Skeletal Muscle and Its Relevance in Cancer
Cancer is the second leading cause of death in the United States, and sarcopenia is one of the most common cancer- and treatment-related side effects that oncology patients experience. In this article, Dr. Paul Henning investigates the role the maintenance of muscle mass plays in patients health during treatment.More
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Cancer is the second leading cause of death in the United States. Although great advances in radiological and pharmacological treatments for cancer have been made, there is an expanding recognition of the modifiable risk factors that lead to tumor development, with physical activity being one of the chief beneficial lifestyle choices.Sarcopenia is the loss of skeletal muscle mass and strength and is often combined with an increased deposition of fat mass (sarcopenic obesity).
Sarcopenia is one of the most common cancer- and treatment-related side effects that oncology patients experience and its incidence ranges from 14% to 79%(1).
Sarcopenia is considered a key feature of cachexia that many oncology patients experience. Cachexia is a complex syndrome characterized by systemic inflammation and involuntary weight loss, irrespectively of whether it is originated from the loss of skeletal muscle mass or adipose tissue. Cachexia cannot be fully counterbalanced by conventional nutritional supplements or pharmacological interventions(2).
In the context of the pathophysiology of cancer-associated sarcopenia, skeletal muscle homeostasis is altered, and the balance between anabolism and catabolism, i.e., between protein synthesis and degradation, is disrupted, leading to progressive muscle wasting.
Figure. Sarcopenia is a serious clinical condition experienced by many oncology patients because of the disease and/or intensive anticancer therapies, which lead to an increased inflammatory milieu, the upregulation of muscle atrophy genes, and patients’ malnutrition. Catabolic processes exceed the anabolic ones, leading to muscle atrophy. Skeletal muscle mass loss combined with a reduced functional capacity, as reflected by fatigue and an increased risk of falls, constitute the cancer-associated sarcopenia(3).
Exercise and Sarcopenia
In the last decade, more evidence has indicated that exercise is a safe and effective complementary therapy during cancer treatment. Exercise limits cancer and treatment related side effects and is now seriously considered to be incorporated into the daily routine of oncology patients.As mentioned above, sarcopenia is a common adverse effect that oncology patients experience due to muscle catabolism, which results from either the disease or the intensive anticancer therapies, and threatens their survival and overall prognosis. Physical exercise has been proposed as the most effective non-pharmaceutic intervention for both the prevention and management of sarcopenia during the various stages of cancer progression(4). The positive effects of exercise on the maintenance of muscle mass are due to its anabolic effects and the acute and/or chronic beneficial adaptations in various physiological systems that can counterbalance the cancer-related catabolism. Specifically, exercise regulates systemic chronic inflammation, protein synthesis, muscle stem cells and mitochondria function, as well as the hypothalamic–pituitary–adrenal (HPA) axis, which in turn, control skeletal muscle function even in the context of tumor development and progression.
Figure. (a) Several mechanisms, directly or indirectly disturbed by the disease and cancer treatments, lead to cancer-related skeletal muscle wasting; (b) Physical exercise prevents muscle atrophy and/or reverses the sarcopenic phenotype of skeletal muscle by regulating these mechanisms, even in the context of cancer. HPA: hypothalamic–pituitary–adrenal axis; ↑: increase; ↓: decrease(3).
Why is muscle critical during cancer?
Physical weakness plays an essential role in those with advanced cancer with about 33% of all cancer deaths attributed to a wasting syndrome called cachexia. Clinicians have also identified sarcopenia (usually associated with aging), as an important indicator of prognosis in advanced cancer patients. Essentially, the less muscle mass an advanced cancer patient has, the lower their chance of surviving the disease. New evidence indicates that early-stage cancer patients are also at risk and building more muscle may help patients recover.A recent study followed 3,241 stage 2 and stage 3 breast cancer patients concluded that patients with low muscle tissue at the time of diagnosis had a lower chance of survival than patients without sarcopenia(5). In addition, they found that although sarcopenia occurs in more than 33% of newly diagnosed non-metastatic breast cancer patients, the condition has been under-recognized among the population. Sarcopenia in combination with high body fat worsens patients’ outlooks even further. In fact, it was shown that cancer patients who had both sarcopenia and high body fat were 89% more likely to die from the disease(5).Based on these recent findings, clinicians are being advised by the scientific community to recommend strength training to patients with non-metastatic disease. Lean mass is crucial in preventing and aiding cancer patients. Lean mass was found to be an independent determinant of cancer treatment toxicity. Also, evidence indicates that reversal of muscle wasting led to prolonged survival in a cancer cachexia model, demonstrating that lean mass indeed played a causal role in affecting mortality in cancer(6).
Thus, lean mass is not only important for patients’ mobility and quality of life, but also for the therapeutic efficacy and toxicity of cancer therapy. Skeletal muscle is regarded as an endocrine tissue which interacts and communicates with other organs and tissues through the synthesis and secretion of bioactive molecules. The most well-known muscle-secreted bioactive molecules are the myokines, myomiRs, growth factors, chemokines, and exosomes, and muscle contraction augments their production and secretion(7). These muscle secreted factors mediate some of the beneficial effects of exercise on cancer patients’ clinical outcomes. In the context of sarcopenia, where myokine signaling has been proposed to be altered, muscle contraction plays a determining role in protein synthesis stimulation and muscle mass growth promotion(8). The number of myokines shown to counteract muscle mass loss, not only in healthy populations but also under the prism of cancer, is steadily increasing. Overall, cancer patients should be referred to exercise interventions, as it is a promising complementary therapeutic approach, which countermeasures muscle wasting processes and protein catabolism, even after the onset of sarcopenia.There are many mechanisms in which skeletal muscle acts in helping with cancer. Skeletal muscle can react to the wasting stimuli by activating compensatory responses (see figure below)
Figure. Muscle compensatory mechanisms activated in response to tumor growth. The skeletal muscle is a plastic tissue able to autonomously respond to the wasting stimuli to maintain the homeostasis. Muscle loss occurs because of the failure to adapt to the alterations induced by the tumor.
Summary
It is well established that physical inactivity is linked to high cancer incidence. Conversely, regular exercise has been associated with decreased cancer risk and the regulation of cancer development and progression.
Reduced lean mass is an important prognostic indicator for patients with different types of cancer and is now recognized as a crucial organ to fight against cancer.Muscle-derived factors, myokines and miRNAs, secreted in response to contraction mediate exercise-induced beneficial effects and be responsible for inter-tissue communications that can control cancer dynamics. The muscle secretome can modulate cancer evolution directly by affecting cancer cells and indirectly by stimulating the immune response and by compensating cancer-related sarcopenia, which affects patients’ quality of life.
References: 1. S. M: Prevalence of Sarcopenia in Cancer Patients: Review and Future Directions. Int. J. Phys. Med. Rehabil. 4, 2016 2. Peixoto da Silva S, Santos JMO, Costa ESMP, et al: Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia. J Cachexia Sarcopenia Muscle 11:619-635, 2020 3. Papadopetraki A, Giannopoulos A, Maridaki M, et al: The Role of Exercise in Cancer-Related Sarcopenia and Sarcopenic Obesity. Cancers (Basel) 15, 2023 4. Mavropalias G, Sim M, Taaffe DR, et al: Exercise medicine for cancer cachexia: targeted exercise to counteract mechanisms and treatment side effects. J Cancer Res Clin Oncol 148:1389-1406, 2022 5. Caan BJ, Cespedes Feliciano EM, Prado CM, et al: Association of Muscle and Adiposity Measured by Computed Tomography With Survival in Patients With Nonmetastatic Breast Cancer. JAMA Oncol 4:798-804, 2018 6. Zhou X, Wang JL, Lu J, et al: Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142:531-43, 2010 7. Papadopetraki A, Maridaki M, Zagouri F, et al: Physical Exercise Restrains Cancer Progression through Muscle-Derived Factors. Cancers (Basel) 14, 2022 8. Barbalho SM, Flato UAP, Tofano RJ, et al: Physical Exercise and Myokines: Relationships with Sarcopenia and Cardiovascular Complications. Int J Mol Sci 21, 2020
