Severe muscle wasting and weakness commonly associated with cancer growth (i.e. cachexia) can be prevented simply by being deprived of FNDC5, the precursor to the exercise hormone irisin, found researchers at the Indiana University School of Medicine.
When cancer patients develop cachexia, their body wastes away. Cachexia is marked by extreme fatigue, weight loss, anemia, and inflammation, among other life-threatening symptoms. One of the hallmarks of this life-threatening disease is the transformation of calorie-storing white fat cells into fat-burning, heat-producing brown cells. Because irisin, a hormone that floods the body during vigorous physical activity, is known to turn white fatty tissue brown, the researchers wondered if removing irisin would ameliorate the devastating effects of cachexia in carrier mice. of tumours.
Fabrizio Pin, assistant professor of anatomy, cell biology, and physiology at the medical school, presented the findings today at the annual meeting of the American Society of Bone and Mineral Research in Austin, Texas, USA. United.
The study involved mice in which the gene encoding the protein FNDC5 (protein 5 containing the fibronectin type III domain) had been disrupted or ‘knocked out’. Because FNDC5 is a precursor to irisin, which is released by muscle cells during exercise, these genetically modified knockout mice were unable to produce the calorie-burning hormone.
Mice were implanted with cells causing Lewis lung carcinoma or MC38 metastatic colorectal cancer. Male knockout mice developed both types of tumors, but unlike normal mice, no cancerous cachexia. They maintained normal body weight and skeletal muscle mass unlike control mice carrying the same tumor mass. Lack of FNDC5/irisin protected male knockout mice against muscle weakness; they maintained normal total locomotor activity compared to control mice. In contrast, female knockout mice showed no significant protective effect from their lack of irisin.
The researchers observed high levels of UCP1, a browning-inducing gene, in the adipose tissue of normal tumor-bearing mice compared to non-tumor-bearing mice. In contrast, mice lacking FNDC5 show no elevation of adipose tissue, comparable to healthy mice.
They also examined knockout mice to find evidence that their tumors activated or elevated pro-atrophic pathways in their skeletal muscle, such as phosphorylation of STAT3 and expression of Atrogin1 and Murf1, all regulators important in protein catabolism. Additionally, signs of metabolic alteration such as increased levels of pyruvate dehydrogenase kinase 4 and succinate dehydrogenase activity were examined. Surprisingly, these regulators were unchanged in knockout mice and similar to those in tumor-free mice.
Although these animals were protected from the muscle wilting effects of the tumors, they showed little or no protection against tumor-induced bone loss, suggesting a muscle-targeted effect. These observations suggest that FNDC5/irisin has sex-dependent effects on muscle, where deletion protects males from cancer cachexia but not females.