Differentially expressed alternatively spliced genes in skeletal muscle from cancer patients with cachexia

Abstract

BackgroundAlternative splicing (AS) is a post‐transcriptional gene regulatory mechanism that contributes to proteome diversity. Aberrant splicing mechanisms contribute to various cancers and muscle‐related conditions such as Duchenne muscular dystrophy. However, dysregulation of AS in cancer cachexia (CC) remains unexplored. Our objectives were (i) to profile alternatively spliced genes (ASGs) on a genome‐wide scale and (ii) to identify differentially expressed alternatively spliced genes (DASGs) associated with CC.MethodsRectus abdominis muscle biopsies obtained from cancer patients were stratified into cachectic cases (n = 21, classified based on International consensus diagnostic framework for CC) and non‐cachectic controls (n = 19, weight stable cancer patients). Human transcriptome array 2.0 was used for profiling ASGs using the total RNA isolated from muscle biopsies. Representative DASG signatures were validated using semi‐quantitative RT–PCR.ResultsWe identified 8960 ASGs, of which 922 DASGs (772 up‐regulated and 150 down‐regulated) were identified at ≥1.4 fold‐change and P < 0.05. Representative DASGs validated by semi‐quantitative RT–PCR confirmed the primary findings from the human transcriptome arrays. Identified DASGs were associated with myogenesis, adipogenesis, protein ubiquitination, and inflammation. Up to 10% of the DASGs exhibited cassette exon (exon included or skipped) as a predominant form of AS event. We also observed other forms of AS events such as intron retention, alternate promoters.ConclusionsOverall, we have, for the first time, conducted global profiling of muscle tissue to identify DASGs associated with CC. The mechanistic roles of the identified DASGs in CC pathophysiology using model systems is warranted, as well as replication of findings in independent cohorts.

Lipid is heterogeneously distributed in muscle and associates with low radiodensity in cancer patients

“…A number of studies have used RA biopsies in cancer patients to delineate biological features associated with low muscle mass and radiodensity . The primary aim of this study was to gain an appreciation of the variation in muscle radiodensity within the RA.…”

Metabolic disorders in heart failure and cancer

“…It is associated with worse clinical outcomes, quality of life and survival. In genomic studies, cachexia-related body mass index alterations in gastrointestinal cancer patients were found to be linked to the Cytokinesis 1 gene 108 and a transcriptome array study by Narasimhan et al 109 identified specific abnormalities in alternative splicing of genes in patients with cancer cachexia. 103 Among the more recent findings, Iwata et al 107 demonstrated that muscle wasting in cancer cachexia follows a different pathway of muscular damage from the one established in muscle dystrophies.…”

“…103 Among the more recent findings, Iwata et al 107 demonstrated that muscle wasting in cancer cachexia follows a different pathway of muscular damage from the one established in muscle dystrophies. In genomic studies, cachexia-related body mass index alterations in gastrointestinal cancer patients were found to be linked to the Cytokinesis 1 gene 108 and a transcriptome array study by Narasimhan et al 109 identified specific abnormalities in alternative splicing of genes in patients with cancer cachexia.…”

Contemporary publication patterns in the Journal of Cachexia, Sarcopenia and Muscle by type and sub‐speciality: facts and numbers

“…8,9 One of the strongest emerging fields are detailed clinical series of ageing effects, both detailed physiological evaluations 10,11 and large scale cohort reports. [12][13][14][15][16][17] In the area of translational studies in the mechanisms of cachexia, studies were published on expression of spliced skeletal muscle genes, 18 along with scientific evaluations of skeletal muscle physiology, 19,20 growth, wasting, 21-23 preservation, 24,25 and regeneration. 26 Basic science approaches were also used to study the growing interest in the cardiac and cardio-metabolic effects of cancerrelated cachexia and of modern cancer therapies.…”