Exercise-induced myokines and their role in chronic diseases

Abstract

Physical inactivity has recently been identified as a major and independent risk factor for the development of dementia and cognitive decline. In addition to the effect of exercise with regard to protection against neurodegenerative diseases, it is well-established that physical inactivity increases the risk of type 2 diabetes, cardiovascular diseases (CVD), colon cancer and postmenopausal breast cancer. These diseases constitute a network of related diseases, also called “the diseasome of physical inactivity”. In this review, physical inactivity is given the central role as an independent and strong risk factor for accumulation of visceral fat and consequently the activation of a network of systemic inflammatory pathways, which promote development of neurodegeneration as well as insulin resistance, atherosclerosis, and tumour growth. The recent finding that muscles produce and release myokines provides a conceptual basis for understanding some of the molecular mechanisms underlying organ cross talk, including muscle-fat cross talk. Accumulating data suggest that contracting skeletal muscles release myokines, which may work in a hormone-like fashion, exerting specific endocrine effects on visceral fat or mediating direct anti-inflammatory effects. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation.

Introduction

Recent evidence suggests that physical inactivity is an independent player in the development of dementia (Aarsland et al., 2010). Physical exercise appears to be a factor that strongly affects brain plasticity. In rodents, physical exercise improves memory function and structural parameters such as synapse density, neuronal complexity, and hippocampal neurogenesis (Wu et al., 2008). It has also been established that exercise induces neuroprotection in animal models of stroke (Hayes et al., 2008), traumatic brain injury (Griesbach et al., 2007), and Parkinson disease (Yoon et al., 2007) and that voluntary running significantly restores hippocampal neurogenesis after irradiation (Naylor et al., 2008). These experimental studies suggest that physical exercise has an impact on cognitive performance.

In humans, it has been shown that higher levels of cardiovascular fitness are associated with increased hippocampal volume as well as better memory function (Erickson et al., 2009). Moreover, a recent study measured hippocampus size in response to 12 weeks of aerobic training in patients with schizophrenia and healthy controls. Following exercise training, relative hippocampal volume increased significantly in patients (12%) and healthy subjects (16%), with no change in the non exercise group of patients (−1%) (Pajonk et al., 2010).

A couple of meta-analyses demonstrate a positive association between cardiovascular (or ‘‘aerobic’’) fitness and cognitive performance in elderly subjects (Angevaren et al., 2008, Colcombe and Kramer, 2003, Etnier et al., 2006, Heyn et al., 2004). Physical activity during midlife appears to protect against dementia or cognitive decline and to improve cognitive performance in older adults with memory impairment (Rovio et al., 2005, Sun et al., 2010, Etgen et al., 2010, Liu-Ambrose et al., 2010, Andel et al., 2008, Lautenschlager et al., 2008) and recently, a strong statistical association was found between fitness and intelligence in the youngsters (Aberg et al., 2009).

Thus, there appears to be accumulating evidence suggesting that regular exercise protects against dementia and cognitive decline. Moreover, exercise may also offer some protection to the occurrence of depression (Sui et al., 2009). In addition to the effect of exercise with regard to protection against neurodegenerative diseases, it is well-established that physical inactivity increases the risk of type 2 diabetes (Tuomilehto et al., 2001), cardiovascular diseases (CVD) (Nocon et al., 2008), colon cancer (Wolin et al., 2009), and postmenopausal breast cancer (Monninkhof et al., 2007).

Type 2 diabetes is associated with impaired cognitive function as well as with both Alzheimer’s disease and vascular dementia, and individuals with type 2 diabetes also have a high prevalence of affective illness, including major depression, reviewed in Komulainen et al. (2008). Other studies report that type 2 diabetes is associated with an elevated risk of CVD (Diamant and Tushuizen, 2006), colon and breast cancer, as well as pancreatic, liver, and endometrial cancer (Richardson and Pollack, 2005).

Thereby, dementia and depression together with type 2 diabetes, cardiovascular diseases, colon cancer and postmenopausal breast cancer constitute a network or a cluster of diseases, which we have previously identified as “the diseasome of physical inactivity” (Pedersen, 2009). The diseasome of physical inactivity represents diseases with highly different phenotypical presentation. However, these diseases appear to share important pathogenetic mechanisms. It is well-established that independently of body mass index (BMI), physical inactivity is a risk factor for all-cause mortality (Pedersen, 2007). Moreover, chronic systemic inflammation is associated with physical inactivity independent of obesity (Fischer et al., 2007). Based on the prevailing literature, it is suggested that physical inactivity leads to accumulation of visceral fat and consequently the activation of a network of inflammatory pathways, which promote development of neurodegenation as well as insulin resistance, atherosclerosis, and tumour growth and thereby the development of the diseases belonging to the “diseasome of physical inactivity”, Fig. 1.