Progressive decrease of phosphocreatine, creatine and creatine kinase in skeletal muscle upon transformation to sarcoma

Abstract

In biological systems, ATP is the universal energy currency. Excitable cells and tissues, such as skeletal and cardiac muscle, brain, photoreceptor cells, spermatozoa and electrocytes all depend on the immediate availability of vast amounts of energy that may be used in a pulsed or fluctuating manner [1,2]. Because the adenylate pool and the ATP : ADP ratio are key regulators influencing many fundamental metabolic In vertebrates, phosphocreatine and ATP are continuously interconverted by the reversible reaction of creatine kinase in accordance with cellular energy needs. Sarcoma tissue and its normal counterpart, creatine-rich skeletal muscle, are good source materials to study the status of creatine and creatine kinase with the progression of malignancy. We experimentally induced sarcoma in mouse leg muscle by injecting either 3-methylcholanthrene or live sarcoma 180 cells into one hind leg. Creatine, phosphocreatine and creatine kinase isoform levels decreased as malignancy progressed and reached very low levels in the final stage of sarcoma development; all these parameters remained unaltered in the unaffected contralateral leg muscle of the same animal. Creatine and creatine kinase levels were also reduced significantly in frank malignant portions of human sarcoma and gastric and colonic adenocarcinoma compared with the distal nonmalignant portions of the same samples. In mice, immunoblotting with antibodies against cytosolic muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase showed that both of these isoforms decreased as malignancy progressed. Expressions of mRNA of muscle-type creatine kinase and sarcomeric mitochondrial creatine kinase were also severely downregulated. In human sarcoma these two isoforms were undetectable also. In human gastric and colonic adenocarcinoma, brain-type creatine kinase was found to be downregulated, whereas ubiquitous mitochondrial creatine kinase was upregulated. These significantly decreased levels of creatine and creatine kinase isoforms in sarcoma suggest that: (a) the genuine muscle phenotype is lost during sarcoma progression, and (b) these parameters may be used as diagnostic marker and prognostic indicator of malignancy in this tissue. Abbreviations

Creatine: a miserable life without it

“…The fact that creatine supplementation restored the impaired creatine-CK system in tumor cells led the authors to surmise that inhibition of AGAT and/or GAMT, which is thought to support cancer cell metabolism by contributing to polyamine and methionine synthesis, as shown by Locasale (2013), may be one of the reasons for the anti-cancer effects of creatine. The data reported by Campos Ferraz et al (2016) are in accord with similar data by Patra et al (2008), and suggest a potential therapeutic effect of creatine for the treatment of cancer (Pal et al 2016). The latter authors present evidence that creatine supplementation should be viewed as an adjuvant therapeutic intervention together with methylglyoxal (MG), a long-known anti-cancer agent.…”

The transcriptional cascade associated with creatine kinase down-regulation and mitochondrial biogenesis in mice sarcoma

“…The histological cross sections showed that upon transformation to sarcoma, the muscle tissue lost the muscle-specific phenotypes. The fiber-like nature of the skeletal muscle gradually disappeared as tumor development advanced, and the tissue became a mass of unorganized cells with no evidence of the presence of myofibres [7]. These observations suggested that the malignant transformation involved severe degradation of the muscle fibers.…”

“…Appropriate measures were taken to minimize the pain and discomfort to the animals. Sarcoma was induced as described earlier with 3MC in the hind legs of 45-day old Swiss albino female mice with a body weight of 20-22 g [7]. A stock solution of 3MC was prepared by dissolving 2 mg per 1 ml of hot olive oil, and cooling to room temperature.…”

“…These studies convincingly showed the importance of MyoD and Mef2 in CK expression. In our previous study, we observed that in mice sarcoma tissue, CK expression decreased severely [7]. The total CK activity in sarcoma was reduced by 99% in comparison to healthy skeletal muscle.…”

Architectural and functional remodeling of cardiac and skeletal muscle cells in mice lacking specific isoenzymes of creatine kinase

“…Initial findings suggest that Cr, PCr and CK levels decrease as malignancy progresses. Concentrations of all these proteins can reach very low levels in the final stages of sarcoma development (Patra et al 2008). …”