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How cancer messengers destroy the muscles

MHH scientists are investigating how pro-inflammatory cytokines intervene in the metabolism of muscles and actively remodel them.

Dr Arnab Nayak, private lecturer, investigates the effect of pro-inflammatory messengers on muscle wasting in cancer. 

Cancer patients often lose an excessive amount of weight. This affects up to 80 percent of patients and is mainly due to the loss of muscle mass and fatty tissue. This cancer-induced cachexia (CIC) is triggered by cancer cytokines, i.e. inflammation-promoting messenger substances that the tumor cells themselves emit. It is not uncommon for the heart muscle to be affected, which further weakens the patient. Depending on the type of cancer, CIC is responsible for 20 to 50 percent of all cancer-related deaths worldwide. There is no curative therapy. In order to find an effective treatment approach, a research team led by associate professor (PD) 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 "Chromatin and SUMO Physiology" working group, the molecular biologist has shown that the cancer cytokines intervene directly in 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 the ability to contract

The researchers investigated the effect of CIC on the skeletal and heart muscle cells of mice and rats in cell culture. They tested the contractile properties of the muscle cells after electrical stimulation and measured the release of calcium within the muscle cells. They also used a high-resolution microscope to monitor how CIC affects the organization of the sarcomeres, the smallest functional units of the muscle. They also analyzed the signal transmissions in the cells that regulate which muscle-specific genes are switched on or off. "We observed a drastic loss of contraction of striated muscle cells in CIC, which was primarily due to acutely disorganized sarcomere structures and an impaired calcium transport process," states PD Dr. Nayak.

However, the proinflammatory 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 supposed to remove faulty proteins from the cell. In this case, however, the degradation system ensures that functioning muscle proteins are destroyed. In addition, the cytokines influence a central signaling pathway within the muscle cells that regulates their growth, division, metabolism and survival.

SUMO signaling pathway as a therapeutic approach

Current therapies tend to focus on alleviating the symptoms. For example, dietary supplements such as polyunsaturated omega-3 fatty acids in combination with vitamin D3 and endurance and strength exercises are used in an attempt to stop muscle atrophy. Cardiac medication such as ACE inhibitors or beta-blockers should also help to at least reduce muscle loss. PD Dr. Nayak relies on molecular biological methods, or more precisely, the so-called SUMO signaling pathway. In this mechanism, the protein SUMO (small ubiqutin-like modifier) is bound to other proteins in order to change their function. The SUMO signaling pathway plays an important role in muscle breakdown. The SUMO-specific enzymes SENP3 and SENP7 regulate epigenetic processes in the muscle-specific genes. These control gene activity without changing the DNA itself.

In cachexia, the enzymes are degraded and, as a result, their muscle-specific target genes are downregulated. As a result, the sarcomeres, the smallest functional units of the muscle, can no longer form as intended and the muscles lose their ability to develop strength. "In our study, we upregulated SENP3 and SENP7 and observed a decrease in muscle degradation," says the molecular biologist. However, whether this approach works beyond cell culture still needs to be investigated further. PD Dr. Nayak and his team therefore want to test the muscle-saving effect in a mouse model next.

Text: Kirsten Pötzke

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The original paper "Calcium Handling Machinery and Sarcomere Assembly are Impaired Through Multipronged Mechanisms in Cancer Cytokine-Induced Cachexia" can be found here.

How chemotherapy drug sorafenib causes muscle wasting

Research team clarifies molecular basis for cachexia.

Chemotherapy fights cancer, but can also damage the muscles. Researching muscle atrophy caused by chemotherapy. 

Chemotherapeutic agents are often used to treat cancer. They combat tumour growth, but also have a number of undesirable side effects. One of these is severe muscle wasting, known as chemotherapy-induced cachexia. This chronic disease causes uncontrollable breakdown of fat and muscle tissue as well as weight loss. However, in order to improve treatment strategies, the molecular basis must first be understood. This is where PD Dr Arnab Nayak, a scientist at the Institute of Molecular and Cellular Physiology at Hannover Medical School (MHH), comes in. With his research group ‘Chromatin and SUMO Physiology’, the molecular biologist has shown that the chemotherapeutic agent sorafenib actively remodels skeletal muscle cells and thus triggers cachexia. The work has been published in the journal ‘iScience’.

Formation and function of skeletal muscle fibres impaired

Sorafenib is used for liver cell carcinoma (HCC) and renal cell carcinoma (RCC), among others. The chemotherapeutic agent belongs to the so-called tyrosine kinase inhibitors, which attack chemical messengers that are important for tumour development. Sorafenib targets several enzymes involved in cell growth as well as the formation of new blood vessels triggered by the tumour itself, which tumours use to ensure their supply of oxygen and nutrients. At the same time, sorafenib interferes with epigenetic regulation in muscle-specific genes. Epigenetics describes mechanisms that do not influence the genes themselves, but their activity.

In this way, epigenetic processes control which genes are switched on or off and therefore also have an influence on whether and when a disease breaks out or not. Through epigenetic mechanisms, cells react to environmental influences, among other things.

In the case of sorafenib, the researchers have uncovered an unusual molecular mechanism in transcription, i.e. in the reading of the DNA sections relevant to the muscle fibres and their transfer into the corresponding blueprint. In the case of sorafenib, the researchers have uncovered an unusual molecular mechanism in transcription, i.e. in the reading of the DNA sections relevant to the muscle fibres and their transfer into the corresponding blueprint.This leads to impaired development of the skeletal muscle fibres.

Basis for therapeutic fine-tuning

The researchers also investigated the drugs nilotinib and imatinib, which belong to the same class of chemotherapeutic agents. Nilotinib is used in particular for chronic lymphocytic leukaemia (CLL), while imatinib is used to treat acute lymphoblastic leukaemia (ALL) and gastrointestinal stromal tumours (GIST). ‘Interestingly, these two tyrosine kinase inhibitors did not show a similar effect on muscle cell function,’ says PD Dr Nayak. According to the cell biologist, the critical evaluation of cancer-specific chemotherapeutic agents with regard to their effects on muscle physiology is the key to developing better therapies. ‘The detailed findings from our study provide the background and framework for similar future investigations to fine-tune chemotherapeutic treatment. The correct selection of drugs with minimal side effects or potentially harmful effects that can be counteracted is only possible with knowledge of the underlying affected signalling pathways.

Therefore, the implications of these findings for the development of balanced combination therapies for affected individuals to improve treatment are of immediate importance. Nevertheless, sorafenib is currently one of the best therapeutics for the treatment of HCC and RCC. ‘However, our findings have the potential to develop new therapeutic regimens to minimise chemotherapy-induced cachexia,’ says PD Dr Nayak.

The original paper ‘Sorafenib induces cachexia by impeding transcriptional signalling of the SET1/MLL complex on muscle-specific genes’ can be found here.

Text: Kirsten Pötzke