Endocrine Function of Muscle and Exercise as Anti-Inflammatory

The Inflammatory Cascade of Physical Inactivity

Physical inactivity leads to a cascade of events in the body, which promote the epidemic of chronic conditions currently seen in the United States. ¹ In a review, Pederson commented that “physical inactivity leads to accumulation of visceral fat and consequently the activation of a network of inflammatory pathways, which promote development of neurodegeneration as well as insulin resistance, atherosclerosis, and tumor growth and thereby the development of the diseases belonging to the ‘diseasome of physical inactivity.’” ² In another review, Mathur and Pedersen commented that physical inactivity might be a stronger predictor of chronic disease, compared with such risk factors as hypertension, hyperlipidemia, diabetes, and obesity, for all-cause mortality. ³

Emerging research offers a clearer understanding of the links among muscle as an endocrine organ, inflammatory states, and the importance of exercise. Pratesi and colleagues commented: “In recent years, studies have shown a role of skeletal muscle as a secretory organ of cytokines and other peptides, denominated myokines (IL[interleukin]6, IL8, IL15, brain-derived neurotrophic factor, and leukemia inhibitory factor), which have autocrine, paracrine, or endocrine actions and are deeply involved in inflammatory processes.” ⁴ Pratesi et al. affirmed the dangers of physical inactivity, stating that it promotes an imbalance among “these substances towards a pro-inflammatory status, thus favoring the vicious circle of sarcopenia, accumulation of fat—especially visceral—and development of cardiovascular diseases, type 2 diabetes mellitus, cancer, dementia and depression.” ⁴ Mathur and Pedersen stated that, in fact, “[p]lasma concentrations of IL-6 and TNF-α [tumor-necrosis factor–α] have been shown to predict the risk of myocardial infarction in several studies, and CRP [C-reactive protein] has emerged as a particularly stronger independent risk factor for cardiovascular disease than the low-density lipoprotein cholesterol level.” ³

Muscle Release of Myokines

Görgens and colleagues point out that, as the largest organs in the body, both skeletal muscle and adipose tissue may be considered to be endocrine organs that release bioactive molecules. These researchers commented: “Skeletal muscle has gained considerable interest as an endocrine organ, and the release of myokines from contracting muscle is assumed to be at least partly responsible for the health-promoting effects of physical activity.” ⁵

Bente Klarlund Pedersen, MD, DMSc—a professor of integrative medicine and the director of the Center of Inflammation and Metabolism and Center for Physical Activity Research, of the Rigshospitalet and University of Copenhagen, in Denmark, The Netherlands—commented:

The identification of skeletal muscle as an endocrine organ provides clinicians with a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones, and brain. In addition, several myokines exert their effects within the muscle itself. Many proteins produced by skeletal muscle are dependent upon contraction. Therefore, it is likely that myokines may contribute in the mediation of the health benefits of exercise and with regard to the prevention of chronic disease.

Pedersen continued:

The prototype myokine IL-6 appears to have systemic effects on the liver, adipose tissue, and the immune system, and mediates crosstalk between the intestine and pancreas. Other myokines improve the endothelial function of the vascular system and impact bone health. Some myokines exert anti-inflammatory effects—which is important—because persistent systemic inflammation, as seen with many chronic diseases, is associated with a high cardiovascular risk and predisposes [people] to type 2 diabetes and muscle wasting. These disorders can lead to decreased physical activity, exacerbating inflammation and the development of a network of chronic diseases, thus establishing a “vicious cycle” of chronic inflammation.

Görgens et al. stated: “The most extensively studied myokine is interleukin-6…, which is profoundly upregulated during acute exercise and assumed to play a key role in the anti-inflammatory effect of acute exercise. However, it is now evident that skeletal muscle secretes hundreds of myokines, with many of them being regulated by muscle contraction.” ⁵

Exercise as an Anti-Inflammatory

In a culture of excessive sitting, applied knowledge and interventions are needed more than ever before to address the inflammatory effects of physical inactivity. It is well-known that exercise helps prevent chronic disease and improve its management, and guidelines are clear about the amount of daily exercise that both children and adults should be achieving each day. ⁶ The more recent understanding of muscle as an endocrine organ promotes better understanding of how skeletal muscle contraction is a key player for preventing disease. In fact, physical activity releases myokines that trigger a wide range of effects in the body including improved insulin sensitivity, osteogenesis, anti-inflammatory actions, antitumor defense, pancreas function and more. ⁷ Pedersen and Febbraio commented that “the finding that muscles produce and release myokines provides a molecular basis for understanding how physical activity could protect [people] against premature mortality.” ⁷

Pratesi and colleagues said that several studies have shown a protective effect of regular physical activity on morbidity and all-cause mortality and added that “myokines released by contracting skeletal muscles, by creating a systemic anti-inflammatory environment and exerting endocrine effects on visceral fat and glucose and lipid metabolism, may be, at least partially, responsible for the beneficial effects of exercise.” ⁴ The researchers added: “In this light, healthy aging can be viewed as the ability not only to power the age-associated proinflammatory state, but also to stimulate and potentiate anti-inflammatory mechanisms.” ⁴ Further research is needed to understand the complex interaction of muscles and myokines with other organs in the body.

In terms of helping clinicians and patients make the link between muscle as an endocrine organ and exercise as an anti-inflammatory, Pedersen commented:

As a physician, I know that I have been overwhelmed by the enormous amount of data showing that regular exercise may prevent a whole network of diseases and that exercise should be prescribed as medicine. It is important to understand, however, how this occurs, and that regular exercise disrupts the vicious cycle of chronic inflammation directly by the production of the IL-6 myokine after each bout of exercise, and indirectly, by improving comorbidities and cardiovascular risk factors.

While today's patients have come to perceive certain organs, such as the thyroid gland and pancreas, as powerhouses of hormonal release, clinicians can help make the connection for patients when it comes to the endocrine activity of muscle. Pedersen commented: “I sometimes ask a patient to close his eyes and imagine that he is jogging. He can feel that his respiratory rate is increased and that his heart rate goes up but, what he cannot feel is that hundreds of myokines are produced, ensuring that he will have enough energy during the exercise, but also ensuring that training adaptation will occur, and that untold health benefits are occurring as a result of this physical activity.”

Epidemiologic studies support the fact that long-term exercise training and increased physical activity may reduce the occurrence of chronic disease significantly. ⁸ Allen and colleagues stated that “regardless of the mechanism, the acute and potent induction of anti-inflammatory cytokines after exercise has profound effects on inflammation and immune function.” Of course, chronic strenuous and vigorous prolonged exercise can lead to increased inflammation and, as Allen and colleagues stated, “accounting for intensity, duration, and recovery from exercise is key to understanding the time course and resolution of the inflammatory response.” ⁸

Conclusion

Simply affirming for patients that exercise is good for their health may be helpful, however adding to that explanation the understanding that exercise is a powerful anti-inflammatory may help relay further the importance of adopting a physically active lifestyle. Pedersen and Febbraio stated: “Given that muscle is the largest organ in the body, the identification of the muscle secretome could set a new agenda for the scientific community.” ⁷  ■