Interaction between cytokine gene polymorphisms and the effect of physical exercise on clinical and inflammatory parameters in older women: study protocol for a randomized controlled trial

Daniele S Pereira 1 Brbara Z Queiroz 1 Elvis CC Mateo 3 Alexandra M Assumpo 1 Diogo C Felcio 1 Aline S Miranda 3 Daniela MC Anjos 1 Fabianna Jesus-Moraleida 1 Rosngela C Dias 1 Danielle AG Pereira 1 Antnio L Teixeira 3 Leani SM Pereira 0 1 2 0 Departamento de Fisioterapia, Universidade Federal de Minas Gerais / UFMG , Av. Antonio Carlos, 6627, CEP 31270-901, Belo Horizonte, MG , Brazil 1 Department of Physical Therapy, Graduate Program in Rehabilitation Sciences, School of Physical Education, Physical Therapy and Occupational Therapy, Universidade Federal de Minas Gerais , Belo Horizonte, MG , Brazil 2 Departamento de Fisioterapia, Universidade Federal de Minas Gerais / UFMG , Av. Antonio Carlos, 6627, CEP 31270-901, Belo Horizonte, MG , Brazil 3 Department of Internal Medicine, School of Medicine, Universidade Federal de Minas Gerais (UFMG) , Belo Horizonte , Brazil Background: Aging is associated with chronic low-grade inflammatory activity with an elevation of cytokine levels. An association between regular physical activity and reduction of blood levels of anti-inflammatory cytokines is demonstrated in the literature pointing to an anti-inflammatory effect related to exercise. However, there is no consensus regarding which type of exercise and which parameters are the most appropriate to influence inflammatory markers. Evidence indicates that the single nucleotide polymorphism (SNP) can influence the synthesis of those cytokines affecting their production. Methods/Design: The design of this study is a randomized controlled trial. The aim of this study is to investigate the interaction between the cytokine genes SNP and the effect of physical activity on older women. The main outcomes are: serum levels of sTNFR-1, sTNFR-2, interleukin (IL)-6, IL-10, measured by the ELISA method; genotyping of tumor necrosis factor- (TNF)-alpha (rs1800629), IL6 (rs1800795), IL10 (rs1800896) by the TaqMan Method (Applied Biosystems, Foster City, CA, USA); and physical performance assessed by Timed Up and Go and 10-Meter Walk Tests. Secondary outcomes include: Geriatric Depression Scale, Perceived Stress Scaleand aerobic capacity, assessed by the six-minute walk; and lower limb muscle strength, using an isokinetic dinamometer (Biodex Medical Systems, Inc., Shirley, NY,USA). Both exercise protocols will be performed three times a week for 10 weeks, 30 sessions in total. Discussion: Investigating the interaction between genetic factors and exercise effects of both protocols of exercise on the levels of inflammatory cytokine levels can contribute to guide clinical practice related to treatment and prevention of functional changes due to chronic inflammatory activity in older adults. This approach could develop new perspectives on preventive and treatment proposals in physical therapy and in the management of the older patient. Trial registration: (ReBEC) RBR9v9cwf - Background Aging is associated with a chronic low-grade inflammatory process characterized by a systemic elevation, from two to four times, of plasma levels of cytokines as interleukin (IL)-1, tumor necrosis factor alpha (TNF-), IL-6, acute phase proteins, soluble TNF receptors (sTNFR) and IL-10, among others [1]. The balance between production and release of those cytokines has been related to the emergence or aggravation of chronic conditions related to aging, disability and increased mortality in olderadults[1,2]. High levels of cytokines are associated with a reduction of physical performance and muscle function [3-7]. The underlying mechanism by which these cytokines contribute to a functional deterioration in olderadults seems to be their catabolic effect, leading to a reduction in muscle mass and strength that are related to sarcopenia [1,8]. TNF- is an early mediator of inflammation since it starts and coordinates the acute phase response and induces the production of a second wave of cytokine expression, such as IL-6, IL-8 and C-reactive protein [9]. It also stimulates the production of sTNFR that acts as its natural inhibitor; therefore, regulating its biological function. Since these receptors are more stable molecules than TNF- in circulation, they are more reliable markers of plasma TNF- levels, and hence of the inflammatory response [10]. A few authors argue that TNF- is behind the age-related inflammatory changes [11,12], being associated with the development of insulin resistance and metabolic syndrome [13], and also with reduction of muscle mass and strength loss due to its catabolic action [14]. IL-6 is a cytokine that has both pro- and antiinflammatory roles and is involved in controlling and coordinating inflammatory responses. It is produced by different cell types, which include the skeletal muscle cells [15]. On the other hand, IL-10 is an anti-inflammatory cytokine that is essential to inflammatory activity control and resolution that is triggered and sustained by other mediators [16]. The IL-10 inhibitory effect on IL-6 and TNF- cytokines is well established in acute inflammatory processes [17], but not in chronic inflammation, such as we see during aging. The impact of physical exercises on their plasma levels is not known. Differences seen in protein expression among people can occur as a result of functional genetic variations in the promoter area of these molecules gene [18]. The most common variations seen on human genomes are the single nucleotide polymorphism (SNP). Evidence points that SNPs, which are present in the genes of several molecules involved in inflammation, could affect their gene transcription and synthesis [18], modulating the inflammatory response severity. Some polymorphisms are associated with a greater production of inflammatory mediators. Thus, gene variations could explain in part the variability in the production of cytokines, and the greater liability of certain people to clinical conditions that are mediated by the elevation of these markers production, such as chronic conditions related to aging and longevity [19-21]. The expression of TNF-, IL-6 and IL-10 is influenced by functional polymorphisms at their promoter areas. The polymorphisms in TNF- (rs1800629), IL-6 (rs1800795) and IL-10 (rs1800896) have been associated with several acute and chronic diseases and with longevity as well [1,19,22]. For instance, Oberbach et al. [22] identified that changes in the IL-6 plasma levels in response to exercise were influenced by the -174 G/C polymorphism, suggesting that genetic factors related to cytokine production could be determinant to individual effects of the anti-inflammatory response promoted by exercise. However, literature presents contradictory results related to their activity and effects on plasma levels of these mediators, especially considering the older population. One possibility is that differences shown in the literature are due to interactions between lifestyle and gene factors, along with cultural and ethnic differences of the different studied samp (...truncated)