Sarcopenia is defined as the age-related reduction in skeletal muscle mass and function and is considered one of the main contributors to morbidity and physical disability [9]. Menopause impacts sarcopenia, which not only affects very old women but also middle-aged women [10]. A sharp decrease in muscle mass and function occurs following the age of 50, about the years of menopausal transition [11]. The skeletal muscle is an important organ for energy expenditure and makes up about 50% of the human body. A gradual loss of skeletal muscle mass including reduced energy expenditure with mitochondrial dysfunction following menopause relates to an increase in visceral adipose tissue [12]. There-fore, sustaining skeletal muscle mass seems to be imperative to protect from menopause-associated metabolic syndrome in women.

Cross-sectional studies [13–15] including the research by the Study of Women’ s Health Across the Nation (SWAN) [13] reported that lean mass was lower in postmenopausal compared to premenopausal women. However, little was known about whether skeletal muscle mass and the prevalence of sarcopenia differ between the menopausal stages. Using a self-reported menstrual cycle assessment according to the Stages of Re-productive Aging Workshop (STRAW) criteria, our recent cross-sectional study [16] determined that peri-menopausal stage appears to be a vul-nerable period for the significant loss of skeletal muscle mass. Our research team recruited 144 healthy women (aged 30-70 years) classified as 5 different menopausal stages: premenopausal, early/late perimenopaus-al, and early/late postmenopausal. Appendicular lean mass, measured using dual-energy x-ray absorptiometry, was 10 and 9 % lower in late peri- and post-menopausal, respectively, compared to early perimeno-pausal women. The prevalence of sarcopenia was 3 and 30% in early and late peri-menopausal women, respectively. Our findings showed a significant reduction in muscle mass and a rapid increase in the prevalence of sarcopenia from early to late peri-menopausal women, implying that muscle loss has already been started during peri-menopausal stage (i.e., menopausal transition). Our results highlight the necessity to investigate the major hormonal factors contributing to the loss of skeletal muscle mass and its further mechanisms.

Menopause transition has been believed to trigger the underlying mechanisms associated with sarcopenia. This suggests that menopause transition may be a critical time to introduce strategies to lessen the significant loss of muscle mass and function, which can result in greater physical frailty and disability later in life. More studies are needed to elu-cidate the extent to which menopause augments sarcopenia, and if this muscular deterioration is associated with which sex hormones including estrogens. However, menopause is 1) the period that both estradiol and testosterone decrease; and 2) the consequence of both gonadal and chronologic aging. The complex, mixed changes in hormones and the aging process make it difficult to isolate a single cause of sarcopenia in older women. Accumulating evidence has suggested that alterations in the gonadal hormones during the menopause transition appear to be a strong determinant of skeletal muscle mass and strength in women. Among sex hormones, estrogen deficiency has been believed to be the most important clinical feature contributing to the development of sarcopenia [3]. Furthermore, assessment of estrogens and follicular stimulating hormone can confirm the diagnosis of menopause. The circulating levels of these hormones vary significantly during the menopause transition, such that the sharp reduction in estrogens and increase in follicular stimulating hormone occurs after the age of 50 in women [17].

Whereas the underlying mechanism of menopause-related changes in body composition are unclear, previous research suggests that reduced level of physical activity [18], rather than changes in food consumption [19], likely plays a critical role in developing menopause-related loss of muscle mass and a consequent metabolic dysfunction. Women are more physically inactive than men, and research revealed that about 60% of women fail to meet the guidelines of physical activity [20]. This phenomenon of physical inactivity appears to be more profound in the aged compared to young women. In line with this trend, the number of women 65 years of age and older exhibits a greater prevalence of physical inactivity compared to aged men. Maintaining physically active is very important in aged women as an inverse association between mortality and physical activity has been reported [20]. Decreased physical activity level is known to impair aerobic fitness [21], which loss is a high risk factor for mortality [22].

Menopause impacts physical activity level in women, directly through the deterioration of skeletal muscle function and indirectly through behavioral changes such as reduced physical activity. Due to the incredible plasticity, skeletal muscle can be atrophied and eventually appears to be weak and malfunctioned following the less use of skeletal muscle. Pre-clinical rodent studies [23–27] using ovariectomy (OVX), a good model to study human menopause, support the menopausal phenomenon of physical inactivity in women. Ovariectomy resulted in a dramatic reduction in physical activity of 30-80% and this was not attributable to the effect of surgery. Physical activity was rescued in OVX rodents treated by estradiol add-back. The estrogenic regulation of physical activity was further supported by the observation that only estradiol but not proges-terone add-back rescued physical activity to the normal level in OVX rodents [28]. These previous findings advocate the existence of a primary physiological factor resulting from menopause. Increasing evidence suggest that estradiol might be a major controller for behavioral modifications in women.

The dopamine (DA) signaling in the nucleus accumbens (NAc) is a key controller for voluntary activity [29–31]. Previous studies have impli-cated that mesolimbic dopamine circuits can significantly contribute to physical activity through the regulation of motivation [32], reward [33], and motor control [34]. Among the dopamine circuits, NAc is a part of the ventral striatum, a primary element in the affective processing of voluntary motor action [30]. In the striatum, DA neurons are responsible for the control of motor activity [31]. Also, DA signals in the NAc play a critical role in the behaviors related to natural reinforcers, e.g. food intake, incentive learning, and sexual behavior [35–37]. Physical activity was a natural and strong reinforcer prior to urbanization, primarily for food gathering and sexual behavior in women. Knab and Lightfoot [29] suggest that DA signal in the NAc is a key controller for voluntary running. Research on DA signal and the motivation of physical activity can be comparable to addiction studies [38,39]. The DA signal can deliver the rewarding and pleasurable feelings that can motivate to perform ad-ditional physical activity. This hypothesis is partially congruent with the previous studies using rodents. The rodent study using gene knock-out model found that DA transporter helps DA re-uptake into pre-synaptic site, while DA transporter gene deletion results in decreased voluntary activity [40]. Furthermore, DA knock-out rodents reduced motivation for high effortful tasks [41]. The study using specific agonist/antagonists demonstrated the importance of DA signal in regulating physical activity. They found that injecting the agonist for DA D1 receptor into the NAc enhances physical activity [42], whereas the antagonist injection reduced physical activity [43]. To sum up, it is suggested that DA signal and its activity regulate physical activity levels by changing motivation.

Two types of DA receptors, stimulatory and inhibitory, exist in dopamine neurons. The first is the DA D1-like stimulatory receptors (D1 and 5) containing no introns and acting by Gs-proteins to activate adenylyl cyclase, which increases cyclic adenosine monophosphate (cAMP) production and stimulates downstream neurons. The second is the DA D2-like inhibitory receptors (D 2, 3, and 4) containing introns and acting through Gi-proteins. These can inhibit adenylyl cyclase and in turn decrease cAMP production along with neural excitation [44,45]. While post-synaptic sites of the DA neuron possess both DA stimulatory and inhibitory receptors, the D2 and D3 auto-receptors are positioned at DA pre-synaptic site to inhibit DA activity and production [46]. Nearly most neurons of the brain showed DA receptor expression, however, the greater expression of the receptors has been found in nigrostriatal/mesolimbic circuits [47]. Interestingly, the estrogenic signal can regulate DA function in several steps for DA metabolism and its overall production at pre- and post- synaptic sites [48]. In the next session, using previous research, the author described the estrogen receptor (ER) regulation on DA signals and behaviors including voluntary physical activity.

During menopausal transition, women experience menopausal symptoms including hot flashes, night sweats, and psychological changes but also the metabolic syndromes with weight gain and muscle loss, which are strongly associated with reduced estrogen level [6]. Among those symptoms, psychological changes are critical as it can impact weight gain and muscle loss partially by reducing motivation to exercise in the consequence of physical inactivity. Menopause-associated reduction in physical activity has been considered as the brain-mediated pathway of estrogen deficiency. Estrogen may directly impact skeletal muscle or other cells via ER signaling [49] and also indirectly through behavioral changes (i.e., reduced physical activity including free-living activity and exercise-associated activity) [28,50]. Deficiency of estrogen attenuates voluntary running motivation along with impaired DA signals [28,51]. The regulation of voluntary running activity is attributed to levels of estrogen and its intact receptors in female rodents [52,53]. In rodents, OVX decreased levels of circulating estrogen and voluntary running distance to less than 1 km/day which is 5-10 times lower than pre-OVX rodents [28,51,53]. Estrogenic signal is the important mediator of physical activity in female, and Morgan et al. [54] suggests the possible role of estrogenic modulation for neurotransmitters including DA. Estrogen may provide a tonic stimulus for striatal DA receptors, while chronic stimulations maintains the activity of DA. The loss of this chronic stimulations following OVX was rescued by estrogen-based hormone replacement therapy, which conserved the upregulated stimulatory DA receptors when treated immediately after OVX [55,56]. In genomic regulation, a translo-cated ER directly binds to targeted DNA binding sites associated with enhancing DA receptor expression or other DA-related proteins [57].

DA is produced and secreted into the synaptic cleft using vesicles. DA activates either stimulatory D1-like (D1 & 5) or inhibitory D2-like (D2, 3, & 4) receptors. DA remained in the synaptic cleft is turned back to pre-synaptic terminal through DA transporter (DAT), and transformed to 3,4-dihydroxy-phenyl-acetic acid (DOPAC) via monoamine oxidase (MAO). Some of D2-like receptors are located at pre-synaptic terminal, and inhibits DA release. Most importantly, activated ERα generates and activates D1-like receptors, while it decreases D2-like receptors.

Estrogen mainly works through its receptors and most of all organs including skeletal muscle express ERs with ERα and β [58–60]. Pre-clini-cal studies using ER knock out rodents suggest ERα, but not ERβ, leads to impairments in metabolic health (i.e., glucose and insulin metabolism) [61,62], suggesting the important role of ERα. ERα also expresses in the brain, and is an obligatory link for OVX-induced reductions in voluntary physical activity [52]. At both pre- and post- synaptic regions, estrogen works in genomic pathway, a slow pathway via the translocation of ERα and β to nucleus [57]. In OVXed mice, decreased wheel running activity was rescued by estrogen-based hormone replacement therapy, whereas the treatment with phytoestrogen coumesterol having a similar affinity to estrogen through ERβ failed to alter wheel running behavior [63]. This finding suggests that, compared to ERα-, ERβ-pathway ap-pears less involved in increased wheel running activity in OVX mice. Ogawa et al. [52] also demonstrated that estrogen-based hormone replacement therapy increased spontaneous cage activity in ERβ-, but not in ERα-KO mice. This also partially supports the hypothesis that estrogen-associated increase in spontaneous physical activity is mediated by ERα pathway. In line with the previous study, the implantation of estrogen into anterior hypothalamus including primarily ERα increases wheel running physical activity in OVX rats [64]. To our knowledge, however, none of the studies investigated the role of ERα pathway on DA receptor and activity, and whether the ERα–associated enhancement of DA activity results in enhanced voluntary running physical activity.

Despite the aforementioned phenomenon that menopause or OVX decreased ER signaling and activity, the early phase of post-menopause or OVX is accompanied by an instant, compensated up-regulation of ERs and aromatase, an enzyme responsible for the biosynthesis of estrogens, in the human midbrain [65]. Such enhancement via de novo production of estrogens from cholesterol or testosterone is a key to compen-sate for the deficiency of circulating estrogens via the upregulated ERα in a auto/paracrine way [65–67]. This compensatory mechanism of ERα and aromatase expressions were documented in OVX monkey [68] and rat brain cultures [69]. The compensatory mechanism of estrogen loss may play a critical role in the brain control prior to the body’ s adaptation to menopause. The lack of proper compensation may contribute to a significant health problem of the brain such as depression and dementia [65]. A study [70] using OVXed mice showed that the administration of aromatizable androgens attenuated the OVX-associated reduction in voluntary wheel running activity. Future studies are necessary to investigate the time window (i.e., early/late peri- or post-menopause) to which menopause or OVX impairs ERs and DA-related mRNA expressions and protein contents in the brain. By elucidating the time-dependent changes in molecular signals following menopause, future research can generate the optimal strategies to combat the menopause-associated health problems by more specific exercise prescription or hormone replacement therapy.

Women with high motivation to run may protect from the meno-pause-associated reduction in running capacity partially owing to greater intrinsic motivation to run compared to sedentary or obese women. A previous study [71] partially supports our hypothesis in that high voluntary running rats, compared to low voluntary running rats, were physically active partially due to enhanced DA-associated transcriptomes in the NAc. In line with this study, compared to control mice, highly active mice showed greater DA activity in the mesolimbic DA circuit [72,73]. Whereas the role of the NAc DA signaling in facilitating the rewarding nature of running has been somewhat reported, whether enhancing DA activity protects against the menopause or OVX-induced decrease in voluntary running is still vague. To test this, our group used the rats selectively bred for high aerobic capacity (HCR) and low aerobic capacity (LCR), which model was developed by researchers in the University of Michigan [74]. They found a unique divergence in running behavior between two rat lines, with a significant 5-fold greater voluntary running distance in HCR rats compared to LCR rats. Using this rat model, our group determined the potential role of NAc DA signaling in voluntary wheel running in OVXed female rats [75]. This study demonstrated that HCR rats had greater wheel running distance and the activation of dopamine signaling compared to LCR rats. While HCR rats gradually decreased their weekly running distance following OVX, LCR rats started low but gradually increased weekly running over 11 weeks. To investigate the underlying mechanism, we investigated their mRNA expressions in the NAc. We found that HCR rats had greater D1 stimulatory receptors and lower D3 and 4 inhibitory receptor mRNA expressions compared to LCR rats. However, OVX significantly upregulated inhibitory dopamine receptors (i.e., D2 and 4 receptor mRNA expressions) in HCR rats, implying a strong effect of OVX independent of one’ s aerobic capacity or running motivation. More studies are needed to confirm our findings in clinical and other non-clinical research.