The diseasome of physical inactivity--and the role of myokines in muscle--fat cross talk

Abstract

Type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, dementia and depression constitute a cluster of diseases, which defines 'a diseasome of physical inactivity'. Both physical inactivity and abdominal adiposity, reflecting accumulation of visceral fat mass, are associated with the occurrence of the diseases within the diseasome. Physical inactivity appears to be an independent and strong risk factor for accumulation of visceral fat, which again is a source of systemic inflammation. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration and tumour growth. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the anti-inflammatory effect of regular exercise, which can be mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. The finding that muscles produce and release myokines provides a conceptual basis to understand the mechanisms whereby exercise influences metabolism and exerts anti-inflammatory effects. According to our theory, contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation.

Figure 1

Type 2 diabetes, cardiovascular diseases, colon cancer, postmenopausal breast cancer, dementia and depression constitute a cluster of diseases, which can be identified as ‘the diseasome of physical inactivity’

Figure 2

Hypothesis: Physical inactivity leads to accumulation of visceral fat and consequently to the activation of a network of inflammatory pathways, which promotes development of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth, leading to the development of ‘the diseasome of physical inactivity’

Figure 3. Biological role of contraction-induced IL-6

Skeletal muscle expresses and releases myokines into the circulation. In response to muscle contractions, both type I and type II muscle fibres express the myokine IL-6, which subsequently exerts its effects both locally within the muscle (e.g. through activation of AMPK) and – when released into the circulation – peripherally in several organs in a hormone-like fashion. Specifically, in skeletal muscle, IL-6 acts in an autocrine or paracrine manner to signal through a gp130Rβ/IL-6Rα homodimer, resulting in activation of AMP kinase and/or PI3 kinase to increase glucose uptake and fat oxidation. IL-6 is also known to increase hepatic glucose production during exercise or lipolysis in adipose tissue. Modified from Pedersen & Febbraio (2008) with permission from the American Physiological Society and from Pedersen and Fischer (2007) with permission from Elsevier.

Figure 4

The diseasome of low circulating levels of brain derived neurotropic factor (BDNF) has a major overlap with the diseases included in the diseasome of physical inactivity

Figure 5. Comparison of sepsis-induced versus exercise-induced increases in circulating cytokines

During sepsis, there is a marked and rapid increase in circulating TNF-α, which is followed by an increase in IL-6. In contrast during exercise the marked increase in IL-6 is not preceded by elevated TNF-α. From Pedersen & Febbraio (2008) with permission from the American Physiological Society.

Figure 6. The proposed cytokine signalling pathways for macrophages and contracting skeletal muscle

While it is well known that transcription of IL-6 and other pro-inflammatory cytokines such as TNF-α and IL-β is principally regulated by the TLR receptor signalling cascade that results in nuclear translocation and activation of NFκB, evidence in contracting skeletal muscle suggests that contraction leads to increased cytosolic Ca²⁺ and activation of p38 MAPK and/or calcineurin, which leads to activation of transcription factors depending upon these upstream events. From Pedersen & Febbraio (2008) with permission from the American Physiological Society.