Blocking of FNDC5, a precursor to the exercise hormone, irisin, protects mice from cancer-induced cachexia


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Researchers from Indiana University School of Medicine have found that severe muscle atrophy and weakness associated with cancer growth (i.e. cachexia) can be prevented simply by deprivation of FNDC5, a precursor to the exercise hormone irisin.

When cancer patients Develop cachexia, their bodies fade. cachexia is characterized by extreme fatigue, Weight lossAnemia and infections, among other deadly symptoms. One feature of this fatal condition is that white fat cells that store calories are converted into brown cells that burn fat and produce heat. Since irisin, a hormone that fuels the body during vigorous physical activity, is known to turn white adipose tissue brown, the researchers wondered whether deleting irisin would mitigate the devastating effects of cachexia in tumor-bearing mice.

Fabrizio Bean, assistant professor of anatomy, cell biology and physiology at Faculty of medicineresults today at the annual meeting of the American Society for Bone and Mineral Research in Austin, Texas, US.

The study involved mice in which the FNDC5 protein-encoding gene (type III fibronectin-containing domain 5) had been disrupted or ‘disabled’. Because FNDC5 is a precursor of irisin, which is released from muscle cells During exercise, the genetically modified “knockout” mice were unable to produce the calorie-burning hormone.

The cells were transplanted into mice with Lewis lung cancer or metastatic colorectal carcinoma MC38. Male knockout mice developed both types of tumors, but in contrast normal mice, No cancer cache. They maintained normal body weight and skeletal muscle mass unlike mice with the same tumor mass. Absence of FNDC5/irisin protected male knockout mice muscle weakness; They maintained normal total locomotor activity compared to control mice. In contrast, female knockout mice showed no significant protective effects from irisin deficiency.

The researchers observed high levels of UCP1, Brown color-inducible gene, in adipose tissue of normal tumor-bearing mice compared to non-tumour-bearing mice. In contrast, mice lacking FNDC5 show no elevation in adipose tissue, compared to healthy mice.

They also examined the knockout mice for evidence that their tumors activated or upregulated pro-atrophic pathways in their skeletal muscle, such as STAT3 phosphorylation and Atrogin1 and Murf1 expression, all of which are important regulators of protein catabolism. In addition, evidence of metabolic alteration such as increased levels of pyruvate dehydrogenase kinase 4 and succinate dehydrogenase activity was examined. Surprisingly, these regulators were unchanged in the knockout mice and were similar to those in mice lacking tumors.

Although these animals were protected from the muscle-letting effects of tumors, they showed little or no protection from tumor-induced bone loss, suggesting a targeted effect on muscle. These observations indicate that FNDC5/irisin has sex-dependent effects on muscle, with the deletion protecting males from cancer cachexia but not females.

Exercise-induced irisin is associated with novel mechanisms of bone metabolism

Submitted by the American Society for Bone and Mineral Research

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