we used RNA sequencing to analyze miRNAs and mRNAs expression profiles in tibialis anterior (TA) muscles of the Lewis lung carcinoma model of cancer cachexia. In addition, we compared these findings with RNA-Seq data from C2C12 myotubes treated in vitro with the cachectic factors tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Extracellular matrix (ECM) alterations were validated by picrosirius staining, western blot, and fractal dimension analyses. We found 1,008 mRNAs and 18 miRNAs differentially expressed in cachectic mice. This set of genes was associated with the ECM, proteolysis, and inflammatory response. Enrichment analysis of transcriptional factor binding sites revealed activation of the atrophy-related transcriptional factors: NF-κB, Stat3, AP-1, and FoxO. Furthermore, the integration of mRNA and miRNA expression profiles identified posttranscriptional regulation by miRNAs of genes involved in ECM organization, cell migration, transcription factors binding, ion transport, and FoxO signaling pathway. C2C12 myotubes treated with TNF-α and IFN-γ similarly down-regulate subsets of ECM genes, including collagens. Our integrative analysis of miRNA-mRNA co-profiles comprehensive characterized regulatory relationships of molecular pathways and revealed miRNAs targeting ECM-associated genes in cancer cachexia. We also confirmed in C2C12 myotubes that changes in ECM-associated genes are dependent on inflammatory signaling of the cytokines TNF-α and IFN-γ.

show abstract

“…Our observation revealed that XBP1 is an essential factor for myogenic differentiation. Recently, Jheng et al reported that knockdown of XBP1 by siRNA transfection after differentiation onset affected cellular development at a late stage during myogenic differentiation [41]. However, the expression of MyoD and MRF4, which are involved in the process of myoblast specification, is already lower in XBP1-knockdown cells than in control cells [1,42].…”

Section: Discussionmentioning

confidence: 99%

IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts

Tokutake

Yamada

Hayashi

et al. 2019

IJMS

View full text Add to dashboard Cite

In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1–XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1–XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1–XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1–XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.

show abstract

The double‐edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbation

Cited by 36 publications

References 68 publications

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

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

MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia

IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts

Contact Info

Product

Resources

About