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More research is needed before the use of oestrogen can be recommended for muscle damage
Oestrogen may affect muscle damage and inflammation, but the physiological significance of this, particularly potential effects on muscle repair and recovery in humans, and the mechanisms of its actions are as of yet unknown.
Over the last decade, evidence has accumulated that oestrogen may act to diminish skeletal muscle damage and inflammatory responses after unaccustomed exercise or other damaging insult. These prophylactic effects are similar to the effect of oestrogen in diminishing damage and inflammation in other tissues such as cardiac muscle, liver, and nervous tissue.1–3 What is not clear is the physiological significance of this effect of oestrogen and whether it is physiologically meaningful or results in significantly differential responses in skeletal muscle after over-exertion in humans.4 The mechanisms by which oestrogen exerts its effect on skeletal muscle responses to damaging exercise, and whether its influence extends to differential rates of muscle repair and recovery also require further investigation.
The primary practical implication of a role for oestrogen in post-exercise muscle damage, recovery, and repair mechanisms is likely to be for postmenopausal women who have reduced oestrogen concentrations, and thus may be more susceptible to muscle damage and slower recovery than premenopausal women. Sex differences in susceptibility to muscle damage are also of interest. This overview will briefly examine these questions and summarise the current evidence for oestrogenic influence on skeletal muscle damage, inflammation, and repair. Considerable research is still needed before any conclusions can be reached about the physiological significance of these effects of oestrogen in humans.
INFLUENCE OF OESTROGEN ON SKELETAL MUSCLE DAMAGE
Oestrogen is a strong antioxidant and a membrane stabiliser.5,6 We have proposed that these properties, which are unique to oestrogen as a steroid hormone, may account for some of its mitigating effects on post-exercise muscle damage indices.7,8 Indeed, early studies by Bär and Amelink9 showed a significant in vivo and in vitro attenuation of muscle creatine kinase leakage and lower blood creatine kinase activity in oestrogen treated rodents after damaging contractions. Although creatine kinase release from skeletal muscle is not a good index of muscle structural damage, it is considered a reasonable indicator of muscle membrane and sarcolemma stability and disruption. Hence, a primary effect of oestrogen may be to protect muscle membranes from exercise induced muscle damage.7 The reduction of muscle membrane disruption may also be important in inflammatory responses and muscle repair.
Only a few studies have addressed the possibility of direct oestrogenic influence on muscle structural damage after exercise, and, of these, none have found direct evidence of oestrogen involvement. The most comprehensive of these studies10 found significant sex differences in histochemical and biochemical indices of muscle damage after downhill running in rats. The attenuation of post-exercise muscle damage reported in the female rats was potentially attributed to differences in circulating oestrogen concentrations. The limited number of studies that have attempted to histochemically quantify differences in indices of post-exercise muscle damage in men and women from biopsy samples have had conflicting results.7 Human sex differences in exercise induced muscle damage may be masked by small sample sizes and variability of data obtained from small biopsy samples.11 However, other indicators of muscle damage in humans after exercise have generally also not found major sex differences.4 Probably a more important human health issue related to oestrogen is the potential differences in susceptibility to exercise induced muscle damage between premenopausal and postmenopausal women. As of yet, no studies have directly addressed this issue. However, it has been reported that a postmenopausal loss of oestrogen may result in greater aging related strength loss and a reduced rate of strength gain in older women.12 Hence, although some information is available, definitive studies on the influence of oestrogen on skeletal muscle damage, particularly in humans, are lacking and further investigation is warranted.
INFLUENCE OF OESTROGEN ON MUSCLE INFLAMMATION AFTER EXERCISE
Although there are still some conflicting data, particularly in the few human studies that have addressed this issue, oestrogen has generally been shown to inhibit inflammation related leucocyte infiltration into both skeletal7 and cardiac2 muscle after unaccustomed exercise or other damaging insult such as ischaemia-reperfusion injury. Leucocytes such as neutrophils and macrophages play important roles in muscle recovery by assisting the removal of damaged tissue during inflammation and the activation of muscle satellite cells during muscle regeneration.5,6 However, neutrophils in particular may also further exacerbate post-exercise damage by generating oxidising agents. Hence it has been suggested that limiting leucocyte infiltration into skeletal muscle during the inflammatory period may lessen total muscle disruption.6 Indeed, evidence from studies on cardiac, neural, and other tissues suggest that limiting neutrophil infiltration with oestrogen will reduce damage and speed healing in these tissues.1–3
Several studies have suggested that oestrogen does indeed attenuate muscle neutrophil infiltration after exercise, particularly in animal models. Attenuation of muscle neutrophil infiltration has been repeatedly shown in oestrogen supplemented male and ovariectomised female rats after unaccustomed exercise or ischaemia-reperfusion induced injury.8,13,14 A further study has also reported delays in macrophage infiltration into skeletal muscle in female compared with male rats after damage.15 However, the physiological implications of these effects of oestrogen on subsequent muscle damage and repair have yet to be experimentally documented.
The mechanisms by which oestrogen attenuates muscle neutrophil infiltration after exercise are not fully understood. We have suggested that the antioxidant and/or membrane stabilising characteristics of oestrogen may play a role in decreasing neutrophil chemo-attraction to disrupted muscle, possibly by decreasing calpain activation or by influencing other membrane related neutrophil capture, adhesion, or diapedesis mechanisms.7,8 As there is evidence for the presence of oestrogen receptors on skeletal muscle,16 it is possible that oestrogen may also affect inflammation related responses by direct receptor mediated mechanisms.7,8 Further experimental evidence is needed to confirm the mechanism(s) by which oestrogen affects muscle inflammation and ultimately the physiological significance of this effect, particularly in human models.
INFLUENCE OF OESTROGEN ON SKELETAL MUSCLE REPAIR
One consequence of the attenuation of muscle leucocyte infiltration by oestrogen may be a change in the rate of skeletal muscle repair or recovery from injury. As previously noted, leucocytes may exacerbate muscle damage caused by exercise as a consequence of their role in the clearance of damaged tissue. The attenuation of leucocyte infiltration by oestrogen may therefore diminish extraneous damage, leading to faster healing. Alternatively, infiltration of muscle by leucocytes (particularly macrophages) may be important in activating muscle satellite cells and initiating their critical role in muscle regeneration. Hence any attenuation of leucocyte infiltration may delay important stages in the muscle recovery process.6
There is other evidence that oestrogen can influence NO and inducible nitric oxide synthase (iNOS) activity in a number of tissues and by so doing influence damage and recovery processes.17,18 As NO and iNOS are important regulators of skeletal muscle satellite cell activation,19 oestrogen may also affect muscle regenerative processes through iNOS mediated influence on muscle satellite cells or other recovery related parameters.
Despite these theoretical postulations, there is as yet almost no experimental evidence on the potential for oestrogen to influence muscle recovery or repair mechanisms. Very recent preliminary work from our laboratory, which compared ovariectomised, oestrogen supplemented female rats with unsupplemented rats found greater numbers of active muscle satellite cells in hindlimb muscles of rats 72 hours after an intense eccentric exercise bout.20 If these preliminary findings are confirmed by more extensive experimentation and more comprehensive measures of muscle recovery, the role and importance of oestrogen in muscle repair could be further clarified. Any such information would add to the current discussions on the benefits versus drawbacks of postmenopausal hormone replacement therapy.
A ROLE FOR PROGESTERONE?
As much of the animal based research noted above has used oestrogen supplemented male or ovariectomised animals, the physiological significance of progesterone in muscle damage and repair may have been under-reported. There is little evidence that progesterone has any direct effect on muscle damage, inflammation, or repair mechanisms. However, a number of studies have reported antagonistic effects of progesterone on oestrogen actions in other tissues. A recent study found that, with vascular injury in ovariectomised rats, oestrogen supplementation reduced leucocyte infiltration by 50% and progesterone had no independent effect on leucocyte infiltration after damage.21 However, when progesterone was supplemented in combination with oestrogen, it completely negated the attenuating influence of oestrogen on post-damage vascular leucocyte infiltration. Oestrogen and progesterone interactions have also recently been reported in relation to their potential to influence muscle fatigue.22
Hence the potential interactive effects of oestrogen and progesterone need to be further investigated, particularly in relation to the in vivo physiological significance of oestrogenic influence on muscle recovery in women.
SUMMARY AND CONCLUSIONS
Experimental evidence, primarily from animal models, suggests a role for oestrogen in mitigating muscle damage and disruption and in inflammation related leucocyte infiltration into skeletal muscle. There are also a number of theoretical reasons to suspect that oestrogen has some effect on the rate of skeletal muscle recovery and repair. However, much more research is required before any physiologically significant role of oestrogen in muscle repair and recovery can be attributed, particularly in human females. Hence, any practical application of oestrogen supplementation, particularly in postmenopausal women, as a prophylactic to muscle damage or catalyst to muscle healing must await further experimentation.
More research is needed before the use of oestrogen can be recommended for muscle damage
Competing interests: none declared