Proteomic profiling of skeletal and cardiac muscle in cancer cachexia: alterations in sarcomeric and mitochondrial protein expression.

BACKGROUND: Cancer cachexia is observed in more than 50% of advanced cancer patients, and impairs quality of life and prognosis. A variety of pathways are likely to be dysregulated. Hence, a broad-spectrum understanding of the disease process is best achieved by a discovery based approach such as proteomics. RESULTS: More than 300 proteins were identified with > 95% confidence in correct sequence identification, of which 5-10% were significantly differentially expressed in cachectic tissues (p-value of 0.05; 27 proteins from gastrocnemius, 34 proteins from soleus and 24 proteins from heart). The two most pronounced functional groups being sarcomeric proteins (mostly upregulated across all three muscle types) and energy/metabolism proteins (mostly downregulated across all muscle types). Electron microscopy revealed disintegration of the sarcomere and morphological aberrations of mitochondria in the cardiac muscle of colon 26 (C26) carcinoma mice. MATERIALS AND METHODS: The colon 26 (C26) carcinoma mouse model of cachexia was used to analyse soleus, gastrocnemius and cardiac muscles using two 8-plex iTRAQ proteomic experiments and tandem mass spectrometry (LCMSMS). Differentially expressed proteomic lists for protein clustering and enrichment of biological processes, molecular pathways, and disease related pathways were analysed using bioinformatics. Cardiac muscle ultrastructure was explored by electron microscopy. CONCLUSIONS: Morphological and proteomic analyses suggested molecular events associated with disintegrated sarcomeric structure with increased dissolution of Z-disc and M-line proteins. Altered mitochondrial morphology, in combination with the reduced expression of proteins regulating substrate and energy metabolism, suggest that muscle cells are likely to be undergoing a state of energy crisis which ultimately results in cancer-induced cachexia.

A Micropatterned Human Pluripotent Stem Cell-Based Ventricular Cardiac Anisotropic Sheet for Visualizing Drug-Induced Arrhythmogenicity.

A novel cardiomimetic biohybrid material, termed as the human ventricular cardiac anisotropic sheet (hvCAS) is reported. Well-characterized human pluripotent stem-cell-derived ventricular cardiomyocytes are strategically aligned to reproduce key electrophysiological features of native human ventricle, which, along with specific selection criteria, allows for a direct visualization of arrhythmic spiral re-entry and represents a revolutionary tool to assess preclinical drug-induced arrhythmogenicity.

Cardiac and skeletal muscles show molecularly distinct responses to cancer cachexia.

Cancer cachexia is a systemic, paraneoplastic syndrome seen in patients with advanced cancer. There is growing interest in the altered muscle pathophysiology experienced by cachectic patients. This study reports the microarray analysis of gene expression in cardiac and skeletal muscle in the colon 26 (C26) carcinoma mouse model of cancer cachexia. A total of 268 genes were found to be differentially expressed in cardiac muscle tissue, compared with nontumor-bearing controls. This was fewer than the 1,533 genes that changed in cachectic skeletal muscle. In addition to different numbers of genes changing, different cellular functions were seen to change in each tissue. The cachectic heart showed signs of inflammation, similar to cachectic skeletal muscle, but did not show the upregulation of ubiquitin-dependent protein catabolic processes or downregulation of genes involved in cellular energetics and muscle regeneration that characterizes skeletal muscle cachexia. Quantitative PCR was used to investigate a subset of inflammatory genes in the cardiac and skeletal muscle of independent cachectic samples; this revealed that B4galt1, C1s, Serpina3n, and Vsig4 were significantly upregulated in cardiac tissue, whereas C1s and Serpina3n were significantly upregulated in skeletal tissue. Our skeletal muscle microarray results were also compared with those from three published microarray studies and found to be consistent in terms of the genes differentially expressed and the functional processes affected. Our study highlights that skeletal and cardiac muscles are affected differently in the C26 mouse model of cachexia and that therapeutic strategies cannot assume that both muscle types will show a similar response.

Cancer cachexia: molecular targets and pathways for diagnosis and drug intervention.

Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Skeletal muscle wasting is a prominent feature of the disease and is believed to result from the loss of balance between protein synthesis and degradation. Quality of life and prognosis are severely compromised in patients with cancer cachexia. Despite current knowledge on the mediators involved in cancer cachexia, treatment targeting a single molecule has rendered limited effectiveness. This article aims to review the mediators of cancer cachexia and interventions attempted in the literature and discuss the common pathways leading to protein loss that these mediators modulate during cachexia. We believe that by targeting downstream effectors that are common in these pathways, a better therapeutic approach to reverse muscle wasting and maintain muscle function during cancer cachexia will be achieved.

Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting.

Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Loss of skeletal muscle is a defining characteristic of patients with cancer cachexia and is associated with poor survival. The present study reveals the involvement of a myogenic transcription factor Myocyte Enhancer Factor (MEF) 2C in cancer-induced skeletal muscle wasting. Increased skeletal muscle mRNA expression of Suppressor of Cytokine Signaling (Socs) 3 and the IL-6 receptor indicative of active IL-6 signaling was seen in skeletal muscle of mice bearing the Colon 26 (C26) carcinoma. Loss of skeletal muscle structural integrity and distorted mitochondria were also observed using electron microscopy. Gene and protein expression of MEF2C was significantly downregulated in skeletal muscle from C26-bearing mice. MEF2C gene targets myozenin and myoglobin as well as myokinase were also altered during cachexia, suggesting dysregulated oxygen transport capacity and ATP regeneration in addition to distorted structural integrity. In addition, reduced expression of calcineurin was observed which suggested a potential pathway of MEF2C dysregulation. Together, these effects may limit sarcomeric contractile ability and also predispose skeletal muscle to structural instability; associated with muscle wasting and fatigue in cachexia.