Logan Steele
Muscle weakness is a common and debilitating consequence of many types of cancer, negatively impacting patient well-being and treatment outcomes. While the specific mechanisms are not yet fully understood, cancer-induced muscle weakness is believed to result from a combination of factors, including loss of muscle mass (muscle atrophy or cachexia), impaired intrinsic capacity, neuromuscular disconnection, and tumour-related factors. Cachexia, a wasting syndrome characterised by severe weight loss and muscle atrophy, is estimated to affect up to 80% of people with advanced cancer. It causes a negative protein balance, leading to muscle wasting and weakness. Tumour metastasis to bone can also disrupt normal bone remodelling, stimulating excessive osteoclast activity and releasing growth factors that fuel tumour growth and bone destruction, ultimately contributing to muscle weakness. Lung cancer patients often experience muscle weakness due to breathing difficulties and oxygen deprivation in muscles. Various treatments, including physical therapy, pharmacological interventions, and novel targeted therapies, are being explored to manage cancer-related muscle weakness.
| Characteristics | Values |
|---|---|
| Cancer type | Lung cancer, breast cancer |
| Muscle weakness causes | Loss of muscle mass, loss of muscle function, impaired intrinsic capacity, neuromuscular disconnection, malnutrition, inactivity, chemotherapy, radiotherapy, metastasis of tumour cells to bone, oxidative stress, abnormal metabolism, inflammation, calcium deficiency, vitamin D deficiency |
| Treatments | Physical therapy, light exercise, over-the-counter pain relievers, muscle relaxants, steroid medicines, antibiotics, antidepressants, appetite stimulants, anamorelin |
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What You'll Learn
Tumour metastasis to bone
Bone metastasis is when cancer spreads to the bones from another part of the body. It often affects people with breast, lung, and prostate cancer. Bone pain is the most common symptom, but bone fractures also frequently occur. Bone metastasis typically affects the spine, but can also affect the arms, legs, ribs, pelvis, upper arm bone (humerus), and skull.
Bone metastasis makes bones more fragile and likely to break, even without a fall. Bone fractures cause sharp, severe pain and can cause sudden immobility. Cancer in the bone may cause severe pain before the bone breaks. When cancer spreads to the bones of the spine, it can press on the spinal cord. This can cause nerve damage that may lead to paralysis if not treated immediately.
When osteoclasts break down bone cells faster than usual, tiny holes are created in the bone, making it weaker and more prone to breakage. Metastatic tumours in the bone stimulate excessive osteoclast activity, which causes the release of growth factors stored in the mineralized bone matrix. These factors fuel a vicious cycle of tumour growth in the bone and bone destruction. This release of growth factors can act systemically to cause muscle weakness.
Muscle weakness is a common co-morbidity of osteolytic bone metastases, often associated with cancer cachexia. Cachexia is a common paraneoplastic syndrome characterised by severe wasting due to loss of skeletal muscle mass, with or without loss of fat mass, due to a negative protein balance caused by abnormal metabolism. Cancer cachexia is a multifactorial syndrome common in advanced malignancy, occurring in around 80% of patients, and leading to significant function deficits. It cannot be reversed by nutritional support and is estimated to be responsible for 20% of cancer-related deaths.
There is a lack of therapies to treat cancer-associated muscle weakness, highlighting the need for novel interventions. However, accumulating evidence suggests that loss of muscle function precedes atrophy, and improving muscle function and mobility in cancer patients would positively impact adherence to treatment regimens and overall health.
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Cancer cachexia
The exact mechanism of cancer cachexia is not fully understood, but it is believed to be caused by factors of catabolism produced by tumours in the systemic circulation and physiological factors such as imbalanced inflammatory activation, proteolysis, autophagy, and lipolysis. Cancer cachexia is also associated with increased insulin resistance, where the cells no longer respond to insulin, leading to high blood sugar (hyperglycaemia). This can cause a loss of appetite, muscle and fat loss, and increased metabolism, contributing to severe weight loss.
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Impaired intrinsic capacity
Cancer patients often experience muscle weakness, which can be caused by impaired intrinsic capacity, among other factors. Impaired intrinsic capacity refers to the loss of muscle function and strength due to contractile dysfunction and intramuscular impairments. This can be further broken down into two main mechanisms:
Excitation-Contraction Coupling Impairments
Firstly, cancer can disrupt the normal process of excitation-contraction coupling in skeletal muscles. Normally, during muscle contraction, calcium is released from the sarcoplasmic reticulum into the cytoplasm, allowing calcium-dependent actin-myosin cross-bridging and subsequent muscle contraction. Maladaptive modifications of the ryanodine receptor/calcium release channel (RyR1) due to chronic oxidative stress can lead to impaired calcium handling and reduced muscle contraction. This is seen in various diseases characterised by contractile dysfunction, including muscular dystrophy.
Crossbridge Cycling Issues
Secondly, cancer can interfere with the process of crossbridge cycling, which is essential for muscle contraction. This involves the interaction between actin and myosin filaments within muscle fibres. In a healthy muscle, oxygen provides vital nutrients to these filaments via red blood cells, stimulating energy and strength. However, in cancer patients, especially those with lung cancer, breathing difficulties due to tumours can lead to a lack of oxygen supply to the muscles, resulting in fatigue and weakness.
Additionally, cancer-induced inflammation, known as myositis, can also contribute to impaired intrinsic capacity. Myositis occurs when the immune system is constantly fighting cancer tumours, leading to muscle inflammation, weakness, swelling, and pain.
The impaired intrinsic capacity in cancer patients is a complex interplay of these mechanisms, and it negatively impacts both patient well-being and outcomes across a range of cancer types.
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Chemotherapy
Some chemotherapy drugs can damage the nerves that transmit signals between the central nervous system and the limbs, resulting in a condition called chemotherapy-induced peripheral neuropathy (CIPN). This nerve damage can cause muscle weakness in the legs, along with tingling, numbness, or pain in the hands and feet. While CIPN often resolves within a short period, it can sometimes persist or become permanent.
The mechanism by which chemotherapy induces muscle weakness is still being elucidated, but oxidative stress is believed to play a crucial role. Doxorubicin, for example, can induce oxidative stress through redox cycling or TNF-signalling, leading to negative effects on skeletal muscle function. Other chemotherapeutic agents can also produce oxidative stress by decreasing antioxidant levels, compromising the cell's defences against elevated oxidants. This oxidative stress has been associated with muscle weakness and accelerated fatigue.
Additionally, cancer and chemotherapy have been linked to cachexia, a condition characterised by weight loss, depletion of fat and muscle, increased fatigue, reduced quality of life, and high mortality. Cachexia results in skeletal muscle wasting and weakness, which significantly impair the quality of life and worsen survival outcomes for cancer patients. However, there are currently no approved treatments for cachexia, highlighting the need for further research and the development of novel interventions.
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Radiotherapy
Radiation can also deplete MuSCs (muscle satellite cells), which are essential for skeletal muscle growth, maintenance, and repair. Additionally, radiation can damage nearby blood vessels that nourish the muscles, leading to reduced blood flow and oxygen supply, which can contribute to muscle weakness.
The side effects of radiotherapy vary depending on the type and location of the cancer, the dose of radiation, and the patient's overall health. Some people experience few or no side effects, while others may have several. Most side effects of radiotherapy go away within a few months after completing treatment. However, radiation-induced muscle weakness can be a long-term complication, and the lack of effective therapies to prevent or treat it is a critical gap in cancer survivorship care.
To manage muscle weakness caused by radiotherapy, physical therapy and rehabilitation play crucial roles. Exercise during and after radiotherapy can help improve muscle strength, flexibility, and range of motion. Additionally, physical therapy can focus on postural retraining, core strengthening, and stretching to reduce energy demands and pain associated with muscle weakness. Early intervention and long-term adherence to a home exercise program can provide significant benefits for patients experiencing muscle weakness due to radiotherapy.
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Frequently asked questions
Cachexia is a wasting syndrome that leads to dramatic weight loss and muscle atrophy. It occurs in up to 80% of people with advanced cancer. It is characterized by a negative protein balance caused by abnormal metabolism. Cachexia cannot be reversed by nutritional support.
Cancer can cause muscle weakness through multiple mechanisms. Tumors can cause muscle inflammation, known as myositis, leading to weakness, swelling, and pain. Cancer patients may also experience breathing difficulties due to the location of tumors near the lungs, resulting in a lack of oxygen supply to the muscles and subsequent fatigue and weakness. Additionally, cancer treatments such as chemotherapy and malnutrition can contribute to muscle weakness.
There is currently no cure for cancer-associated muscle weakness. However, physical therapy and light exercises several times a week can help reduce muscle weakness and improve strength and mobility in cancer patients. Doctors can also prescribe medications such as muscle relaxants, steroid medicines, and antidepressants to manage associated symptoms.
