Point:Counterpoint: Estrogen and sex do/do not influence post-exercise indexes of muscle damage, inflammation, and repair

POINT: ESTROGEN AND SEX DO INFLUENCE POSTEXERCISE INDEXES OF MUSCLE DAMAGE, INFLAMMATION, AND REPAIR Estrogen and sex influences due to difference in estrogen exposure have been consistently reported to attenuate damage and/or inflammation and to accentuate repair in a variety of tissues and organs (4, 13, 22). Consistent with these findings, rodent models have provided compelling evidence of the efficacy of estrogen in decreasing indexes of post-exercise damage and inflammation in skeletal muscle (10, 29). In addition, we recently demonstrated tantalizing indications of the potential for estrogen to accentuate factors involved in muscle repair (5, 6, 28). Although less consistent than the findings in rodents, human studies focusing on sex differences have also provided some evidence for positive estrogenic influences of skeletal muscle damage and repair (18, 23). This article will present an overview of the evidence for estrogen to 1) ameliorate indexes of post-exercise muscle damage, 2) diminish post-exercise muscle inflammatory responses, and 3) accentuate factors related to muscle repair, as well as the possible mechanisms by which estrogen may act. Estrogen diminishes indexes of post-exercise muscle damage. Several lines of evidence, primarily from animal studies, indicate that exposure to estrogen will diminish indexes of muscle damage. In one of the few studies to directly examine histological evidence of muscle damage, Komulainen et al. (10) reported that for up to 96 h post-downhill running male rats exhibited earlier and greater indexes of damage to muscle structural proteins and more muscle fiber swelling than female rats. They also noted significantly elevated levels of -glucuronidase ( -glu) activity in the muscles of male relative to female rats. -glu is a lysosomal enzyme activated in response to muscle disruption and considered to be a quantitative indicator of muscle damage (17). Our laboratory has also reported that ovariectomized female rats with estrogen replacement have significantly diminished elevations in muscle -glu activities following downhill running relative to sham-supplemented animals (5, 6). Since skeletal muscle possesses both and -estrogen receptors (9), we tested the hypothesis that estrogen influence on post-exercise muscle damage may manifest through receptor-mediated mechanisms. Using the pure estrogen receptor blocker ICI-182,780, we recently demonstrated that the ability of estrogen to attenuate exercise-induced muscle damage, as quantified by reduced muscle -glu activation is not receptor mediated and may instead be related to other characteristics of estrogen as discussed below (6). Although not a specific indicator of structural muscle damage, serum creatine kinase (CK) levels have been used as reliable semi-quantitative indicators specifically of sarcolemma membrane disruption (7). As noted by Clarkson and Sayers (3) pioneering studies by Amelink and colleagues in the 1980s conclusively established that estrogen will attenuate post-damage muscle CK release in male and ovariectomized female rats. The most compelling of these studies avoided possible in vivo confounds by demonstrating that isolated muscle from exercised male rats with prior estrogen exposure released CK into the surrounding medium significantly slower than untreated male rats (1). Studies examining sex differences in humans have also reported higher post-exercise serum CK levels in men relative to women as well as a greater preponderance of high post-exercise CK responders in men (18, 23). Estrogen attenuates inflammation-related muscle leukocyte infiltration and damage. The potential for estrogen to stabilize muscle membranes and diminish sarcolemma disruption may be a mechanism by which estrogen acts to reduce exerciseinduced muscle damage and inflammatory responses (27). We have proposed that estrogen may act both as an antioxidant against exercise-induced membrane phospholipid peroxidation and as a cholesterol-like influence on membrane fluidity and stability (26, 27). Findings from our laboratory have consistently demonstrated an estrogen-induced attenuation of post-damage, inflammation-related neutrophil infiltration of red and white skeletal muscles in male as well as ovariectomized female rats (6, 16, 29). We suggested that the potential of estrogen to preserve sarcolemma stability following damaging exercise may help maintain muscle calcium homeostasis (27), which may, as we have demonstrated, result in attenuation of postexercise muscle calpain activation (29). Both reductions in muscle sarcolemma disruption and attenuation of calpain activation could contribute to the ability of estrogen to attenuate post-exercise neutrophil infiltration in both red and white skeletal muscle of rats (27). In further support of this theory, we recently demonstrated, with the use of an estrogen receptor blocker, that the ability of estrogen to diminish post-exercise muscle neutrophil infiltration is not estrogen receptor mediated and have suggested that this ability is instead mediated via direct estrogen action on muscle membranes (6). Neutrophils, while important in initiating tissue repair, are also responsible for significant post-exercise, inflammationrelated muscle structural and oxidative damage (14). The attenuation of post-exercise neutrophil infiltration into skeletal muscle by estrogen may thus also be a factor in reducing post-exercise muscle damage progression. Indeed, several studies have reported reduced indexes of oxidative damage in muscles of estrogen supplemented versus unsupplemented ovariectomized female rats following exercise or ischemiainduced disruption (13, 24). Estrogen can enhance potential for skeletal muscle repair. Estrogen can also attenuate post-exercise macrophage infiltration of skeletal muscle (6, 11). Macrophage infiltration of skeletal muscle as well as muscle damage itself are both important for initiating post-damage muscle regeneration and satellite cell activation (25, 30). Hence it is possible that by delaying or diminishing post-exercise macrophage infiltration or reducing damage in skeletal muscle, estrogen may diminish muscle repair-related responses such as satellite cell activation (5, 6). Despite this possibility we recently showed that estrogen supplementation will actually enhance activation and proliferation of satellite cells in muscles following downhill running in male and ovariectomized female rats (5, 6, 28). J Appl Physiol 106: 1010–1015, 2009; doi:10.1152/japplphysiol.90848. 2008.