Abstract
Estrogens (estradiol, estriol, and estrone) are important hormones that directly and indirectly regulate the metabolism and function of bone and skeletal muscle via estrogen receptors. Menopause causes a dramatic reduction in the concentration of estrogen in the body. This contributes to a decline in bone and skeletal muscle function, thereby resulting in osteoporosis and sarcopenia. Menopausal women often experience osteoporosis and muscle wasting, and clinicians recognize estrogen as playing an important role in these conditions, particularly in women. Bone and muscle are closely related endocrine tissues that synthesize and produce various cytokines. These bone- and muscle-derived cytokines, including interleukin-6, irisin, β-aminoisobutyric acid, osteocalcin, fibroblast growth factor-23, and sclerostin, regulate both local and distant tissues, and they mediate the crosstalk between bone and skeletal muscle. This review examines the metabolic effects of estrogen on bone and skeletal muscle and describes cytokine-mediated bone–muscle crosstalk in conditions of estrogen deficiency.
Introduction
Aging is a biological process that causes a decline in body functions (Schumacher et al. 2021). This can result in age-related diseases, such as neurodegeneration, cardiovascular diseases, bone diseases, and muscle diseases (Li et al. 2021). Osteoporosis and sarcopenia are common public health problems that tend to coexist in older individuals. A syndrome termed ‘osteosarcopenia’ was previously described (Clynes et al. 2021), in which there is a strong link between bone and skeletal muscle. Osteoporosis is a systemic skeletal metabolic disease that is characterized by low bone mass and degeneration of the bone microarchitecture. Sarcopenia is characterized by the gradual and widespread loss of muscle weight and a decline in muscle function (Cruz-Jentoft & Sayer 2019). Both osteoporosis and sarcopenia have adverse consequences and cause significant morbidity and mortality. With the population aging, these problems are likely to worsen.
Menopause is the most significant feature of aging in women. Menopause leads to a change in the concentration of hormones, especially that of estrogen (Fuentes & Silveyra 2019, Geraci et al. 2021). In addition, the occurrence of osteoporosis and sarcopenia is closely related to menopause in women. In this review, we describe the effects of estrogen on bone and skeletal muscle and discuss the mutual communication between bone and skeletal muscle. This will allow us to better understand the role of estrogen in these conditions and provide a foundation to develop interventions that simultaneously target osteoporosis and sarcopenia.
Estrogen and osteoporosis
Osteoporosis, which is an age-related skeletal system disorder in which bone mass decreases, is bone microarchitectural deterioration, eventually resulting in bone fragility. According to World Health Organization (WHO) operational definition which based on bone mineral density (BMD), the osteoporosis is defined as a BMD that is 2.5 standard deviations (s.d.) or below the average value of a healthy young adult (Kanis 2002). Osteoporosis affects both men and women, especially prevalent in postmenopausal women (Karaguzel & Holick 2010). Approximately half of the women experienced at least one osteoporotic fracture after menopause (Reid 2020), and it increases mortality, decreases the quality of life, and increases the health burden and socioeconomic costs. Several risk factors can lead to osteoporosis in postmenopausal women, such as estrogen deficiency, aging, genetics, smoking, metabolic diseases, and drug side effects (NAMS 2021). However, osteoporosis in women is mainly caused by estrogen deficiency.
Estrogen and its signaling mechanisms
Estrogens are a group of hormones that include estrone (E1), estradiol (17β-estradiol; E2), and estriol (E3) (Fuentes & Silveyra 2019). Most estrogen is secreted by the ovaries (Li & Wang 2018, Mohamad et al. 2020); however, it is also produced by other tissues, such as adipose tissue, the adrenal glands, the pancreas, and the brain (Barakat et al. 2016). Estrogen plays many important physiological roles in terms of secondary sexual characteristics, sexual maturation, and the female reproductive system. In addition, estrogen has certain effects on bone homeostasis, brain function, and inflammation (Barakat et al. 2016, Li &Wang 2018, Fuentes & Silveyra 2019, Mohamad et al. 2020). As the main estrogens in humans, E2 can be converted into E1, and both E1 and E2 can be converted into E3. E2 and E1 can undergo interconversion, which is catalyzed by 17-hydroxysteroid dehydrogenase (Shoham & Schachter 1996). Estrogens play a basic role in human reproductive system growth and function, and among the estrogens, E2 is regarded as the most important and effective estrogen, followed by E1 and E3 (Shoham & Schachter 1996). E2 is often called ‘the female hormone’ because it maintains female sex characteristics. Therefore, women have high levels of circulating E2 from adolescence to the beginning of menopause; however, menopause, aging, and other factors interfere with its balance, its protective action, and levels decline with time (Alemany 2021). During menopause, E1 is the predominant estrogen, and E2 is lower in postmenopausal women than in premenopausal women (Alemany 2021).
Estrogen exerts its action by binding to specific estrogen receptors (ERs), including nuclear ERs (ERα and ERβ) and the membrane ER (G protein-coupled ER (GPER)). ERα and ERβ are members of the steroid/thyroid hormone nuclear receptor superfamily. They have a high degree of homology in their binding domains (Nilsson et al. 2001), and they act as ligands to activate transcription factors via direct binding to the DNA sequence of the estrogen response element (ERE) (genomic effect) to regulate gene expression (Cooke et al. 2017, Fuentes & Silveyra 2019, Dama et al. 2021). This direct genomic effect is regarded as the classic signaling mechanism. In fact, nearly one-third of the transcription factor genes do not have EREs in their promoter region, making them incapable of direct DNA binding. Therefore, signaling depends on the protein–protein interaction and other transcription factor genes along with response elements, which regulate (activate or repress) target gene expression. This mechanism is referred to as the indirect genomic effect (Vrtacnik et al. 2014, Fuentes & Silveyra 2019).
Unlike the nuclear receptor genomic signaling mechanism, which is associated with target gene transcription and protein translation, membrane receptor non-genomic signaling is a physiological response that is rapidly induced by estrogen and is generally related to the membrane-bound ER, GPER1, along with some ERα and ERβ variants (Vrtacnik et al. 2014, Fuentes & Silveyra 2019). The non-genomic effect of estrogen regulates gene expression by regulating protein kinase signaling cascades (Cooke et al. 2017, Fuentes & Silveyra 2019, Dama et al. 2021). Therefore, studying the estrogen signaling pathway would help us to further understand the role of estrogens in physiological and pathological conditions.
Estrogen and bone metabolism
Estrogen deficiency and bone remodeling
Bone is a dynamic tissue. Osteoblasts generate new bone, while osteoclasts remove old bone, maintaining its homeostasis and metabolism. This process is referred to as bone remodeling and is carried out through the basic multicellular unit (BMU) (Bolamperti et al. 2022). The functions of osteoblasts and osteoclasts are mainly regulated by systemic hormones and local factors in the body, including sex hormones (Kenny & Raisz 2002). During menopause, women experience a decrease in the secretion of the ovarian hormones estrogen and progesterone (Nelson 2008). Therefore, menopause is a special stage of bone metabolism in women (Karlamangla et al. 2021). There are different mechanisms that underpin bone remodeling in the face of estrogen deficiency (Riggs et al. 2002). The increase in bone turnover caused by estrogen deficiency is due to the increased activity of the BMU. Additionally, osteoblast apoptosis increases, bone formation time decreases, and osteoclast apoptosis decreases. Therefore, the bone resorption period is prolonged, thus causing bone remodeling imbalance. In addition, the increase in osteoclast recruitment prolongs the BMU activity cycle (Riggs et al. 2002). Because of these changes, bone resorption exceeds bone formation. In women, the estrogen concentrations, especially the concentration of E2, which is involved in bone remodeling, are increased, and osteoblast and osteoclast activation are elevated during menopause (Velarde 2013, Raehtz et al. 2017, Li & Wang 2018) because of the inability of the new bone to fill the space left by old bone absorption, causing substantial bone loss (Raehtz et al. 2017, Li & Wang 2018). These changes are the pathogenesis of postmenopausal osteoporosis. According to the published data, one-third of women over 50 years of age will experience osteoporotic fractures in their lifetime. In a previous study, an E2 concentration of <5 pg/mL correlated with a 2.5-fold increase in fractures (hip and vertebral) in older women (Cauley 2015). This indicates that the E2 concentration can predict the occurrence of fractures (Cauley 2015), which affect both life expectancy and quality of life.
Effects of estrogen on osteoblasts
Estrogen reduces the activation rate of bone remodeling and maintains the balance between bone filling and bone resorption by influencing the reduction in osteoblast and osteoclast progenitor cells in the bone marrow and promoting the anti-apoptosis of osteoblasts and osteocytes and the pro-apoptosis of osteoclasts (Almeida et al. 2013). Estrogen is the active sex steroid in the adult skeleton of both males and females. ERα and ERβ are both expressed in osteoblasts and osteoblast progenitors (Kousteni et al. 2001). Estrogen regulates bone formation by inhibiting osteoblast apoptosis by modulating c-Jun N-terminal kinase or by activating the Src/Shc/extracellular signal-regulated kinase (ERK) signaling pathway via the extranuclear action of ERs (Kousteni et al. 2001, Kousteni et al. 2003). Wang et al. (Wang et al. 2021) showed that E2 induced silent information regulator-2 homolog 1 and inhibited hFOB 1.19 osteoblast apoptosis via forkhead box O3a (FoxO3a) activation. Another study used the G-292 human osteoblast cell model exposed to apoptotic stimuli and examined the change in apoptosis with E2 treatment, showing that E2 inhibited osteoblast apoptosis via repression of ITPR1 transcription (Bradford et al. 2010).
Schiavi et al. indicated that estrogen deficiency changed MC3T3-E1 osteoblast differentiation and matrix synthesis. The authors concluded that this alteration contributed to bone fragility in postmenopausal osteoporosis (Schiavi et al. 2021), which indicates that estrogen regulates osteoblast differentiation. Other studies on MC3T3-E1 cells have shown that estrogen increases osteoblast differentiation by enhancing Wnt/β-catenin signaling (Wu et al. 2015, Yin et al. 2015), as well as increasing bone morphogenetic protein (BMP)-4 expression by osteoblasts (Matsumoto et al. 2013).
Other researchers assessed osteoblast and adipocyte differentiation in a mouse bone marrow stromal cell (BMSC) line (ST-2), which overexpresses ERα or ERβ with bone BMP-2 induction in response to estrogen. They observed a lineage shift toward osteoblasts, which resulted in direct stimulation of bone formation (Okazaki et al. 2002). The above evidence suggests that estrogen has a positive effect on osteoblast proliferation and differentiation (Plant & Tobias 2002, Hong et al. 2009).
Effects of estrogen on osteoclasts
Lack of estrogen enhances osteoclast activity and is strongly associated with the occurrence of postmenopausal osteoporosis, which can be prevented using estrogen replacement therapy (ERT) (Michael et al. 2005). Osteoclasts are giant multinucleated giant cells that are mainly involved in bone resorption (Lorenzo 2017). Macrophage colony-stimulating factor (MCSF) and receptor activator of nuclear factor (NF)-kB (RANK) ligand (RANKL) play a critical role in osteoclast proliferation and differentiation (Park et al. 2021). RANKL is expressed on the surface of the BMSCs, osteoblast lineage, T lymphocytes, and B lymphocytes (Eghbali-Fatourechi et al. 2003). RANK is a transmembrane signaling receptor that is expressed in osteoclast precursor cells and activates osteoclastogenesis (Michael et al. 2005, Park et al. 2021). Another member of the tumor necrosis factor (TNF) receptor superfamily is osteoprotegerin (Michael et al. 2005), which acts as a decoy receptor. Osteoprotegerin inhibits osteoclast formation by interfering with the interaction between RANK and RANKL. The RANKL/RANK/osteoprotegerin signaling pathway plays an important role in bone remodeling. In human (Hofbauer et al. 1999) and animal (Saika et al. 2001) osteoblasts, estrogen promotes osteoprotegerin expression.
Shevde et al. (Shevde et al. 2000) showed that estrogen inhibits RANKL/M-CSF-induced osteoclastogenesis, both in primary monocytes and osteoclast progenitors. Its mechanism of action is the suppression of RANKL-induced c-Jun gene expression and activation and the downregulation of AP-1 (c-Jun/c-Fos)-mediated gene transcription. Another previous study showed that the binding of E2 to Erα inhibits RANKL-induced cytoskeletal reorganization to generate the Erα/SHP2/c-Src complex and reduce bone resorption (Park et al. 2021). Guo et al. (Guo et al. 2018) found that estrogen has an inhibitory effect on osteoclast differentiation, and microRNA-27a suppresses the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and adenomatous polyposis coli. The decrease in the estrogen concentration is usually accompanied by an increase in certain cytokines, such as MCSF, interleukin (IL)-1, IL-6, and TNF, which contribute to osteoclastogenesis. Kimble et al. (Kimble et al. 1996) demonstrated that in estrogen-deficient mice (ovariectomized (OVX) model), IL-1 and TNF promoted osteoclastogenesis by enhancing the production of soluble MCSF in BMSCs. The evidence demonstrates that the production of IL-1, IL-6, and TNF-a increases in estrogen-deficient conditions (Shevde et al. 2000). Estrogen also increases the levels of the transient receptor potential vanilloid 5 to inhibit bone resorption by osteoclasts through the transcriptional activation of E2/ERα signaling (Song et al. 2018). These data indicate that the effects of estrogen on osteoclast differentiation and activity are underpinned by different mechanisms.
Effects of estrogen on osteocytes
Osteocytes are important cells that comprise 90% of bone cells. These cells are encased in a hard, mineralized matrix (Klein-Nulend et al. 2015). Osteocytes act as mechanical sensors. After mechanical stimulation, osteocytes convert mechanical signals into chemical reactions, thereby producing a series of signaling molecules, including BMP, nitric oxide, and prostaglandin E2, which promote osteoblast and osteoclast activity (Klein-Nulend et al. 2013). The main role of osteocytes is to regulate cell survival and mechanosensing. In vitro experiments (Zaman et al. 2006) have shown that ERα, which is involved in the osteocyte response to estrogen and estrogen deficiency, leads to a decrease in ERα in osteocytes. This is consistent with the estrogen deficiency associated with bone loss and is a consequence of a decrease in the number/activity of ERα. Estrogen deficiency reduces fluid flow-induced intracellular calcium oscillations, which alter the mechanoresponsiveness of MLO-Y4 osteocytes, eventually decreasing osteocyte differentiation and function (Deepak et al. 2017). Evidence suggests that osteocytes are an important target for the actions of estrogen (Khosla et al. 2012). In addition, Jackson et al. (Jackson et al. 2021) using the OVX mouse model and from in vivo study demonstrated that the ability of osteocytes to activate the Wnt/β-catenin signaling pathway in response to mechanical loading was weakened significantly, which further strengthens evidence for the role of estrogen in the mechanosensitivity of osteocytes.
During estrogen deficiency, an increase in osteocyte apoptosis is observed in humans and animals (Tomkinson et al. 1997, 1998). Following estrogen deficiency, osteocytes trigger bone remodeling via crosstalk with bone-lining cells (Bonewald 2011). Conversely, estrogen replacement maintains osteocyte viability by inhibiting apoptosis, increasing connexin-43 gap junction expression and mechanosensitivity, and upregulating osteogenic signaling in MLO-Y4 osteocytes. It has also been reported that during estrogen deficiency, osteoblast–osteocyte differentiation, mineralization, and pro-osteoclastogenic paracrine signaling increase. The increase in osteoclastogenic signaling might be related to a change in the mechanical response of osteocytes during estrogen deficiency (Florencio-Silva et al. 2018, Naqvi et al. 2020). Estrogen increases the expression of semaphorin 3A in osteocytes, which binds to its receptor on osteocytes to increase cell viability and maintain bone homeostasis (Hayashi et al. 2019). Simfia et al. (Simfia et al. 2020) found that the expression of RANKL/osteoprotegerin and MCSF was increased in an in vitro osteocyte model. Osteocytes are an important source of RANKL, which promotes osteoclastogenesis, bone resorption, and osteoclast function (Xiong et al. 2011). Another study showed that osteocyte RANKL plays a role in bone resorption, causing estrogen deficiency (Fujiwara et al. 2016). It is likely that osteocyte initiation of bone resorption is involved in the RANKL-regulated mechanism. Overall, it appears that estrogen changes osteocyte mechanosensitivity, which modulates osteoclast activity. The effects of estrogen on bone cells are summarized in Fig. 1.
Schematic representation of the effects of estrogen on bone and skeletal muscle. Bone is a dynamic tissue that adapts to changes in systemic hormones, such as estrogen, and this process is termed ‘bone remodeling.’ Estrogen binds to its receptors to regulate osteoblasts, osteoclasts, and osteocytes, which participate in bone remodeling to maintain bone homeostasis. Estrogen also modulates muscle satellite cell proliferation and differentiation and preserves muscle mass. These processes are underpinned by different molecular mechanisms. Estrogen exerts vital actions, both in bone and skeletal muscle. A full color version of this figure is available at https://doi.org/10.1530/JOE-23-0116.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-23-0116
Moreover, in addition to the direct negative impact of estrogen deficiency on bone, all kinds of immune cells also regulate osteoblasts and osteoclasts (Fischer & Haffner-Luntzer 2022). T lymphocytes and B lymphocytes might play an important role in uncoupled bone loss under conditions of estrogen deficiency (Wu et al. 2021, Fischer & Haffner-Luntzer 2022). Wu et al. found a new mechanism by which estrogen deficiency induced the production of the proinflammatory cytokines TNFα and IL-17 by converting memory T cells (TM) to effector TM (TEM) (Wu et al. 2021). TNFα not only promotes osteoblast apoptosis but also acts on OC along with its precursor in cooperation with RANKL to stimulate osteoclastogenesis (Wu et al. 2021, Cheng et al. 2022, Fischer & Haffner-Luntzer 2022). IL-17 induces BMSC differentiation toward the osteogenic lineage. However, it also stimulates RANKL production by osteoblasts and upregulates RANK on osteoclast progenitor cells (Fischer & Haffner-Luntzer 2022). It has been reported that inhibiting IL-17 prevented mice from OVX-induced bone mass decreases (Tyagi et al. 2014).
Estrogen and sarcopenia
In both men and women, 35–45% of the lean body mass is muscle (35% in women and 45% in men), and various disorders affect bone quantity and quality (Carson & Manolagas 2015). A previous study showed that both the frequency and intensity of muscle loss increase during menopause (Maltais et al. 2009, Sipila et al. 2020), and progressive muscle degeneration, known as sarcopenia (Pellegrino et al. 2022), increases the risk of falls, fractures, physical disability, and mortality (Buckinx & Aubertin-Leheudre 2022). Estrogen promotes muscle stem cell proliferation, differentiation, and regeneration; thus, estrogen contributes to skeletal muscle health (Collins et al. 2019, Geraci et al. 2021). The most powerful estrogen (estradiol; E2) regulates the function of muscle fibers by binding to E2-specific receptors, thereby directly regulating muscle metabolism (Geraci et al. 2021, Buckinx & Aubertin-Leheudre 2022). Muscle weight and strength decrease in menopausal women, which indicates that a reduction in estrogen and its receptors can cause muscle loss and muscle atrophy (Buckinx & Aubertin-Leheudre 2022). Maintaining skeletal muscle function is important for health and longevity. Therefore, based on the beneficial effects of estrogen on skeletal muscle, it is valuable to examine the role of estrogen in sarcopenia.
Effects of estrogen on skeletal muscle fiber types
Skeletal muscle is composed of different fiber types, which result in differences in skeletal muscle morphology, biochemistry, and function (Chaiyasing et al. 2021). Mammalian skeletal muscle is a heterogeneous tissue that contracts according to its strength, flexibility, and plasticity (Horwath et al. 2021) and comprises different muscle fibers and cell types. According to previous studies, muscle fibers can adjust their phenotypic response to different stimuli (Pette & Staron 2000, Horwath et al. 2021), and the type of muscle fiber has a great impact on endurance, strength, and power (Molsted et al. 2007).
The mammalian myosin heavy chain (MyHC) is composed of different MyHC isoforms (Haizlip et al. 2015). Each fiber contains a predominant MyHC isoform, of which there are four main types in mammalian skeletal muscles: type-I (MyHC-I/β), type-IIA (MyHC-IIa), type-IIX (MyHC-IIx), and type-IIB (MyHC-IIb) (Haizlip et al. 2015). MyHC-IIb tends to be expressed in larger fibers with more abundant glycolytic enzymes, whereas MyHC-I/β is expressed in smaller fibers with more oxidative activity (Haizlip et al. 2015). Unlike rodent skeletal muscle, human skeletal muscle does not express MyHC-IIb. There are also sex differences in MyHC isoform expression, and microarray analysis of male and female vastus lateralis biopsies showed that compared with male skeletal muscle, female skeletal muscle had higher MyHC-I/β (100 ± 11 vs 135 ± 16) expression levels and lower MyHC-IIa (100 ± 7 vs 70 ± 6) and MyHC-IIx (100 ± 20 vs 85 ± 18) expression levels (Welle et al. 2008). The contractile velocity of skeletal muscle is associated with myosin ATPase activity, and according to the above criteria, skeletal muscle fibers can be divided into slow oxidative (I), fast oxidative (IIa), and fast glycolytic (IIb) fibers (Cretoiu et al. 2018). Slow oxidative fibers are predominantly red in color, utilize oxidative phosphorylation for ATP production and do not fatigue for a long period of time. Fast oxidative muscle fibers are red in color, have a higher capacity to produce ATP through oxidative phosphorylation, and are more highly fatigue-resistant than fast glycolytic muscle fibers. Fast muscle fibers are white in color, use glycolysis for ATP production, and easily fatigue (Cretoiu et al. 2018).
During murine C2C12 myoblast differentiation, both ERα and ERβ are reduced; however, E2 supplementation in the differentiation medium partially restores ERβ expression and increases MyHC1/β expression. However, it also decreases MyHC-IIa, MyHC-IIb, and MyHC-IId expression, which indicates that E2 favors slow muscle fiber formation (Ding et al. 2018). A previous study in aging mice (Henique et al. 2015) showed that compared with control mice, aging mice demonstrated a significant decrease in MyHC-I/β (−91%) and MyHC-IIa (−79%) fibers, as well as a marked increase in MyHC-IIb fibers (+96%), which further confirms that aging is associated with a decrease in oxidative capacity. Moreover, compared with that in sham mice, myogenin expression in OVX mice was decreased by 50%; however, myogenic differentiation (Myod) increased two-fold. This is consistent with the shift in muscle fiber type caused by myogenin driving type I fiber formation and Myod driving type II fiber formation, which indicates that OVX mice undergo a fiber-type shift toward less type I oxidative muscle fibers (Rogers et al. 2010).
Effects of estrogen on muscle stem cells
Muscle fibers are made up of a population of stem cells called ‘satellite cells’ that remain quiescent in the sarcolemma and basal layer of the myofibril (Collins et al. 2019). Satellite cells play important roles in muscle maintenance, repair, and regeneration (Pellegrino et al. 2022). Satellite cells are activated in response to a stimulus (injury), which triggers a transition from the quiescent state to the activated state (Collins et al. 2019, Larson et al. 2022, Pellegrino et al. 2022). Satellite cells make up a heterogeneous cell population, and they undergo asymmetric division to produce two daughter cells. One daughter cell further commits to proliferation and differentiation, while the other returns to the quiescent state to maintain the satellite pool (so-called ‘self-renewal’) (Kuang et al. 2007, Troy et al. 2012, Collins et al. 2019, Larson et al. 2022). The number of stem cells varies by fiber type. For example, compared with type II muscle fibers, type I muscle fibers have a higher satellite cell content (Geraci et al. 2021).
According to a previous study (Collins et al. 2019), satellite cell maintenance, self-renewal, and differentiation into muscle fibers are inhibited in OVX mice. In humans, the number of satellite cells decreases during menopause (Collins et al. 2019). Kitajima et al. (Kitajima & Ono 2016) reported that although the number of satellite cells in isolated myofibers does not change, the expansion, differentiation, and self-renewal of skeletal satellite cells decline in response to estrogen deficiency. Estrogen activates satellite cells; thus, stimulating their proliferation via ERs contributes to muscle repair. In a study on satellite cell-specific ERβ-knockout (scKO) mice, female scKO mice demonstrated impaired muscle regeneration following muscle injury, which included reduced satellite cell proliferation and satellite cell apoptosis (Seko et al. 2020).
Effects of estrogen on skeletal muscle mass and strength
Sarcopenia is considered to be a result of an age-related decline in skeletal muscle quality and skeletal muscle weakness, and it is a major cause of frailty in older adults (Fry et al. 2015). Skeletal muscle in females is affected dually by aging because of the concomitant estrogen deficiency. Usually, muscle mass begins to decrease at the age of 30 years, and every 10 years, there is a further 2–7% decline in muscle mass, especially after the age of 60 years (Cho et al. 2022). After menopause, muscle mass decreases by approximately 0.6% every year (Cho et al. 2022). A previous study showed that estrogen is related to changes in body composition and estrogen deficiency, while women also demonstrate an increase in body fat, which can lead to a reduction in lean mass (Dawson-Hughes & Harris 1992). Much evidence suggests that estrogen therapy helps to improve estrogen deficiency in the bones of women. Relevant research on hormone replacement therapy (HRT) has been reported, but the results are inconsistent. A previous clinical trial examined the effects of 12 months of HRT on skeletal muscle in premenopausal women, showing that HRT improves muscle mass, performance, and composition (Sipila et al. 2001). Moreover, another study showed that HRT enhances muscle strength in postmenopausal women (Ronkainen et al. 2009). Greising et al. (Greising et al. 2009) conducted a meta-analysis that showed that HRT is beneficial for muscle strength in postmenopausal women. Dynapenia, which is different from sarcopenia, refers to an age-related loss of muscle strength that is independent of muscle atrophy (Collins et al. 2019). Muscle weakness increases with age in women, and women experience accelerated loss of muscle strength during menopause, suggesting that sex hormones may be vital for maintaining physical fitness (Lowe et al. 2010). Animal experiments also showed that both muscle weight and strength are reduced in OVX mice, and the OVX-induced tibialis anterior (TA) cross-sectional area recovered completely after administration of E2 (Kitajima & Ono 2016). It has been proposed that the ovarian hormones affect muscle strength via a direct effect on contractile proteins, and in OVX mice, treatment with E2 reversed the loss of muscle mass and muscle contractility via modulation of myosin light-chain phosphorylation in skeletal muscle (Lai et al. 2016). However, existing research reports are inconsistent, and 12 randomized clinical trials on the association between HRT and the loss of lean body mass in postmenopausal women aged ≥50 years did not identify an effect of HRT on muscle mass (Javed et al. 2019). A cross-sectional study on postmenopausal women found that oral estrogen accelerated the loss of muscle mass (Gower & Nyman 2000). Prospective studies examining the use of HRT and loss of lean muscle mass in early postmenopausal women found that estrogen did not significantly preserve muscle mass and strength during the first few years after menopause (Maddalozzo et al. 2004). Kenny et al. (Kenny et al. 2003) also demonstrated that the use of E2 replacement therapy had no effect on age-related muscle atrophy.
Estrogen stimulates muscle satellite cell proliferation and differentiation and increases muscle mass and strength to preserve muscle health (Fig. 1). In addition, although estrogen has a strong protective effect on muscles in postmenopausal women, ERT is still controversial. Many factors affected the abovementioned clinical trial; these factors included age, treatment duration, menopausal transition period, estrogen dose, and study inclusion criteria. On this basis, more in-depth research is needed. In addition, intervention measures (physical activity, nutrition, and HRT) should be combined to better prevent or treat muscle atrophy in menopausal women.
Mechanisms underpinning the effects of estrogen on muscle mass and strength
A previous study showed that protein homeostasis is a key cause of sarcopenia (Tan et al. 2020). When estrogen is deficient, the balance of muscle protein is disrupted, shifting from protein synthesis to protein breakdown. This causes fiber atrophy and eventually leads to loss of muscle mass and strength (Collins et al. 2019). The main signaling molecules that control protein turnover in skeletal muscle include insulin-like growth factor 1 (IGF1) and its downstream anabolic and catabolic targets, the mammalian target of rapamycin (mTOR), and the transcription factor FoxO (Sandri et al. 2013).
IGF1 signaling pathways
The IGF1 signaling pathway plays a central role in modulating muscle mass. An increase in muscle mass and muscle fiber size is termed ‘hypertrophy,’ which is associated with protein synthesis. Conversely, a decrease in muscle mass is termed ‘atrophy,’ which is linked to protein degradation (Latres et al. 2005). With an increase in IGFI expression, muscle tissue demonstrates obvious hypertrophy. Therefore, the increase in IGFI expression increases muscle size (Stitt et al. 2004). A study performed in transgenic mice showed that persistent IGF1 overexpression in muscle causes myofiber hypertrophy (Coleman et al. 1995). Olivieri et al. (Olivieri et al. 2014) showed that IGF1 signaling is increased in skeletal muscle in women after HRT. Another study showed that the expression of IGF1 and IGF1 receptors in postmenopausal women receiving HRT is significantly higher than that in control subjects not receiving HRT (Ahtiainen et al. 2012), suggesting that HRT plays a regulatory role in IGF1 signaling.
IGF1 binds to its receptor (IGF1R) and activates and phosphorylates phosphatidylinositol 3-kinase (PI3K), leading to phosphoinositide-dependent kinase-1 activation and phosphorylation. In turn, this leads to the phosphorylation of the serine/threonine kinase Akt (also called PKB) (Latres et al. 2005, Timmer et al. 2018). Akt is a serine–threonine protein kinase that not only induces muscle hypertrophy but also suppresses muscle atrophy via direct or indirect regulation of downstream target genes (Leger et al. 2006, Glass 2010, Cui et al. 2020).
Akt/mTOR pathway
Akt phosphorylates and activates the downstream target mTOR, which is a key mechanism affecting muscle protein synthesis. mTOR is a class of evolutionarily conserved serine/threonine kinases that belong to the PI3K-related kinase family (Hodson et al. 2019). After mTOR is activated, it phosphorylates Thr389 of p70S6 kinase (p70S6K), promoting the translation of mRNA via phosphorylation of ribosomal protein S6 and activating eukaryotic elongation factor 2 (Murton 2015, Timmer et al. 2018, Hodson et al. 2019). In addition, activated mTOR phosphorylates eukaryotic translation initiation factor 4E (eIF-4E)-binding protein 1 (4E-BP1; also called PHAS-1). When 4E-BP1 is phosphorylated, it is separated from eIF-4E. eIF-4E recruits the initiation factors eIF-4G and eIF-4A to form eIF-4F complexes, which bind to the 5′ end of the mRNA to initiate protein translation (Murton 2015, Gruner et al. 2016). In summary, mTOR controls protein synthesis through the p70S6K and 4E-BP1 pathways. A previous study showed that using genetic technology to activate the Akt/mTOR pathway induces hypertrophy and resistant atrophy (Bodine et al. 2001b ), while blocking the Akt/mTOR pathway suppresses hypertrophy in vivo. Skeletal muscle atrophy caused by estrogen deficiency in OVX rats is mainly due to the myostatin/Akt/mTOR signaling pathway (Tang et al. 2021). In addition, OVX Sprague–Dawley rats failed to recover their atrophied muscle mass compared with sham Sprague–Dawley rats, which correlated with a decrease in the phosphorylation of both Akt and p70S6K (Sitnick et al. 2006). Therefore, the Akt/mTOR signaling pathway is involved in muscle hypertrophy.
Akt/FoxO pathway
Aside from the impairment in protein synthesis, the loss of muscle protein occurs mainly through protein degradation. The ubiquitin‒proteasome pathway of protein degradation plays a critical role in muscle protein breakdown. Muscle atrophy F-box (MAFbx) (also called atrogin-1) and muscle RING-finger protein-1 (MuRF1) are E3 ubiquitin ligases that allow ubiquitin to bind to protein substrates (Latres et al. 2005, Timmer et al. 2018). Previous studies have shown that MuRF1 and MAFbx expression is increased in many atrophy models (Bodine et al. 2001a , Gomes et al. 2001), and mice lacking either MuRF1 or MAFbx demonstrate resistance to atrophy. However, overexpression of MuRF1 induces atrophy (Bodine et al. 2001a ). The increase in MAFbx and MuRF1 expression can be antagonized by treatment with IGF1 or through Akt activation, which indicates that Akt suppresses muscle atrophy and stimulates muscle hypertrophy (Bodine et al. 2001a , Sandri et al. 2004, Stitt et al. 2004). It has also been reported that the IGF1/PI3K/Akt pathway blocks dexamethasone-induced atrophy involved in Akt-induced phosphorylation, activates downstream gene expression, and suppresses the FoxO family of transcription factors (Sandri et al. 2004, Stitt et al. 2004). FoxO is essential for the expression of MuRF1 and MAFbx, which are regulated by Akt. The phosphorylation of FoxO transcription factors by Akt prevents FoxO from translocating to the nucleus. Therefore, FoxO remains in the cytoplasm where it cannot transcribe atrophic target genes (Brunet et al. 1999, Stitt et al. 2004). The FoxO transcription factor family includes FoxO1, FoxO3a, and FoxO4, all of which are expressed in skeletal muscle. Akt blocks the function of FoxO transcription factors via the phosphorylation of all three conserved residues (Bodine et al. 2001a , Sandri et al. 2004). FoxO1 and FoxO3 mRNA expression shows a trend toward upregulation in different skeletal muscle atrophy conditions (Lecker et al. 2004). Activated FoxO3 acts on the promoter of atrogin-1, promotes the transcription of atrogin-1, and rapidly reduces the size of myotubes and myofibers (Sandri et al. 2004). A previous study showed that the expression of FoxO3a in older women is higher than that in younger women, and muscle mass is lower in older women than in younger women (Raue et al. 2007).
Crosstalk between bone and muscle: myokines and osteokines
Skeletal muscle and bone are major parts of the body that are anatomically and physiologically connected to maintain tissue structure and function. The connection between skeletal muscle and bone acts as a medium for mechanotransduction; therefore, applying mechanical force to bone regulates bone metabolism (Bakker & Jaspers 2015, Kirk et al. 2020). A previous study showed that bone and skeletal muscle are endocrine organs that secrete a variety of cytokines, namely, myokines and osteokines, respectively (Gomarasca et al. 2020). These cytokines are autocrine when they act locally and paracrine/endocrine when they act on distant organs and tissues (Fig. 2).
Role of osteokines and myokines in the crosstalk between bone and skeletal muscle. Bone and skeletal muscle are connected anatomically and physiologically. In addition, mechanotransduction signals cause bone and skeletal muscle to produce biochemical factors named osteokines and myokines, respectively. Osteokines (osteocalcin, fibroblast growth factor-23, and sclerostin) regulate skeletal muscle metabolism. Myokines (interleukin-6, irisin, and β-aminoisobutyric acid) also affect bone tissue, suggesting that these cytokines bridge the communication between bone and muscle. Estrogen deficiency is associated with different pathological conditions, which affect metabolism and function through these biochemical factors and their downstream signaling targets. A full color version of this figure is available at https://doi.org/10.1530/JOE-23-0116.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-23-0116
Myokines and bone metabolism
Interleukin-6
Myokines are produced by myocytes in response to muscle contraction. IL-6 is a typical inflammatory cytokine that is expressed in different cell types (Bakker & Jaspers 2015). IL-6 is also secreted by contracting skeletal muscle (Ostrowski et al. 1998). During exercise, IL-6 secretion surges (Steensberg et al. 2000), which exerts autocrine, paracrine, and endocrine effects. Through the gp130Rβ/IL-6Ra homodimer, muscle-derived IL-6 can help to maintain blood glucose homeostasis (Steensberg et al. 2000) and fatty acid oxidation (Guo et al. 2017, Karsenty & Mera 2018). Although IL-6 is an inflammatory factor, it exerts an anti-inflammatory effect when it is released by contracting muscles (Zunner et al. 2022). Moreover, exercise-induced IL-6 molecular signaling by osteoblasts promotes osteoclastogenesis during osteocalcin release (Chowdhury et al. 2020). Intramuscular IL-6 production under mechanical load promotes osteoclast differentiation (Juffer et al. 2014). To confirm the link between muscle wasting and inflammatory factors in elderly individuals in the community, previous studies have shown that muscle wasting is associated with increased IL-6 concentrations (Bian et al. 2017, Rong et al. 2018).
In bone tissue, IL-6 stimulates RANKL expression in osteoblasts, promotes the formation and differentiation of osteoclasts, and indirectly induces bone resorption (Bakker & Jaspers 2015, Lombardi et al. 2016). OVX mice (estrogen-deficient) demonstrate an increased number of osteoclasts, which is counteracted by IL-6-neutralizing antibodies, suggesting that IL-6 regulates osteoclast development after estrogen deficiency (Passeri et al. 1993). Lazzaro et al. (Lazzaro et al. 2018) reported that the inhibition of IL-6 trans-signaling (soluble receptor) prevents the increase in osteoclast number and the loss of trabecular bone that occur with estrogen deficiency. Bone loss from estrogen deficiency is prevented in IL-6 knockout mice (Poli et al. 1994, Zhu et al. 2018a ).
Irisin
Irisin is a type I membrane protein cleavage product that is encoded by the fibronectin type III domain-containing protein 5 (Fndc5) gene. Skeletal muscle produces irisin after exercise in mice and humans (Bostrom et al. 2012). Irisin is an important substance that is involved in the browning and energy consumption of adipose tissue, and it is regulated by PPAR-γ coactivator 1-α (Bostrom et al. 2012). Conditioned medium collected from myoblasts from mice after exercising enhances BMSC osteoblast differentiation compared with that from mice housed in resting conditions, indicating that myokines play a regulatory role in bone (Colaianni et al. 2014). The in vitro and in vivo results of Estell et al. showed that irisin has a direct effect on the induction of osteoclast differentiation and the promotion of bone resorption, but induction and mineralization of osteoblasts by irisin were not observed (Estell et al. 2020). Colaianni et al. (Colaianni et al. 2015) injected low-dose irisin into mice and found that with the increase in bone strength, the cortical bone mass increased significantly, mainly due to osteoblast activation and osteoclast inhibition. It was also found that Fndc5/irisin-null mice had a significantly greater mass of trabecular bone and a higher connectivity density than wild-type mice (Kim et al. 2018). Moreover, the Fndc5 global knockout mice could resist the loss of trabecular bone caused by estrogen absence (Kim et al. 2018). This may be partly mediated by inhibiting osteocyte and osteoclast function and reducing osteoclast number (Kim et al. 2018). After intraperitoneal injection of recombinant irisin (r-irisin) into OVX mice for 5 weeks, the BMD and bone mass of mice were higher in the r-irisin group than in the saline group. Moreover, the number of osteoblasts on the trabecular surface was increased and the number of osteoclasts was decreased in the r-irisin group compared with the saline group (Luo et al. 2020). Kawao et al. (Kawao et al. 2021) examined the changes in skeletal metabolism and myokine levels in OVX mice with chronic exercise. They found that the content of irisin in the gastrocnemius and soleus muscles with treadmill exercise was significantly elevated, and the trabecular BMD was also increased. The BMD of rats was higher and the number of osteoclasts was lower in the OVX rats with weekly irisin treatment than in untreated OVX rats (Morgan et al. 2021). A clinical trial showed decreased plasma irisin concentrations in women with postmenopausal osteoporosis (Engin-Ustun et al. 2016). Another study showed an inverse correlation between irisin concentration and previous osteoporotic fracture among postmenopausal women (Anastasilakis et al. 2014).
At present, there are still differences between cell culture and animal studies in terms of the effects of irisin on bone metabolism and homeostasis. However, clinical research has reported a significant inverse association between serum irisin concentrations and osteoporosis or bone fracture in postmenopausal women. Nevertheless, more studies are needed to validate these findings (Kornel et al. 2021).
β-aminoisobutyric acid (BAIBA)
BAIBA is a novel small-molecule myokine that is secreted by skeletal muscle after exercise (Roberts et al. 2014). BAIBA induces brown adipocyte-specific gene expression in white adipose tissue in vivo, which is dependent on PPAR-α. It also increases fatty acid β-oxidation through PPAR-α (Roberts et al. 2014). Cell assays have indicated that BAIBA stimulates osteoblast proliferation and differentiation through the activation of reactive oxygen species signaling (Zhu et al. 2018b ). Using an established murine model of hindlimb unloading to investigate the effects of l-β-aminoisobutyric acid (l-BAIBA) on skeletal muscle, micro-computed tomography (μCT) data showed that hindlimb-unloaded mice with l-BAIBA had a marked increase in the volume fraction, thickness, and connectivity of trabecular bone compared with mice in the control group. The authors identified that the mechanism through which BAIBA protected osteocytes from reactive oxygen species-induced apoptosis was via Mas-related G protein-coupled receptor type D to preserve mitochondrial integrity (Kitase et al. 2018). Moreover, the lower gamma-aminobutyric acid (GABA) concentration among older women with osteoporotic fracture (60–80 years) indicated that a marked correlation exists between GABA and bone metabolism with aging (Wang et al. 2020).
After menopause, women demonstrate a decrease in energy expenditure because of a sedentary lifestyle and physical inactivity, which promote the development of sarcopenia (Buckinx & Aubertin-Leheudre 2022). The benefits of exercise in postmenopausal women are vast, with the most prominent being the maintenance of muscle mass, bone mass, and strength (Mishra et al. 2011, Buckinx & Aubertin-Leheudre 2022); exercise-induced myokines also exert their effects in this condition. However, it is important to note that the benefits of exercise on bone mass and muscle function diminish with aging, making this a complex topic (Borer 2005, Di Lorito et al. 2021).
Osteokines and muscle metabolism
Osteocalcin
Osteocalcin is a noncollagen protein that is produced by osteoblasts. Generally, there are two types of osteocalcin in the blood: fully carboxylated osteocalcin and uncarboxylated osteocalcin. Only uncarboxylated osteocalcin is used as an effective endocrine hormone to target the pancreas and other insulin-sensitive tissues, such as skeletal muscle, depending on the degree of carboxylation (Ducy 2011). It has been suggested that osteocalcin has a positive regulatory effect on insulin secretion, insulin resistance, and energy metabolism (Lee et al. 2007). Ferron et al. (Ferron et al. 2008) examined the long-term treatment of wild-type mice with osteocalcin, which increased insulin concentration, improved blood glucose tolerance, and improved insulin sensitivity. This indicates that the bone-derived hormone osteocalcin has a certain regulatory effect on energy metabolism.
In male rats, low uncarboxylated osteocalcin values were associated with decreased muscle strength (Lin et al. 2016). There is evidence suggesting that the physiological content of uncarboxylated osteocalcin increases intramuscular glucose uptake in AS 160 phosphorylated both in the extensor digitorum longus and soleus muscles (Lin et al. 2017). Mera et al. (Mera et al. 2016a) showed that osteocalcin signaling in muscle fibers promotes exercise adaptation. This is, in part, because osteocalcin signaling increases the muscle production of IL-6 during training but is also due to the presence of a feed-forward regulatory loop that integrates osteocalcin secretion in bone and IL-6 production in muscle. The production of muscle and exogenous osteocalcin is an important means to improve the exercise capacity of young mice. Therefore, osteocalcin signaling in myofibers might be considered a novel strategy to resist the age-related decrease in skeletal muscle function. Moreover, osteocalcin, to a certain extent, promotes protein synthesis in aging mice to maintain muscle quantity. Thus, exogenous osteocalcin therapy is sufficient to improve muscle quantity and quality (Mera et al. 2016b). In addition, uncarboxylated osteocalcin promotes C2C12 myoblast proliferation by activating PI3K/Akt and p38 mitogen-activated protein kinase signaling and other signaling pathways, such as the GPRC6A-ERK1/2 pathway (Liu et al. 2017).
The above evidence suggests that uncarboxylated osteocalcin plays a critical role in muscle maintenance and muscle strength; however, this role remains to be clarified. There is a significant correlation between the percent uncarboxylated osteocalcin (percent uncarboxylated osteocalcin/total osteocalcin) and lower-limb strength in older women, thereby promoting the effects of uncarboxylated osteocalcin on human bone and muscle (Levinger et al. 2014). Plasma-circulating carboxylated osteocalcin, but not uncarboxylated osteocalcin content, is significantly correlated with lean leg mass in postmenopausal women without fractures. However, both carboxylated osteocalcin and uncarboxylated osteocalcin levels are significantly associated with lean muscle mass in postmenopausal women with fractures. This illustrates the different associations of carboxylated osteocalcin and uncarboxylated osteocalcin with the skeletal unit, which is consistent with the complexity of osteocalcin regulation of skeletal muscle (Vitale et al. 2021). A large cohort study showed that a higher uncarboxylated osteocalcin/total osteocalcin ratio in older women is associated with decreased muscle function (strength and physical) and an increased risk of fall-related hospitalization (Smith et al. 2021). The Shea et al. study (Shea et al. 2017) indicated that taking vitamin K supplements reduced uncarboxylated osteocalcin, but does not change lean or fat mass in older men and women living in the community for more than 3 years. Moreover, Moriwaki et al. (Moriwaki et al. 2019) showed that in community residents, osteocalcin is not significantly correlated with muscle indicators. Thus far, there is no clear concept of the effects of uncarboxylated osteocalcin on muscle metabolism, and further studies are needed to understand the connection between them.
Fibroblast growth factor-23 (FGF-23)
FGF-23 is a bone-derived cytokine that is secreted by osteoblasts and osteocytes (Liu et al. 2006). FGF-23 has a significant inhibitory effect on renal phosphate reabsorption, 1,25-dihydroxyvitamin D synthesis (Avin et al. 2018), and parathyroid hormone secretion. This action depends on the FGF receptor and coreceptor Klotho, which regulate the expression of downstream genes (Sato et al. 2016). Excess FGF-23 causes hereditary hypophosphatemia disorders, such as X-linked hypophosphatemic rickets/osteomalacia or autosomal dominant/recessive hypophosphatemic rickets/osteomalacia, as well as acquired hypophosphatemic disorders, including tumor-induced rickets/osteomalacia and McCune–Albright syndrome/fibrous dysplasia (Aono et al. 2011, Quarles 2012). Moreover, a decrease in FGF-23 can lead to tumoral calcification.
In a previous study, the concentration of FGF-23 in postmenopausal osteoporosis was significantly higher than that in postmenopausal osteopenia and postmenopausal nonosteoporosis. Compared with individuals who had experienced menopause for 10 years or 5–10 years, FGF levels were significantly higher in individuals who had experienced menopause for <5 years, indicating that FGF-23 plays a vital role in bone turnover in the early period of postmenopausal osteoporosis (Celik et al. 2013). Another study showed that an FGF-23-neutralizing antibody increases muscle strength and the frequency of spontaneous activity in adult Hyp mice (Aono et al. 2011). Higher levels of FGF-23 were independently correlated with prevalent frailty and prefrailty in older adults in a large community cohort (Beben et al. 2016). Moreover, FGF-23 is independently associated with general frailty (according to the frailty phenotypic criteria of weight loss, weakness, fatigue, slowness, and decreased physical activity) and susceptibility to frailty. FGF-23 may be a biomarker of early susceptibility to frailty risk. Avin et al. (Avin et al. 2018) showed that in the Cy/+ rat model (a naturally occurring rat model of chronic kidney disease–mineral bone disorder), skeletal muscle dysfunction occurred in parallel with the increase in FGF-23 levels. Furthermore, FGF-23 had no significant impact on the proliferation of C2C12 cells and myogenic gene expression. FGF-23 did not impact the contractility of the extensor digitorum longus and soleus muscles in CD-1 mice. This indicates that FGF-23 treatment does not directly change the development of skeletal muscle or its function in high- and low-frequency stimulation conditions, so they thought that other intrinsic factors might be required to work in cooperation with FGF-23 or other substances to promote abnormal skeletal muscle function in CKD or in hereditary hypophosphatemic rickets. Exercise increases the content of FGF-23, improves mitochondrial function, and reduces the production of excess reactive oxygen species and hydrogen peroxide, suggesting a novel role for FGF-23 in skeletal muscle (Li et al. 2016). However, further evaluation of the functions of FGF-23 is needed.
Sclerostin
Sclerostin, which is a circulating glycoprotein that is mainly derived from mature osteocytes, inhibits the Wnt/β-catenin signaling pathway, thereby suppressing bone formation (Ahn et al. 2022). Studies in humans (Balemans et al. 2005) and animals (Morse et al. 2014) have shown that the mutation or deletion of the SOST gene leads to bone growth and higher bone mass. The anti-sclerostin monoclonal antibody romosozumab increases BMD and bone formation and decreases bone resorption in postmenopausal women (McClung et al. 2014). Additionally, romosozumab has been approved in some countries for the treatment of severe postmenopausal osteoporosis due to its efficacy (Hesse et al. 2019). Although the key function of sclerostin in the regulation of bone metabolism is paracrine dependent, recent evidence (Morse et al. 2014, Han et al. 2018) confirms the endocrine regulation of sclerostin in nonskeletal tissues. Mirza et al. (Mirza et al. 2010) compared serum sclerostin levels between premenopausal and postmenopausal women and found that the serum sclerostin content was significantly increased along with a downward trend in E1, E2, and free estrogen index in postmenopausal women. This suggests that serum sclerostin levels in postmenopausal women are regulated by estrogen. Another study showed that E2 plays a role in determining the serum sclerostin concentration in postmenopausal women (Ardawi et al. 2011).
Sclerostin inhibits breast cancer-induced activation of TGF-β1 and p38/NF-κB signaling, thereby preventing breast cancer-induced muscle fiber atrophy and loss of muscle function (Hesse et al. 2019). Mice fed a high-fat diet and C2C12 myocytes treated with palmitate showed enhanced sclerostin expression. C2C12 myocytes treated with recombinant sclerostin aggravate insulin signaling by activating mTOR phosphorylation and inhibiting autophagy, resulting in ER stress (Oh et al. 2022). Moriwake et al. (Moriwaki et al. 2019) investigated the relationship between serum-, bone-, and muscle-related factors and age, sex, body composition, and physical function. The researchers found that sclerostin correlated with sex and bone metabolism, but there was no correlation between sclerostin and muscle function. Another cross-sectional study examined the sclerostin level in 240 healthy nondiabetic subjects and found that in the low muscle mass group, the sclerostin level was higher than that in the normal muscle mass group (Kim et al. 2019), which suggests that sclerostin is involved in the regulation of skeletal muscle mass. Therefore, the concentration of sclerostin circulating in the blood could serve as an effective biomarker for identifying reduced muscle mass.
Summary and perspective
Estrogen is a very powerful sex hormone that plays an important role in both skeletal muscle and bone. Estrogen regulates these tissues directly or indirectly through ERs. Decreased circulating estrogen contributes to the quality and functional integrity of bone and skeletal muscle, thereby promoting osteoporosis and muscle wasting. It is generally believed that aging-related molecular mechanisms cause osteoporosis and sarcopenia. As with aging, estrogen deficiency also works in concert with aging-related mechanisms, exacerbating the negative regulation of bone and skeletal muscle. Therefore, researchers should pay more attention to the impact of estrogen on the above conditions, especially in women.
There is sufficient evidence to show that estrogen affects the skeleton in menopausal women. Estrogen also promotes the proliferation, differentiation, and muscle fiber type of satellite cells and protein synthesis and degradation and skeletal muscle mass, strength, and function. However, compared with the skeleton, there are fewer available studies on skeletal muscle, and the results are inconsistent. In addition to low protein intake and physical activity decline, menopause is the most significant aging phenomenon in women, and sarcopenia onset is closely related to menopause in women. Therefore, changes in estrogen in the body are also an important cause of muscle atrophy.
Estrogen replacement and selective ER modulators have proven effective for the treatment of postmenopausal osteoporosis. However, currently known ERTs are not effective in ameliorating skeletal muscle loss. Therefore, ERT remains a matter of debate in the context of sarcopenia treatment. Proper nutritional supplementation and exercise are still the main methods to avoid muscle atrophy. Many studies have demonstrated that both bone and skeletal muscle have endocrine functions and secrete cytokines, and the two types of tissue communicate through these cytokines. Therefore, future research should focus on developing novel interventions that simultaneously target these cytokines for the treatment of both osteoporosis and sarcopenia.
Declaration interest
The authors declare no conflicts of interest, financial or otherwise.
Funding
This study was supported by the National Natural Science Foundation of China (Grant No. 31300648 to L Tian) and the Sichuan Science and Technology Program (Grant No. 2023YFSY0039 to L Tian).
Author contribution statement
Writing-original draft preparation: L Y L and L T; writing-review and editing: L Y L and L T. All authors have read and agreed to the published version of the manuscript.
Acknowledgements
We acknowledge TopEdit LLC for linguistic editing and proofreading during the preparation of this manuscript.
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