DUSP1 promotes muscle atrophy by inhibiting myocyte differentiation in cachectic patients

Abstract

BackgroundSkeletal muscle atrophy is the major hallmark of cancer cachexia. The mechanisms underlying muscle wasting remain elusive in cachectic patients. Our research seeks to identify differentially expressed genes (DEGs) between non-cachectic and cachectic cancer patients and elucidate their functions.MethodsWe screened the DEGs of skeletal muscle between patients with and without cachexia from microarray data. Biological function of DEGs is analyzed through gene enrichment analysis, while an interaction network is constructed to visualize how genes are related. A Spearman’s correlation analysis demonstrated the clinical significance of DUSP1 related to cancer cachexia. Skeletal muscle samples were collected and histomorphology studies were conducted. Function of DUSP1 on myogenesis was clarified by qPCR, western blotting, and immunofluorescence.ResultsWe screened 324 DEGs in skeletal muscle from patients with and without cachexia. The results of the gene enrichment analysis indicated that inflammatory cytokines and immune responses contribute significantly to the pathological condition of cachexia. DUSP1 was one of the key genes in the regulating network. DUSP1 protein and mRNA levels were increased significantly in skeletal muscle tissues from patients with cancer cachexia. DUSP1 expression in cachectic group was found to have negative correlation with SMA, prealbumin and BMI and positive correlation with TNFα, IL6 and weight loss. Significant changes of myogenesis related genes were observed in myocyte after DUSP1 was overexpressed and knocked down.ConclusionIn skeletal muscle of cachectic patients, DUSP1 expression was observed to be higher and thus DUSP1 promote muscle atrophy by inhibiting myogenesis. DUSP1 is expected to be a specific target in cancer cachexia for preventing and treating muscle atrophy.

Single Nuclei RNA Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

“…InteresOngly, FKBP5 is a pepOdyl proyl isomerase that has been linked mechanisOcally to myogenesis 71 . DUSP1, a dualspecificity protein phosphatase involved in regulaOon of the cell cycle and apoptosis, was also upregulated in PAD and has been associated with atrophy due to impaired myoblast differenOaOon in cancer cachexia 72 . ANKRD1 was also uniquely expressed in two subpopulaOons of RegeneraOng myonuclei in PAD muscle (Figure 3F).…”