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.
References
Ahn SH, Jung HW, Lee E, Baek JY, Jang IY, Park SJ, Lee JY, Choi E, Lee YS, Hong S, et al.2022 Decreased serum level of sclerostin in older adults with sarcopenia. Endocrinology and Metabolism 37 487–496. (https://doi.org/10.3803/EnM.2022.1428)
Ahtiainen M, PÖllänen E, Ronkainen PHA, Alen M, Puolakka J, Kaprio J, Sipilä S & & Kovanen V 2012 Age and estrogen-based hormone therapy affect systemic and local IL-6 and IGF-1 pathways in women. Age (Dordr) 34 1249–1260. (https://doi.org/10.1007/s11357-011-9298-1)
Alemany M 2021 Estrogens and the regulation of glucose metabolism. World Journal of Diabetes 12 1622–1654. (https://doi.org/10.4239/wjd.v12.i10.1622)
Almeida M, Iyer S, Martin-Millan M, Bartell SM, Han L, Ambrogini E, Onal M, Xiong J, Weinstein RS, Jilka RL, et al.2013 Estrogen receptor-alpha signaling in osteoblast progenitors stimulates cortical bone accrual. Journal of Clinical Investigation 123 394–404. (https://doi.org/10.1172/JCI65910)
Anastasilakis AD, Polyzos SA, Makras P, Gkiomisi A, Bisbinas I, Katsarou A, Filippaios A & & Mantzoros CS 2014 Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months. Osteoporosis International 25 1633–1642. (https://doi.org/10.1007/s00198-014-2673-x)
Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T, Yamashita T & & Fukumoto S 2011 Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. Journal of Bone and Mineral Research 26 803–810. (https://doi.org/10.1002/jbmr.275)
Ardawi MS, AI-Kadi HA, Rouzi AA & & Qari MH 2011 Determinants of serum sclerostin in healthy pre- and postmenopausal women. Journal of Bone and Mineral Research 26 2812–2822. (https://doi.org/10.1002/jbmr.479)
Avin KG, Vallejo JA, Chen NX, Wang K, Touchberry CD, Brotto M, Dallas SL, Moe SM & & Wacker MJ 2018 Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility. American Journal of Physiology- Endocrinology and Metabolism 315 E594–E604. (https://doi.org/10.1152/ajpendo.00343.2017)
Bakker AD & & Jaspers RT 2015 IL-6 and IGF-1 signaling within and between muscle and bone: how important is the mTOR pathway for bone metabolism? Current Osteoporosis Reports 13 131–139. (https://doi.org/10.1007/s11914-015-0264-1)
Balemans W, Cleiren E, Siebers U, Horst J & & Van Hul W 2005 A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 36 943–947. (https://doi.org/10.1016/j.bone.2005.02.019)
Barakat R, Oakley O, Kim H, Jin J & & Ko CJ 2016 Extra-gonadal sites of estrogen biosynthesis and function. BMB Reports 49 488–496. (https://doi.org/10.5483/bmbrep.2016.49.9.141)
Beben T, Ix JH, Shlipak MG, Sarnak MJ, Fried LF, Hoofnagle AN, Chonchol M, Kestenbaum BR, de Boer IH & & Rifkin DE 2016 Fibroblast growth Factor-23 and frailty in elderly community-dwelling individuals: the cardiovascular health study. Journal of the American Geriatrics Society 64 270–276. (https://doi.org/10.1111/jgs.13951)
Bian AL, Hu HY, Rong YD, Wang J, Wang JX & & Zhou XZ 2017 A study on relationship between elderly sarcopenia and inflammatory factors IL-6 and TNF-alpha. European Journal of Medical Research 22 25. (https://doi.org/10.1186/s40001-017-0266-9)
Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, et al.2001a Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294 1704–1708. (https://doi.org/10.1126/science.1065874)
Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, et al.2001b Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nature Cell Biology 3 1014–1019. (https://doi.org/10.1038/ncb1101-1014)
Bolamperti S, Villa I & & Rubinacci A 2022 Bone remodeling: an operational process ensuring survival and bone mechanical competence. Bone Research 10 48. (https://doi.org/10.1038/s41413-022-00219-8)
Bonewald LF 2011 The amazing osteocyte. Journal of Bone and Mineral Research 26 229–238. (https://doi.org/10.1002/jbmr.320)
Borer KT 2005 Physical activity in the prevention and amelioration of osteoporosis in women : interaction of mechanical, hormonal and dietary factors. Sports Medicine 35 779–830. (https://doi.org/10.2165/00007256-200535090-00004)
Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, et al.2012 A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481 463–468. (https://doi.org/10.1038/nature10777)
Bradford PG, Gerace KV, Roland RL & & Chrzan BG 2010 Estrogen regulation ofapoptosis in osteoblasts. Physiology and Behavior 99 181–185. (https://doi.org/10.1016/j.physbeh.2009.04.025)
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J & & Greenberg ME 1999 Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96 857–868. (https://doi.org/10.1016/s0092-8674(0080595-4)
Buckinx F & & Aubertin-Leheudre M 2022 Sarcopenia in menopausal women: current perspectives. International Journal of Women’s Health 14 805–819. (https://doi.org/10.2147/IJWH.S340537)
Carson JA & & Manolagas SC 2015 Effects of sex steroids on bones and muscles: similarities, parallels, and putative interactions in health and disease. Bone 80 67–78. (https://doi.org/10.1016/j.bone.2015.04.015)
Cauley JA 2015 Estrogen and bone health in men and women. Steroids 99 11–15. (https://doi.org/10.1016/j.steroids.2014.12.010)
Celik E, Guzel S, Abali R, Guzelant AY, Celik Guzel E & & Kucukyalcin V 2013 The relationship between fibroblast growth factor 23 and osteoporosis in postmenopausal women. Minerva Medica 104 497–504.
Chaiyasing R, Sugiura A, Ishikawa T, Ojima K, Warita K & & Hosaka YZ 2021 Estrogen modulates the skeletal muscle regeneration process and myotube morphogenesis: morphological analysis in mice with a low estrogen status. Journal of Veterinary Medical Science 83 1812–1819. (https://doi.org/10.1292/jvms.21-0495)
Cheng CH, Chen LR & & Chen KH 2022 Osteoporosis due to hormone imbalance: an overview of the effects of estrogen deficiency and glucocorticoid overuse on bone turnover. International Journal of Molecular Sciences 23 1376–1392. (https://doi.org/10.3390/ijms23031376)
Cho EJ, Choi Y, Jung SJ & & Kwak HB 2022 Role of exercise in estrogen deficiency-induced sarcopenia. Journal of Exercise Rehabilitation 18 2–9. (https://doi.org/10.12965/jer.2244004.002)
Chowdhury S, Schulz L, Palmisano B, Singh P, Berger JM, Yadav VK, Mera P, Ellingsgaard H, Hidalgo J, Brüning J, et al.2020 Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts. Journal of Clinical Investigation 130 2888–2902. (https://doi.org/10.1172/JCI133572)
Clynes MA, Gregson CL, Bruyère O, Cooper C & & Dennison EM 2021 Osteosarcopenia: where osteoporosis and sarcopenia collide. Rheumatology (Oxford) 60 529–537. (https://doi.org/10.1093/rheumatology/keaa755)
Colaianni G, Cuscito C, Mongelli T, Oranger A, Mori G, Brunetti G, Colucci S, Cinti S & & Grano M 2014 Irisin enhances osteoblast differentiation in vitro. International Journal of Endocrinology 2014 902186. (https://doi.org/10.1155/2014/902186)
Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, Lu P, Sartini L, Di Comite M, Mori G, et al.2015 The myokine irisin increases cortical bone mass. Proceedings of the National Academy of Sciences of the United States of America 112 12157–12162. (https://doi.org/10.1073/pnas.1516622112)
Coleman ME, Demayo F, Yin KC, Lee HM, Geske R, Montgomery C & & Schwartz RJ 1995 Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. Journal of Biological Chemistry 270 12109–12116. (https://doi.org/10.1074/jbc.270.20.12109)
Collins BC, Arpke RW, Larson AA, Baumann CW, Xie N, Cabelka CA, Nash NL, Juppi HK, Laakkonen EK, Sipilä S, et al.2019 Estrogen regulates the satellite cell compartment in females. Cell Reports 28 368–381.e6. (https://doi.org/10.1016/j.celrep.2019.06.025)
Cooke PS, Nanjappa MK, Ko C, Prins GS & & Hess RA 2017 Estrogens in male physiology. Physiological Reviews 97 995–1043. (https://doi.org/10.1152/physrev.00018.2016)
Cretoiu D, Pavelescu L, Duica F, Radu M, Suciu N & & Cretoiu SM 2018 Myofibers. Advances in Experimental Medicine and Biology 1088 23–46. (https://doi.org/10.1007/978-981-13-1435-3_2)
Cruz-Jentoft AJ & & Sayer AA 2019 Sarcopenia. Lancet 393 2636–2646. (https://doi.org/10.1016/S0140-6736(1931138-9)
Cui C, Han SS, Shen XY, He HR, Chen YQ, Zhao J, Wei YH, Wang Y, Zhu Q, Li DY, et al.2020 ISLR regulates skeletal muscle atrophy via IGF1-PI3K/Akt-Foxo signaling pathway. Cell and Tissue Research 381 479–492. (https://doi.org/10.1007/s00441-020-03251-4)
Dama A, Baggio C, Boscaro C, Albiero M & & Cignarella A 2021 Estrogen receptor functions and pathways at the vascular immune interface. International Journal of Molecular Sciences 22 4254–4267. (https://doi.org/10.3390/ijms22084254)
Dawson-Hughes B & & Harris S 1992 Regional changes in body composition by time of year in healthy postmenopausal women. American Journal of Clinical Nutrition 56 307–313. (https://doi.org/10.1093/ajcn/56.2.307)
Deepak V, Kayastha P & & McNamara LM 2017 Estrogen deficiency attenuates fluid flow-induced [Ca2+]I oscillations and mechanoresponsiveness of MLO-Y4 osteocytes. FASEB Journal 31 3027–3039. (https://doi.org/10.1096/fj.201601280R)
Di Lorito C, Long A, Byrne A, Harwood RH, Gladman JRF, Schneider S, Logan P, Bosco A & & van der Wardt V 2021 Exercise interventions for older adults: a systematic review of meta-analyses. Journal of Sport and Health Science 10 29–47. (https://doi.org/10.1016/j.jshs.2020.06.003)
Ding JJ, Peng ZH, Wu D, Miao JN, Liu B & & Wang LL 2018 A transcriptomics study of differentiated C2C12 myoblasts identified novel functional responses to 17β-estradiol. Cell Biology International 42 965–974. (https://doi.org/10.1002/cbin.10962)
Ducy P 2011 The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism. Diabetologia 54 1291–1297. (https://doi.org/10.1007/s00125-011-2155-z)
Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL & & Riggs BL 2003 Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. Journal of Clinical Investigation 111 1221–1230. (https://doi.org/10.1172/JCI17215)
Engin-Ustun Y, Caģlayan EK, GÖcmen AY & & Polat MF 2016 Postmenopausal osteoporosis is associated with serum chemerin and irisin but not with apolipoprotein M Levels. Journal of Menopausal Medicine 22 76–79. (https://doi.org/10.6118/jmm.2016.22.2.76)
Estell EG, Le PT, Vegting Y, Kim H, Wrann C, Bouxsein ML, Nagano K, Baron R, Spiegelman BM & & Rosen CJ 2020 Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo. eLife 9 e58172. (https://doi.org/10.7554/eLife.58172)
Ferron M, Hinoi E, Karsenty G & & Ducy P 2008 Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proceedings of the National Academy of Sciences of the United States of America 105 5266–5270. (https://doi.org/10.1073/pnas.0711119105)
Fischer V & & Haffner-Luntzer M 2022 Interaction between bone and immune cells: implications for postmenopausal osteoporosis. Seminars in Cell and Developmental Biology 123 14–21. (https://doi.org/10.1016/j.semcdb.2021.05.014)
Florencio-Silva R, Sasso GRS, Sasso-Cerri E, Simões MJ & & Cerri PS 2018 Effects of estrogen status in osteocyte autophagy and its relation to osteocyte viability in alveolar process of ovariectomized rats. Biomedicine and Pharmacotherapy 98 406–415. (https://doi.org/10.1016/j.biopha.2017.12.089)
Fry CS, Lee JD, Mula J, Kirby TJ, Jackson JR, Liu FJ, Yang L, Mendias CL, Dupont-Versteegden EE, McCarthy JJ, et al.2015 Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nature Medicine 21 76–80. (https://doi.org/10.1038/nm.3710)
Fuentes N & & Silveyra P 2019 Estrogen receptor signaling mechanisms. Advances in Protein Chemistry and Structural Biology 116 135–170. (https://doi.org/10.1016/bs.apcsb.2019.01.001)
Fujiwara Y, Piemontese M, Liu Y, Thostenson JD, Xiong J & & O'BRIEN CA 2016 RANKL (receptor activator of NFkappaB ligand). Journal of Biological Chemistry 291 24838–24850. (https://doi.org/10.1074/jbc.M116.742452)
Geraci A, Calvani R, Ferri E, Marzetti E, Arosio B & & Cesari M 2021 Sarcopenia and menopause: the role of estradiol. Frontiers in Endocrinology (Lausanne) 12 682012. (https://doi.org/10.3389/fendo.2021.682012)
Glass DJ 2010 PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. Current Topics in Microbiology and Immunology 346 267–278. (https://doi.org/10.1007/82_2010_78)
Gomarasca M, Banfi G & & Lombardi G 2020 Myokines: the endocrine coupling of skeletal muscle and bone. Advances in Clinical Chemistry 94 155–218. (https://doi.org/10.1016/bs.acc.2019.07.010)
Gomes MD, Lecker SH, Jagoe RT, Navon A & & Goldberg AL 2001 Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proceedings of the National Academy of Sciences of the United States of America 98 14440–14445. (https://doi.org/10.1073/pnas.251541198)
Gower BA & & Nyman L 2000 Associations among oral estrogen use, free testosterone concentration, and lean body mass among postmenopausal women. Journal of Clinical Endocrinology and Metabolism 85 4476–4480. (https://doi.org/10.1210/jcem.85.12.7009)
Greising SM, Baltgalvis KA, Lowe DA & & Warren GL 2009 Hormone therapy and skeletal muscle strength: a meta-analysis. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 64 1071–1081. (https://doi.org/10.1093/gerona/glp082)
Grüner S, Peter D, Weber R, Wohlbold L, Chung MY, Weichenrieder O, Valkov E, Igreja C & & Izaurralde E 2016 The structures of eIF4E-eIF4G complexes reveal an extended interface to regulate translation initiation. Molecular Cell 64 467–479. (https://doi.org/10.1016/j.molcel.2016.09.020)
Guo BS, Zhang ZK, Liang C, Li J, Liu J, Lu AP, Zhang BT & & Zhang G 2017 Molecular communication from skeletal muscle to bone: a review for muscle-derived myokines regulating bone metabolism. Calcified Tissue International 100 184–192. (https://doi.org/10.1007/s00223-016-0209-4)
Guo L, Chen KZ, Yuan J, Huang P, Xu X, Li CW, Qian NQ, Qi J, Shao ZL, Deng LF, et al.2018 Estrogen inhibits osteoclasts formation and bone resorption via microRNA-27a targeting PPARgamma and APC. Journal of Cellular Physiology 234 581–594. (https://doi.org/10.1002/jcp.26788)
Haizlip KM, Harrison BC & & Leinwand LA 2015 Sex-based differences in skeletal muscle kinetics and fiber-type composition. Physiology (Bethesda) 30 30–39. (https://doi.org/10.1152/physiol.00024.2014)
Han YJ, You XL, Xing WH, Zhang Z & & Zou WG 2018 Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Research 6 16. (https://doi.org/10.1038/s41413-018-0019-6)
Hayashi M, Nakashima T, Yoshimura N, Okamoto K, Tanaka S & & Takayanagi H 2019 Autoregulation of osteocyte Sema3A orchestrates estrogen action and counteracts bone aging. Cell Metabolism 29 627–637.e5. (https://doi.org/10.1016/j.cmet.2018.12.021)
Hénique C, Mansouri A, Vavrova E, Lenoir V, Ferry A, Esnous C, Ramond E, Girard J, Bouillaud F, Prip-Buus C, et al.2015 Increasing mitochondrial muscle fatty acid oxidation induces skeletal muscle remodeling toward an oxidative phenotype. FASEB Journal 29 2473–2483. (https://doi.org/10.1096/fj.14-257717)
Hesse E, Schröder S, Brandt D, Pamperin J, Saito H & & Taipaleenmaki H 2019 Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI Insight 5 e125543. (https://doi.org/10.1172/jci.insight.125543)
Hodson N, West DWD, Philp A, Burd NA & & Moore DR 2019 Molecular regulation of human skeletal muscle protein synthesis in response to exercise and nutrients: a compass for overcoming age-related anabolic resistance. American Journal of Physiology-Cell Physiology 317 C1061–C1078. (https://doi.org/10.1152/ajpcell.00209.2019)
Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC & & Riggs BL 1999 Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140 4367–4370. (https://doi.org/10.1210/endo.140.9.7131)
Hong L, Sultana H, Paulius K & & Zhang GQ 2009 Steroid regulation of proliferation and osteogenic differentiation of bone marrow stromal cells: a gender difference. Journal of Steroid Biochemistry and Molecular Biology 114 180–185. (https://doi.org/10.1016/j.jsbmb.2009.02.001)
Horwath O, Moberg M, Larsen FJ, Philp A, Apró W & & Ekblom B 2021 Influence of sex and fiber type on the satellite cell pool in human skeletal muscle. Scandinavian Journal of Medicine and Science in Sports 31 303–312. (https://doi.org/10.1111/sms.13848)
Jackson E, Lara-Castillo N, Akhter MP, Dallas M, Scott JM, Ganesh T & & johnson ML 2021 Osteocyte Wnt/beta-catenin pathway activation upon mechanical loading is altered in ovariectomized mice. Bone Reports 15 101129. (https://doi.org/10.1016/j.bonr.2021.101129)
Javed AA, Mayhew AJ, Shea AK & & Raina P 2019 Association between hormone therapy and muscle mass in postmenopausal women: a systematic review and meta-analysis. JAMA Network Open 2 e1910154. (https://doi.org/10.1001/jamanetworkopen.2019.10154)
Juffer P, Jaspers RT, Klein-Nulend J & & Bakker AD 2014 Mechanically loaded myotubes affect osteoclast formation. Calcified Tissue International 94 319–326. (https://doi.org/10.1007/s00223-013-9813-8)
Kanis JA 2002 Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359 1929–1936. (https://doi.org/10.1016/S0140-6736(0208761-5)
Karaguzel G & & Holick MF 2010 Diagnosis and treatment of osteopenia. Reviews in Endocrine and Metabolic Disorders 11 237–251. (https://doi.org/10.1007/s11154-010-9154-0)
Karlamangla AS, Shieh A & & Greendale GA 2021 Hormones and bone loss across the menopause transition. Vitamins and Hormones 115 401–417. (https://doi.org/10.1016/bs.vh.2020.12.016)
Karsenty G & & Mera P 2018 Molecular bases of the crosstalk between bone and muscle. Bone 115 43–49. (https://doi.org/10.1016/j.bone.2017.04.006)
Kawao N, Iemura S, Kawaguchi M, Mizukami Y, Takafuji Y & & Kaji H 2021 Role of irisin in effects of chronic exercise on muscle and bone in ovariectomized mice. Journal of Bone and Mineral Metabolism 39 547–557. (https://doi.org/10.1007/s00774-020-01201-2)
Kenny AM & & Raisz LG 2002 Mechanisms of bone remodeling: implications for clinical practice. Journal of Reproductive Medicine 47(Supplement) 63–70.
Kenny AM, Dawson L, Kleppinger A, Iannuzzi-Sucich M & & Judge JO 2003 Prevalence of sarcopenia and predictors of skeletal muscle mass in nonobese women who are long-term users of estrogen-replacement therapy. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 58 M436–M440. (https://doi.org/10.1093/gerona/58.5.m436)
Khosla S, Oursler MJ & & Monroe DG 2012 Estrogen and the skeleton. Trends in Endocrinology and Metabolism 23 576–581. (https://doi.org/10.1016/j.tem.2012.03.008)
Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, et al.2018 Irisin mediates effects on bone and fat via alphaV integrin receptors. Cell 175 1756–1768.e17. (https://doi.org/10.1016/j.cell.2018.10.025)
Kim JA, Roh E, Hong SH, Lee YB, Kim NH, Yoo HJ, Seo JA, Kim NH, Kim SG, Baik SH, et al.2019 Association of serum sclerostin levels with low skeletal muscle mass: the Korean Sarcopenic Obesity Study (KSOS). Bone 128 115053. (https://doi.org/10.1016/j.bone.2019.115053)
Kimble RB, Srivastava S, Ross FP, Matayoshi A & & Pacifici R 1996 Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production. Journal of Biological Chemistry 271 28890–28897. (https://doi.org/10.1074/jbc.271.46.28890)
Kirk B, Feehan J, Lombardi G & & Duque G 2020 Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and Adipokines. Current Osteoporosis Reports 18 388–400. (https://doi.org/10.1007/s11914-020-00599-y)
Kitajima Y & & Ono Y 2016 Estrogens maintain skeletal muscle and satellite cell functions. Journal of Endocrinology 229 267–275. (https://doi.org/10.1530/JOE-15-0476)
Kitase Y, Vallejo JA, Gutheil W, Vemula H, Jähn K, Yi JX, Zhou JS, Brotto M & & Bonewald LF 2018 2018 beta-aminoisobutyric acid, l-BAIBA, is a muscle-derived osteocyte survival factor. Cell Reports 22 1531–1544. (https://doi.org/10.1016/j.celrep.2018.01.041)
Klein-Nulend J, Bakker AD, Bacabac RG, Vatsa A & & Weinbaum S 2013 Mechanosensation and transduction in osteocytes. Bone 54 182–190. (https://doi.org/10.1016/j.bone.2012.10.013)
Klein-Nulend J, Van Oers RFM, Bakker AD & & Bacabac RG 2015 Bone cell mechanosensitivity, estrogen deficiency, and osteoporosis. Journal of Biomechanics 48 855–865. (https://doi.org/10.1016/j.jbiomech.2014.12.007)
Kornel A, Den Hartogh DJD, Klentrou P & & Tsiani E 2021 Role of the myokine irisin on bone homeostasis: review of the current evidence. International Journal of Molecular Sciences 22 9136–9163. (https://doi.org/10.3390/ijms22179136)
Kousteni S, Bellido T, Plotkin LI, O'brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, et al.2001 Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104 719–730. (https://doi.org/10.1016/S0092-8674(0100268-9)
Kousteni S, Han L, CHEN JR, Almeida M, Plotkin LI, Bellido T & & Manolagas SC 2003 Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. Journal of Clinical Investigation 111 1651–1664. (https://doi.org/10.1172/JCI17261)
Kuang S, Kuroda K, Le Grand F & & Rudnicki MA 2007 Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129 999–1010. (https://doi.org/10.1016/j.cell.2007.03.044)
Lai SJ, Collins BC, Colson BA, Kararigas G & & Lowe DA 2016 Estradiol modulates myosin regulatory light chain phosphorylation and contractility in skeletal muscle of female mice. American Journal of Physiology-Endocrinology and Metabolism 310 E724–E733. (https://doi.org/10.1152/ajpendo.00439.2015)
Larson AA, Shams AS, McMillin SL, Sullivan BP, Vue C, Roloff ZA, Batchelor E, Kyba M & & Lowe DA 2022 Estradiol deficiency reduces the satellite cell pool by impairing cell cycle progression. American Journal of Physiology-Cell Physiology 322 C1123–C1137. (https://doi.org/10.1152/ajpcell.00429.2021)
Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, Wei Y, Lin HC, Yancopoulos GD & & Glass DJ 2005 Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Journal of Biological Chemistry 280 2737–2744. (https://doi.org/10.1074/jbc.M407517200)
Lazzaro L, Tonkin BA, Poulton IJ, McGregor NE, Ferlin W & & Sims NA 2018 IL-6 trans-signalling mediates trabecular, but not cortical, bone loss after ovariectomy. Bone 112 120–127. (https://doi.org/10.1016/j.bone.2018.04.015)
Lecker SH, Jagoe RT, GIlbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE & & Goldberg AL 2004 Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB Journal 18 39–51. (https://doi.org/10.1096/fj.03-0610com)
Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, et al.2007 Endocrine regulation of energy metabolism by the skeleton. Cell 130 456–469. (https://doi.org/10.1016/j.cell.2007.05.047)
Léger B, Cartoni R, Praz M, Lamon S, Dériaz O, Crettenand A, Gobelet C, Rohmer P, Konzelmann M, Luthi F, et al.2006 Akt signalling through GSK-3beta, mTOR and FoxO1 is involved in human skeletal muscle hypertrophy and atrophy. Journal of Physiology 576 923–933. (https://doi.org/10.1113/jphysiol.2006.116715)
Levinger I, Scott D, Nicholson GC, Stuart AL, Duque G, McCorquodale T, Herrmann M, Ebeling PR & & Sanders KM 2014 Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women. Bone 64 8–12. (https://doi.org/10.1016/j.bone.2014.03.008)
Li DJ, Fu H, Zhao T, Ni M & & Shen FM 2016 Exercise-stimulated FGF23 promotes exercise performance via controlling the excess reactive oxygen species production and enhancing mitochondrial function in skeletal muscle. Metabolism: Clinical and Experimental 65 747–756. (https://doi.org/10.1016/j.metabol.2016.02.009)
Li L & & Wang Z 2018 Ovarian aging and osteoporosis. Advances in Experimental Medicine and Biology 1086 199–215. (https://doi.org/10.1007/978-981-13-1117-8_13)
Li Z, Zhang ZK, Ren YK, Wang YY, Fang JR, Yue H, Ma SS & & Guan FX 2021 Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology 22 165–187. (https://doi.org/10.1007/s10522-021-09910-5)
Lin XZ, Hanson E, Betik AC, Brennan-Speranza TC, Hayes A & & Levinger I 2016 Hindlimb immobilization, but not castration, induces reduction of undercarboxylated osteocalcin associated with muscle atrophy in rats. Journal of Bone and Mineral Research 31 1967–1978. (https://doi.org/10.1002/jbmr.2884)
Lin XZ, Parker L, Mclennan E, Zhang XM, Hayes A, McConell G, Brennan-Speranza TC & & Levinger I 2017 Recombinant uncarboxylated osteocalcin per se enhances mouse skeletal muscle glucose uptake in both extensor digitorum longus and soleus muscles. Frontiers in Endocrinology (Lausanne) 8 330. (https://doi.org/10.3389/fendo.2017.00330)
Liu SG, Zhou JP, Tang W, Jiang X, Rowe DW & & Quarles LD 2006 Pathogenic role of FGF23 in Hyp mice. American Journal of Physiology-Endocrinology and Metabolism 291 E38–E49. (https://doi.org/10.1152/ajpendo.00008.2006)
Liu SF, Gao F, Wen L, Ouyang M, Wang Y, Wang Q, Luo LP & & Jian ZJ 2017 Osteocalcin induces proliferation via positive activation of the PI3K/Akt, P38 MAPK pathways and promotes differentiation through activation of the GPRC6A-ERK1/2 pathway in C2C12 myoblast cells. Cellular Physiology and Biochemistry 43 1100–1112. (https://doi.org/10.1159/000481752)
Lombardi G, Sanchis-Gomar F, Perego S, Sansoni V & & Banfi G 2016 Implications of exercise-induced adipo-myokines in bone metabolism. Endocrine 54 284–305. (https://doi.org/10.1007/s12020-015-0834-0)
Lorenzo J 2017 The many ways of osteoclast activation. Journal of Clinical Investigation 127 2530–2532. (https://doi.org/10.1172/JCI94606)
Lowe DA, Baltgalvis KA & & Greising SM 2010 Mechanisms behind estrogen's beneficial effect on muscle strength in females. Exercise and Sport Sciences Reviews 38 61–67. (https://doi.org/10.1097/JES.0b013e3181d496bc)
Luo Y, Ma Y, Qiao X, Zeng R, Cheng R, Nie Y, Li S, A R, Shen X, Yang M, et al.2020 Irisin ameliorates bone loss in ovariectomized mice. Climacteric 23 496–504. (https://doi.org/10.1080/13697137.2020.1745768)
Maddalozzo GF, Cardinal BJ, Li F & & Snow CM 2004 The association between hormone therapy use and changes in strength and body composition in early postmenopausal women. Menopause 11 438–446. (https://doi.org/10.1097/01.gme.0000113847.74835.fe)
Maltais ML, Desroches J & & Dionne IJ 2009 Changes in muscle mass and strength after menopause. Journal of Musculoskeletal and Neuronal Interactions 9 186–197.
Matsumoto Y, Otsuka F, Takano-Narazaki M, Katsuyama T, Nakamura E, Tsukamoto N, Inagaki K, Sada KE & & Makino H 2013 Estrogen facilitates osteoblast differentiation by upregulating bone morphogenetic protein-4 signaling. Steroids 78 513–520. (https://doi.org/10.1016/j.steroids.2013.02.011)
McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster JY, Zanchetta JR, Wasserman SM, et al.2014 Romosozumab in postmenopausal women with low bone mineral density. New England Journal of Medicine 370 412–420. (https://doi.org/10.1056/NEJMoa1305224)
Mera P, Laue K, Ferron M, Confavreux C, Wei JW, Galán-DÍez M, Lacampagne A, Mitchell SJ, Mattison JA, Chen Y, et al.2016a Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metabolism 23 1078–1092. (https://doi.org/10.1016/j.cmet.2016.05.004)
Mera P, Laue K, Wei JW, Berger JM & & Karsenty G 2016b Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Molecular Metabolism 5 1042–1047. (https://doi.org/10.1016/j.molmet.2016.07.002)
Michael H, Härkönen PL, Väänänen HK & & Hentunen TA 2005 Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. Journal of Bone and Mineral Research 20 2224–2232. (https://doi.org/10.1359/JBMR.050803)
Mirza FS, Padhi ID, Raisz LG & & Lorenzo JA 2010 Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 95 1991–1997. (https://doi.org/10.1210/jc.2009-2283)
Mishra N, Mishra VN & & Devanshi 2011 Exercise beyond menopause: dos and Don'ts. Journal of Mid-Life Health 2 51–56. (https://doi.org/10.4103/0976-7800.92524)
Mohamad NV, Ima-Nirwana S & & Chin KY 2020 Are oxidative stress and inflammation mediators of bone loss due to estrogen deficiency? A review of current evidence. Endocrine, Metabolic and Immune Disorders Drug Targets 20 1478–1487. (https://doi.org/10.2174/1871530320666200604160614)
Molsted S, Eidemak I, Sorensen HT, Kristensen JH, Harrison A & & Andersen JL 2007 Myosin heavy-chain isoform distribution, fibre-type composition and fibre size in skeletal muscle of patients on haemodialysis. Scandinavian Journal of Urology and Nephrology 41 539–545. (https://doi.org/10.1080/00365590701421330)
Morgan EN, Alsharidah AS, Mousa AM & & Edrees HM 2021 Irisin has a protective role against osteoporosis in ovariectomized rats. BioMed Research International 2021 5570229. (https://doi.org/10.1155/2021/5570229)
Moriwaki K, Matsumoto H, Tanishima S, Tanimura C, Osaki M, Nagashima H & & Hagino H 2019 Association of serum bone- and muscle-derived factors with age, sex, body composition, and physical function in community-dwelling middle-aged and elderly adults: a cross-sectional study. BMC Musculoskeletal Disorders 20 276. (https://doi.org/10.1186/s12891-019-2650-9)
Morse A, Mcdonald MM, Kelly NH, Melville KM, Schindeler A, Kramer I, Kneissel M, van der Meulen MC & & Little DG 2014 Mechanical load increases in bone formation via a sclerostin-independent pathway. Journal of Bone and Mineral Research 29 2456–2467. (https://doi.org/10.1002/jbmr.2278)
Murton AJ 2015 Muscle protein turnover in the elderly and its potential contribution to the development of sarcopenia. Proceedings of the Nutrition Society 74 387–396. (https://doi.org/10.1017/S0029665115000130)
NAMS 2021 Management of osteoporosis in postmenopausal women: the 2021 position statement of the North American Menopause Society. Menopause 28 973–997. (https://doi.org/10.1097/GME.0000000000001831)
Naqvi SM, Panadero Pérez JA, Kumar V, Verbruggen ASK & & McNamara LM 2020 A novel 3D osteoblast and osteocyte model revealing changes in mineralization and pro-osteoclastogenic paracrine signaling during estrogen deficiency. Frontiers in Bioengineering and Biotechnology 8 601. (https://doi.org/10.3389/fbioe.2020.00601)
Nelson HD 2008 Menopause. Lancet 371 760–770. (https://doi.org/10.1016/S0140-6736(0860346-3)
Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M & & Gustafsson JA 2001 Mechanisms of estrogen action. Physiological Reviews 81 1535–1565. (https://doi.org/10.1152/physrev.2001.81.4.1535)
Oh H, Park SY, Cho WJ, Abd El-Aty AM, Hacimuftuoglu A, Kwon CH, Jeong JH & & Jung TW 2022 Sclerostin aggravates insulin signaling in skeletal muscle and hepatic steatosis via upregulation of ER stress by mTOR-mediated inhibition of autophagy under hyperlipidemic conditions. Journal of Cellular Physiology 237 4226–4237. (https://doi.org/10.1002/jcp.30873)
Okazaki R, Inoue D, Shibata M, Saika M, Kido S, Ooka H, Tomiyama H, Sakamoto Y & & Matsumoto T 2002 Estrogen promotes early osteoblast differentiation and inhibits adipocyte differentiation in mouse bone marrow stromal cell lines that express estrogen receptor (ER) alpha or beta. Endocrinology 143 2349–2356. (https://doi.org/10.1210/endo.143.6.8854)
Olivieri F, Ahtiainen M, Lazzarini R, Pöllänen E, Capri M, Lorenzi M, Fulgenzi G, Albertini MC, Salvioli S, Alen MJ, et al.2014 Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs. Aging Cell 13 850–861. (https://doi.org/10.1111/acel.12245)
Ostrowski K, Rohde T, Zacho M, Asp S & & Pedersen BK 1998 Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. Journal of Physiology 508 949–953. (https://doi.org/10.1111/j.1469-7793.1998.949bp.x)
Park HJ, Gholam-Zadeh M, Yoon SY, Suh JH & & Choi HS 2021 Estrogen decreases cytoskeletal organization by forming an ERalpha/SHP2/c-Src complex in osteoclasts to protect against ovariectomy-induced bone loss in mice. Antioxidants (Basel) 10 619–633. (https://doi.org/10.3390/antiox10040619)
Passeri G, Girasole G, Jilka RL & & Manolagas SC 1993 Increased interleukin-6 production by murine bone marrow and bone cells after estrogen withdrawal. Endocrinology 133 822–828. (https://doi.org/10.1210/endo.133.2.8393776)
Pellegrino A, Tiidus PM & & Vandenboom R 2022 Mechanisms of estrogen influence on skeletal muscle: mass, regeneration, and mitochondrial function. Sports Medicine 52 2853–2869. (https://doi.org/10.1007/s40279-022-01733-9)
Pette D & & Staron RS 2000 Myosin isoforms, muscle fiber types, and transitions. Microscopy Research and Technique 50 500–509. (https://doi.org/10.1002/1097-0029(20000915)50:6<500::AID-JEMT7>3.0.CO;2-7)
Plant A & & Tobias JH 2002 Increased bone morphogenetic protein-6 expression in mouse long bones after estrogen administration. Journal of Bone and Mineral Research 17 782–790. (https://doi.org/10.1359/jbmr.2002.17.5.782)
Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Ciliberto G, Rodan GA & & Costantini F 1994 Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO Journal 13 1189–1196. (https://doi.org/10.1002/j.1460-2075.1994.tb06368.x)
Quarles LD 2012 Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease. Experimental Cell Research 318 1040–1048. (https://doi.org/10.1016/j.yexcr.2012.02.027)
Raehtz S, Bierhalter H, Schoenherr D, Parameswaran N & & McCabe LR 2017 Estrogen deficiency exacerbates type 1 diabetes-induced bone TNF-alpha expression and osteoporosis in female mice. Endocrinology 158 2086–2101. (https://doi.org/10.1210/en.2016-1821)
Raue U, Slivka D, Jemiolo B, Hollon C & & Trappe S 2007 Proteolytic gene expression differs at rest and after resistance exercise between young and old women. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 62 1407–1412. (https://doi.org/10.1093/gerona/62.12.1407)
Reid IR 2020 A broader strategy for osteoporosis interventions. Nature Reviews. Endocrinology 16 333–339. (https://doi.org/10.1038/s41574-020-0339-7)
Riggs BL, Khosla S & & Melton LJ 3rd 2002 Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews 23 279–302. (https://doi.org/10.1210/edrv.23.3.0465)
Roberts LD, Boström P, O'sullivan JF, Schinzel RT, Lewis GD, Dejam A, Lee YK, Palma MJ, Calhoun S, Georgiadi A, et al.2014 2014 beta-aminoisobutyric acid induces browning of white fat and hepatic beta-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metabolism 19 96–108. (https://doi.org/10.1016/j.cmet.2013.12.003)
Rogers NH, Perfield JW 2nd, Strissel KJ, Obin MS & & Greenberg AS 2010 Loss of ovarian function in mice results in abrogated skeletal muscle PPARdelta and FoxO1-mediated gene expression. Biochemical and Biophysical Research Communications 392 1–3. (https://doi.org/10.1016/j.bbrc.2009.10.072)
Rong YD, Bian AL, Hu HY, Ma Y & & Zhou XZ 2018 Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10. BMC Geriatrics 18 308. (https://doi.org/10.1186/s12877-018-1007-9)
Ronkainen PH, Kovanen V, Alén M, Pöllänen E, Palonen EM, Ankarberg-Lindgren C, Hämäläinen E, Turpeinen U, Kujala UM, Puolakka J, et al.2009 Postmenopausal hormone replacement therapy modifies skeletal muscle composition and function: a study with monozygotic twin pairs. Journal of Applied Physiology 107 25–33. (https://doi.org/10.1152/japplphysiol.91518.2008)
Saika M, Inoue D, Kido S & & Matsumoto T 2001 17beta-estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-alpha. Endocrinology 142 2205–2212. (https://doi.org/10.1210/endo.142.6.8220)
Sandri M, Barberi L, Bijlsma AY, Blaauw B, Dyar KA, Milan G, Mammucari C, Meskers CGM, Pallafacchina G, Paoli A, et al.2013 Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 14 303–323. (https://doi.org/10.1007/s10522-013-9432-9)
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH & & Goldberg AL 2004 Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117 399–412. (https://doi.org/10.1016/s0092-8674(0400400-3)
Sato C, Iso Y, Mizukami T, Otabe K, Sasai M, Kurata M, Sanbe T, Sekiya I, Miyazaki A & & Suzuki H 2016 Fibroblast growth factor-23 induces cellular senescence in human mesenchymal stem cells from skeletal muscle. Biochemical and Biophysical Research Communications 470 657–662. (https://doi.org/10.1016/j.bbrc.2016.01.086)
Schiavi J, Fodera DM, Brennan MA & & Mcnamara LM 2021 Estrogen depletion alters osteogenic differentiation and matrix production by osteoblasts in vitro. Experimental Cell Research 408 112814. (https://doi.org/10.1016/j.yexcr.2021.112814)
Schumacher B, Pothof J, Vijg J & & Hoeijmakers JHJ 2021 The central role of DNA damage in the ageing process. Nature 592 695–703. (https://doi.org/10.1038/s41586-021-03307-7)
Seko D, Fujita R, Kitajima Y, Nakamura K, Imai Y & & Ono Y 2020 Estrogen receptor beta Controls Muscle Growth and Regeneration in Young Female Mice. Stem Cell Reports 15 577–586. (https://doi.org/10.1016/j.stemcr.2020.07.017)
Shea MK, Dawson-Hughes B, Gundberg CM & & Booth SL 2017 Reducing undercarboxylated osteocalcin with vitamin K supplementation does not promote lean tissue loss or fat gain over 3 years in older women and men: a randomized controlled trial. Journal of Bone and Mineral Research 32 243–249. (https://doi.org/10.1002/jbmr.2989)
Shevde NK, Bendixen AC, Dienger KM & & Pike JW 2000 Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Procceedings of the National Academy of Sciences of the United States of America 97 7829–7834. (https://doi.org/10.1073/pnas.130200197)
Shoham Z & & Schachter M 1996 Estrogen biosynthesis--regulation, action, remote effects, and value of monitoring in ovarian stimulation cycles. Fertility and Sterility 65 687–701. (https://doi.org/10.1016/s0015-0282(1658197-7)
Simfia I, Schiavi J & & McNamara LM 2020 Alterations in osteocyte mediated osteoclastogenesis during estrogen deficiency and under ROCK-II inhibition: an in vitro study using a novel postmenopausal multicellular niche model. Experimental Cell Research 392 112005. (https://doi.org/10.1016/j.yexcr.2020.112005)
Sipilä S, Taaffe DR, Cheng S, Puolakka J, Toivanen J & & Suominen H 2001 Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study. Clinical Science 101 147–157. (https://doi.org/10.1042/cs1010147)
Sipilä S, Törmäkangas T, Sillanpää E, Aukee P, Kujala UM, Kovanen V & & Laakkonen EK 2020 Muscle and bone mass in middle-aged women: role of menopausal status and physical activity. Journal of Cachexia, Sarcopenia and Muscle 11 698–709. (https://doi.org/10.1002/jcsm.12547)
Sitnick M, Foley AM, Brown M & & Spangenburg EE 2006 Ovariectomy prevents the recovery of atrophied gastrocnemius skeletal muscle mass. Journal of Applied Physiology 100 286–293. (https://doi.org/10.1152/japplphysiol.00869.2005)
Smith C, Lewis JR, Sim M, Lim WH, lim EM, Blekkenhorst LC, Brennan-Speranza TC, Adams L, Byrnes E, Duque G, et al.2021 Higher undercarboxylated to total osteocalcin ratio is associated with reduced physical function and increased 15-year falls-related hospitalizations: the Perth longitudinal study of aging women. Journal of Bone and Mineral Research 36 523–530. (https://doi.org/10.1002/jbmr.4208)
Song TF, Lin T, Ma J, Guo L, Zhang L, Zhou XH & & Ye TW 2018 Regulation of TRPV5 transcription and expression by E2/ERalpha signalling contributes to inhibition of osteoclastogenesis. Journal of Cellular and Molecular Medicine 22 4738–4750. (https://doi.org/10.1111/jcmm.13718)
Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B & & Klarlund Pedersen B 2000 Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. Journal of Physiology 529 237–242. (https://doi.org/10.1111/j.1469-7793.2000.00237.x)
Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD & & Glass DJ 2004 The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Molecular Cell 14 395–403. (https://doi.org/10.1016/s1097-2765(0400211-4)
Tan KT, Ang SJ & & Tsai SY 2020 Sarcopenia: tilting the balance of protein homeostasis. Proteomics 20 e1800411. (https://doi.org/10.1002/pmic.201800411)
Tang L, Cao WX, Zhao TT, Yu K, Sun LJ, Guo JZ, Fan XS & & Ta