The mechanisms of action of exercise therapy

The comparable effectiveness for different modalities of exercise therapy also suggests that systemic effects might be more important than local effects. One such systemic effect might be systemic inflammation. Individuals who are more physically active show lower levels of proinflammatory markers and resting levels can be reduced through physical exercise programmes.1 Therefore, although no bulk of clinical evidence is available and mediation analyses are lacking, it is suggested that the anti-inflammatory effect of physical exercise is responsible for part of the treatment effects of exercise therapy.1 ,3 ,4

Physical exercise has been reported to induce a very strong cytokine response, with increased interleukin (IL)-6, produced by contracting muscles, being most marked (up to a 100-fold).1 ,4 ,5 The IL-6 production as response to physical exercise seems comparable to that observed during severe infections, with the important exception of the minimal production of proinflammatory cytokines as tumour necrosis factor α and IL-1β after exercise.3 Without the production of these proinflammatory cytokines, IL-6 is regarded as an anti-inflammatory cytokine.3 The production of anti-inflammatory cytokines due to regular physical exercise could decrease the proinflammatory cytokine profile in patients, either by increasing the anti-inflammatory cytokine production or by reducing the proinflammatory cytokine production.1 ,3 ,4 ,6

An example

Osteoarthritis is one such musculoskeletal condition in which low-grade systemic inflammation plays a role in the pathogenesis of the disease, where patients show increased levels of proinflammatory cytokines2 and where higher levels of proinflammatory cytokines are associated with more pain and worse function.7 As for other musculoskeletal conditions, exercise therapy is indicated as the first-line treatment for osteoarthritis, but the mechanisms behind the positive effects are largely unknown.8 Although elevated in osteoarthritis patients, reported levels of IL-6 after physical exercise are ∼30-fold higher than chronic levels reported in osteoarthritis patients. Given the positive effects of physical exercise on osteoarthritic symptoms, it is hard to believe that muscle-derived IL-6 is harmful for the body.6 Rather, the multiple fold increase of IL-6 concentrations after physical exercise might help the body fight the increased levels of proinflammatory cytokines, providing a potential mechanism of action for exercise therapy in osteoarthritis patients. Although suggested, a proper analysis of the mediating role of the anti-inflammatory effect of exercise therapy has never been performed.8

How to target the anti-inflammatory effect of exercise therapy?

Since IL-6 is by far the most marked, anti-inflammatory labelled, cytokine that is released after physical exercise, it is suggested that physical exercise programmes should be adjusted to optimise the IL-6 production to induce a decreased proinflammatory cytokine profile in patients suffering from low-grade systemic inflammation. The IL-6 production after physical exercise depends on:

• The type of muscle contraction, there is a faster increase after concentric contractions than after eccentric contractions;5 ,6

• Duration of the exercise, a longer duration of physical exercise leads to a higher IL-6 production;5

• Mass of activated muscles, greater mass of the active muscles leads to a higher IL-6 production;4 ,6

• Intensity of the exercises, moderate exercise intensity seems to have better results than low or high intensities.4

The potential

In conclusion, there are indications that the anti-inflammatory effect of physical exercise is part of the working mechanism behind the positive effects of exercise therapy for musculoskeletal conditions such as, but certainly not limited to, osteoarthritis. In future work, we and others should study the relative contribution of the anti-inflammatory effect of exercise therapy on the improvement of pain and function. If the anti-inflammatory effect proves to be a substantial or even a strong mediator, future exercise therapy programmes should be designed taking the knowledge of IL-6 production after physical exercise, as described above, into account. In potential, this will enhance the effectiveness of exercise therapy for patients with musculoskeletal conditions, leading to less pain and better function for patients with chronic musculoskeletal conditions and, thus, a lower burden for the patient and healthcare.