swelling (446). Following is an overview of factors hypothesized to promote an EIMD-induced hypertrophic response.
Key Point
Research suggests that EIMD can enhance muscular adaptations, although excessive damage has a negative effect on muscle
development. It remains to be determined the extent to which these mechanisms are synergistic and whether an optimal combination exists to maximize the hypertrophic response to resistance training.
Inflammatory Processes
The body’s response to EIMD can be equated to its response to infection (656). After a damaging exercise bout, neutrophils migrate to the injury site while agents are released by affected fibers that attract macrophages to the region as well (475). This sets off a cascade of events in which inflammatory cells then secrete other substances to facilitate the repair and regeneration of damaged muscle. Inflammatory processes resulting from EIMD can have either a beneficial or deleterious effect on muscular function depending on the
magnitude of the response, previous exposure to the applied stimulus, and injury-specific interactions between the muscle and inflammatory cells (764). Neutrophils are more abundant in the human body than any other type of white blood cell. In addition to possessing phagocytic capabilities, neutrophils release proteases that aid in breaking down cellular debris from EIMD. They also secrete cytolytic and cytotoxic substances that can exacerbate damage to injured muscle and inflict damage to healthy neighboring tissues (764). Hence, their primary role in skeletal muscle is likely confined to myolysis and other facets associated with the removal of cellular debris as opposed to the
regeneration of contractile tissue.
conceivable that they may mediate anabolism by signaling other inflammatory cells necessary for muscle remodeling. One such possibility is reactive oxygen species (ROS) (779), which have been shown to mediate intracellular
signaling in response to intense physical activity (258, 340, 341, 574, 760). Neutrophils are associated with the production of numerous ROS variants, including hydrogen peroxide, superoxide, hydroxyl radical, and hypochlorous acid (372). ROS are associated with hypertrophy of both smooth muscle and cardiac muscle (734), and some speculate that anabolic effects extend to skeletal muscle as well (737). In support of this hypothesis, transgenic mice displaying suppressed levels of selenoproteins (a class of proteins that act as powerful antioxidants) had 50% more muscle mass following synergist
ablation compared to wild-type controls (313). These findings suggest that redox-sensitive signaling pathways may enhance exercise-induced muscular adaptations.
ROS have been shown to mediate anabolism via activation of the MAPK
pathway. The treatment of C2 myoblasts with an ROS variant heightens MAPK signaling, and the temporal response varies between MAPK subfamilies
(ERK1/2, JNK, and p38 MAPK) (357). Given that eccentric exercise is
associated with greater MAPK activation compared to concentric or isometric actions (446, 454), it is conceivable that ROS production contributes to this stimulus. There also is evidence that ROS enhance growth processes by
amplifying IGF-1 signaling. In vitro ROS treatment of mouse C2C12 myocytes significantly increased phosphorylation of the IGF-1 receptor, whereas
phosphorylation was markedly suppressed with antioxidant provision (283). These findings suggest a crucial role for ROS in the biological actions of IGF- 1.
Interestingly, there is evidence that ROS interfere with the signaling of various serine/threonine phosphatases, such as calcineurin. ROS activity impairs calcineurin activation by blocking its calmodulin-binding domain (128). Calcineurin is thought to be involved in both skeletal muscle growth (193, 490) and fiber phenotype transformation (560), and thus its inhibition may be detrimental to anabolism. Moreover, some studies have failed to demonstrate that ROS are in fact activated in response to EIMD (644). When considering the body of literature as a whole, any anabolic effects of ROS are likely dependent on exercise mode (i.e., anaerobic versus aerobic), the species of
ROS produced, and perhaps other factors.
In contrast to neutrophils, research indicates a potential role for macrophages in regenerative processes following EIMD (764), and some researchers even speculate that they are necessary for muscle growth (372). Macrophages appear to exert anabolic effects by secreting local growth factors associated with inflammatory processes. It was originally thought that myodamage directly led to the production of pro-inflammatory myokines (99, 565). Although this would seem to have a logical basis, more recent research
indicates that such myokine production may be largely independent of EIMD. A study by Toft and colleagues (770) showed that IL-6 levels were only modestly elevated relative to increases in creatine kinase following 60 minutes of
eccentric cycle ergometry exercise, suggesting a weak association between EIMD and IL-6 production. These results are consistent with those of others showing poor correlation in the time course of IL-6 and creatine kinase
appearance (164). The totality of findings has led to the supposition that IL-6 release is predominantly a function of muscle contraction. Mechanistically, some researchers have hypothesized that this facilitates the mobilization of substrate from fuel depots so that glucose homeostasis is maintained during intense exercise (214).
It is important to note that only IL-6 and IL-8 have been shown to be released from skeletal muscle in the absence of damaging exercise (129). Many other myokines may play a role in the hypertrophic response to EIMD. Systemic IL- 15 levels and IL-15 mRNA in skeletal muscle are markedly elevated after eccentric (but not concentric) exercise, giving credence to the notion that elevations are contingent on damage to fibers (100, 616). Some studies show that IL-15 directly regulates hypertrophy by increasing muscle protein
synthesis and reducing proteolysis in differentiated myotubes (530, 596), although these findings recently have been challenged (583). There also is evidence that fibroblast growth factors (FGFs)—powerful proliferative agents involved in hypertrophic processes—are preferentially upregulated following eccentric exercise. Research indicates that FGFs are secreted from damaged fibers (142) and that their time course of release parallels the increased creatine kinase levels associated with EIMD (143). These findings lend mechanistic support to the hypothesis that damaging exercise promotes an anabolic stimulus.