Abstract
Simple SummarySkeletal muscle (SkM) represents the largest “organ” in the human body as it constitutes at least 40% of the body mass. SkM mass wasting is a serious conditions since pathological tissue degeneration significantly worsens the prognosis of the associated disease and significantly reduces the quality and life expectancy with an incidence of 10–50% in patients suffering of cancer, chronic infection and inflammation. Therefore, it is urgent to investigate the molecular basis of SkM mass wasting and identify potential therapeutic targets. Apart from cytokines and chemokines, also sphingolipid mediators, particularly sphingosine-1-phosphate and ceramide 1-phosphate (C1P), contribute to cancer and inflammation, however, the contribution of ceramide kinase (CerK), and its product ceramide 1-phosphate (C1P), to SkM mass wasting in these conditions is missing. The present study was developed using mice bearing the C26, or Lewis lung carcinoma (LLC) tumors, well characterized models of cancer-associated SkM atrophy, and in murine and human myotubes treated with conditioned media obtained from C26 or LLC-cells or with the corticosteroid dexamethasone. The results obtained reveal that CerK protein expression and the Ceramide/C1P axis are markedly impaired in all experimental models, demonstrating that the CerK/C1P axis plays a crucial role as molecular regulator of SkM mass associated to cancer or corticosteroids.Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and degradation. Although the signaling pathways involved in SkM mass wasting are multiple, the regulatory role of simple sphingolipids is limited. Here, we report the impairment of ceramide kinase (CerK), the enzyme responsible for the phosphorylation of ceramide to C1P, associated with the accomplishment of atrophic phenotype in various experimental models of SkM atrophy: in vivo animal model bearing the C26 adenocarcinoma or Lewis lung carcinoma tumors, in human and murine SkM cells treated with the conditioned medium obtained from cancer cells or with the glucocorticoid dexamethasone. Notably, we demonstrate in all the three experimental approaches a drastic decrease of CerK expression. Gene silencing of CerK promotes the up-regulation of atrogin-1/MAFbx expression, which was also observed after cell treatment with C8-ceramide, a biologically active ceramide analogue. Conversely, C1P treatment significantly reduced the corticosteroid’s effects. Altogether, these findings provide evidence that CerK, acting as a molecular modulator, may be a new possible target for SkM mass regulation associated with cancer or corticosteroids.
Highlights
In adults, skeletal muscle (SkM) mass adjusts to diverse pathophysiological conditions by controlling pathways that regulate protein turnover [1,2,3]
We demonstrate that ceramide kinase (CerK) is expressed in myoblasts and in murine and human skeletal muscle differentiated cells, indicating a specific functional role of the enzyme for the biology of committed cells as well as mature SkM cells (Figure 7)
The latter conclusion is supported by the main observations, and in vivo as well as in vitro model: (a) CerK protein is markedly down-regulated in the SkM of cachectic C26 and Lewis lung carcinoma (LLC) hosts and in myotubes treated with conditioned medium from cancer cells or with
Summary
Skeletal muscle (SkM) mass adjusts to diverse pathophysiological conditions by controlling pathways that regulate protein turnover [1,2,3]. Endocrine and inflammatory factors, such as increased circulating glucocorticoids (GC), markedly play a part in SkM mass wasting and the pathogenesis of cancer-associated disorders, chronic inflammation or sepsis [4]. In this regard, a conspicuous amount of evidence supports the contribution of pro-inflammatory cytokines to cachexia, causing depletion of both adipose tissue and SkM mass, in view of their ability to inhibit anabolic pathways in favor of catabolic ones [5]. It is urgent to investigate the molecular basis of
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