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MHH scientist investigates how pro-inflammatory cytokines interfere with muscle metabolism and actively transform muscles.
Cancer patients often lose excessive amounts of weight. This affects up to 80 percent of patients and is mainly due to a decrease in muscle mass and fatty tissue. This cancer-induced cachexia (CIC) is triggered by cancer cytokines, i.e. pro-inflammatory messenger substances emitted by the tumour cells themselves. It is also not uncommon for the heart muscle to be affected, which further weakens patients. Depending on the type of cancer, CIC is responsible for 20 to 50 per cent of all cancer-related deaths worldwide. There is no cure. In order to find an effective treatment approach, a research team led by Dr Arnab Nayak, a scientist at the Institute of Molecular and Cell Physiology at Hannover Medical School (MHH), has been investigating the previously unknown molecular mechanisms associated with CIC. With his working group ‘Chromatin and SUMO Physiology’, the molecular biologist has shown that cancer cytokines directly interfere with the metabolism of muscle cells and actively remodel them. They also ensure that the muscle can release less calcium, which impairs muscle contraction, i.e. the active contraction of the muscle. The results have been published in the Journal of Cachexia, Sarcopenia and Muscle.
Loss of contractility
The researchers examined the effect of CIC on skeletal and cardiac muscle cells from mice and rats in cell culture. They tested the contractile properties of the muscle cells after electrical stimulation and measured calcium release within the muscle cells. They also used a high-resolution microscope to monitor how CIC affects the organisation of sarcomeres, the smallest functional units of muscle. In addition, they analysed the signal transmissions in the cells that regulate which muscle-specific genes are switched on or off. ‘We observed a drastic loss of contraction in striated muscle cells in CIC, which was primarily due to acutely disorganised sarcomere structures and an impaired calcium transport process,’ notes Dr Nayak.
However, the pro-inflammatory cytokines not only reduce the muscle's ability to contract, they also destroy the muscle cells themselves. On the one hand, they activate an enzyme that marks muscle proteins for degradation. The system is actually designed to remove defective proteins from the cell. In this case, however, the degradation system causes functioning muscle proteins to be destroyed. In addition, the cytokines influence a central signalling pathway within the muscle cells that regulates their growth, division, metabolism and survival.
SUMO signalling pathway as a therapeutic approach
Current therapies tend to focus on alleviating symptoms. Dietary supplements such as polyunsaturated omega-3 fatty acids in combination with vitamin D3, as well as endurance and strength training, are used in an attempt to halt muscle wasting. Heart medications such as ACE inhibitors or beta blockers are also thought to help reduce muscle loss. Dr Nayak relies on molecular biological methods, more specifically, the so-called SUMO signalling pathway. In this mechanism, the protein SUMO (small ubiquitin-like modifier) binds to other proteins to alter their function. The SUMO signalling pathway plays an important role in muscle breakdown. The SUMO-specific enzymes SENP3 and SENP7 regulate epigenetic processes in muscle-specific genes. These control gene activity without altering the DNA itself.
In cachexia, the enzymes are degraded and, as a result, their muscle-specific target genes are downregulated. This prevents the sarcomeres, the smallest functional units of the muscle, from forming as intended, and the muscles lose their ability to generate force. ‘In our study, we upregulated SENP3 and SENP7 and observed a decrease in muscle breakdown,’ says the molecular biologist. However, further research is needed to determine whether this approach works beyond cell culture. Dr Nayak and his team therefore want to test the muscle-saving effect in a mouse model next.
SERVICE:
For further information please contact Dr Arnab Nayak, nayak.arnab@mh-hannover.de.
The original paper, ‘Calcium Handling Machinery and Sarcomere Assembly are Impaired Through Multipronged Mechanisms in Cancer Cytokine-Induced Cachexia,’ can be found here: https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13776.
Dr Arnab Nayak, private lecturer, investigates the effect of pro-inflammatory messengers on muscle w ...
Copyright: Tim Holler/MHH.
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Dr Arnab Nayak, private lecturer, investigates the effect of pro-inflammatory messengers on muscle w ...
Copyright: Tim Holler/MHH.
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