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Inflammation appears to play an important role in the repair and regeneration of skeletal muscle after damage. We tested the hypothesis that the severity of the inflammatory response in muscle after an acute bout of resistance exercise is associated with single nucleotide polymorphisms (SNPs) previously shown to alter interleukin-1 (IL-1) activity. Using a double-blind prospective design, sedentary young men were screened (n= 100) for enrolment (n= 24) based upon having 1 of 4 haplotype patterns composed of five polymorphic sites in the IL-1 gene cluster: IL-1A (+4845), IL-1B (+3954), IL-1B (−511), IL-1B (−3737) and IL-1RN (+2018). Subjects performed a standard bout of resistance leg exercise and vastus lateralis biopsies were obtained pre-, and at 24, and 72 h post-exercise. Inflammatory marker mRNAs (IL-1β, IL-6 and tumor necrosis factor-α (TNF-α)) and the number of CD68+ macrophages were quantified. Considerable variation was observed in the expression of these gene products between subjects. At 72 h post-exercise, IL-1β had increased in a number of subjects (n= 10) and decreased (n= 4) or did not change (n= 10) in others. Inflammatory responses were significantly associated with specific haplotype patterns and were also influenced by individual SNPs. Subjects with genotypes 1.1 at IL-1B (+3954) or 2.2 at IL-1B (−3737) had approximately a 2-fold higher median induction of several markers, but no increase in macrophages, suggesting that cytokine gene expression is elevated per macrophage. The IL-1RN (+2018) SNP maximized the response specifically within these groups and was associated with increased macrophage recruitment. This is the first report that IL-1 genotype is associated with the inflammation of skeletal muscle following acute resistance exercise that may potentially affect the adaptations to chronic resistance exercise.
Intense physical activities, such as resistance exercise, with a strong eccentric component, cause micro-injury to skeletal muscle (Dolezal et al. 2000). The body senses the trauma and repair is initiated with the induction of a typical acute-phase response (MacIntyre et al. 1995; Tidball, 1995). Cytokines are thought to initiate and regulate this process and have been well characterized systemically (Pedersen & Toft, 2000). Among the first genes activated with almost any challenge to the body are the pro-inflammatory cytokines interleukin (IL)-1β and TNF-α, and with micro-injury to the muscle, quiescent resident macrophages begin to produce these mediators (Tidball, 1995). These cytokines trigger increased proteolysis and act as chemoattractants for an influx of macrophages from the circulation (Rappolee & Werb, 1992; Mansoor et al. 1996; Fielding & Evans, 1997; Wray et al. 2003). Macrophages phagocytize cellular debris and can continue secretion of IL-1β even 5 days post-injury (Fielding et al. 1993). They are also a rich source of growth factors postulated to stimulate myogenesis (Robertson et al. 1993) that involves muscle satellite cell proliferation, migration to the site of injury, and fusion either with existing fibres for repair or with each other to replace degenerated muscle fibres (Vierck et al. 2000). Thus, inflammation may also be involved with the mechanisms of hypertrophy.
Inflammation must be strictly regulated or considerable secondary tissue damage and myopathy can ensue (Authier et al. 1997; Tidball, 2002). Infusion of IL-1β or TNF-α suppresses protein synthesis, induces skeletal muscle catabolism, and results in anorexia in rats (Ling et al. 1997). Increased expression of IL-6 has implicated cytokine-mediated events in reduced skeletal muscle function with age (Ferrucci et al. 1999; Barbieri et al. 2003), but IL-6 may actually possess anti-inflammatory properties within this context (Tilg et al. 1997). The finding that IL-1β stimulates IL-6 production in myoblasts (Gallucci et al. 1998; Pedersen et al. 2003) may also indicate that the coordinated regulation of cytokines is important for muscle repair and myogenesis. Indeed, both IL-6 and the IL-1 receptor antagonist (IL-1RA) increase dramatically in the plasma following strenuous exercise (Pedersen & Toft, 2000). Thus, there probably exists an optimal balance between inflammatory factors and their negative regulators that is most conducive to skeletal muscle health.
At least 90 genes or gene variations have been associated with differences in exercise performance and health-related fitness phenotypes (Perusse et al. 2003). Notably, single nucleotide polymorphisms (SNPs) in two genes, ciliary neurotrophic factor (Roth et al. 2001) and interleukin-6 (Roth et al. 2003), have been associated with strength and/or fat-free mass. Since much of the early injury response is shaped by the local release of IL-1β and TNF-α, we have investigated the influence of IL-1 gene variations among individuals on the muscle response to resistance exercise. The genes for IL-1 biological activity are found in a cluster on chromosome 2 and include the genes that encode the agonists IL-1α, IL-1β, and the antagonist IL-1RA. SNPs have been identified across the IL-1 gene cluster and certain SNPs in this region are in strong linkage disequilibrium (Cox et al. 1998) and define specific IL-1 haplotypes. Three haplotype groups are highly prevalent in Caucasian populations (Cox et al. 1998) and have been associated with altered levels of these proteins and other inflammatory markers (Hurme & Santtila, 1998; Shirodaria et al. 2000; Berger et al. 2002). As a consequence, these SNPs or closely linked SNPs, may influence the severity of the inflammatory response and are associated with disease (Buchs et al. 2001; Kornman & Duff, 2001). IL-1 gene variations have not been examined in relation to inflammatory myopathies or in the normal inflammatory response generated in skeletal muscle after a standard bout of resistance exercise which, if performed chronically, results in increased muscle size and strength. Given that genetic variations are known to influence the inflammatory response in other systems, we hypothesized that the magnitude of inflammatory marker induction in skeletal muscle after a standard bout of acute resistance exercise will be associated with specific IL-1 SNPs. The purpose of this research was to begin investigating the link between inflammation and genetics in relation to the normal metabolic response that leads to hypertrophy. Our results suggest that variations within the IL-1 gene cluster may be predictors of the adaptability of skeletal muscle, as the muscle inflammatory response in young men after weight-lifting was influenced by their IL-1 genotype.