Cancer causes muscle fatigue — and one small tweak could block it
A new study conducted by researchers from the Indiana University School of Medicine has shown that cachexia, the severe muscle loss and weakness commonly associated with underlying cancer growth, could simply be prevented by being deprived of FNDC5, the precursor of the exercise hormone irisin, according to a press release.
Depending on the type of cancer and how well the patient responds to treatment, cachexia is thought to affect up to 80 percent of people with advanced cancer. Additionally, it's estimated to be a direct factor in up to 30 percent of cancer fatalities, sometimes as a result of cardiac or respiratory failure brought on by muscle loss.
This potentially fatal condition is associated with the conversion of white fat cells that store calories, into brown cells that burn fat and generate heat. Therefore, researchers wondered if eliminating irisin would lessen the destructive effects of cachexia in tumor-bearing mice since irisin, a hormone that fills the body during vigorous physical activity, is known to turn white adipose tissue into brown ones.
Knocking out the protein-coding gene FNDC5
The study used mice with damaged or knocked-out versions of the protein-coding gene FNDC5 (fibronectin type III domain‐containing protein 5). Therefore, these genetically altered mice were unable to produce the hormone that burns calories.
Cells that cause Lewis Lung Carcinoma or metastatic MC38 colorectal cancer were injected into the mice. In the end, the knockout male mice developed both of them but no cancer cachexia. They kept their normal body weight and skeletal muscle mass unlike the control mice carrying the same tumor mass.
The lack of FNDC5/irisin prevented male knockout mice to develop muscular weakness; they maintained normal overall locomotor activity. On the female knockout mice, however, the absence of irisin showed no discernible protective effects.
In comparison to mice without any tumor, the researchers found that tumor-bearing mice had higher levels of UCP1, a browning-inducing gene. Comparable to healthy mice, FNDC5-deficient mice have no increase in adipose tissue.
Additionally, they looked for signs in the skeletal muscle of knockout mice that their tumors had increased or activated pro-atrophic pathways, including STAT3 phosphorylation and Atrogin1 and Murf1 expression, two crucial regulators of protein catabolism.
The levels of pyruvate dehydrogenase kinase 4 and succinate dehydrogenase activity were measured to look for signs of metabolic change. Surprisingly, these regulators remained the same in the knockout mice and resembled those in tumor-free mice.
Although these mice were shielded from the effects of tumors that caused muscle atrophy, they displayed little to no protection against tumor-related bone loss, indicating a targeted effect on muscle. Plus, the findings imply that FNDC5/irisin affects muscle differently depending on sex, implying that the deletion method protects only males from cancer cachexia but not females.
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