In yet another great example of "synchronicity" (Synchronicity - Wikipedia), just a few days after posting the study on lack of estrogen and muscle growth, another fascinating study popped into my mailbox.
Estrogen Is NOT Needed For Either Muscle Or Bone Growth / Anabolism
Now, the study below add to the evidence that estrogen is not only not needed for muscle growth and bone health, but blocking its effects (in the brain) leads to such remarkably dense/strong bones in females (mice) that no other known model can even come close to. Simultaneously, the muscle mass of those females also increased dramatically and the authors think the two effects are not a coincidence. I don't know why the effects of blocking estrogen in males were much less pronounced than in females, but I suspect it is due to surges in progesterone activity. Progesterone is highly anabolic in females, but not so much in males. Be that as it may, hopefully this study will lead to serious reconsideration of estrogen therapy in females. The authors think that the anabolism from blocking estrogen in the brain reduces mating and physical activity in the females, and the resulting surplus of energy was diverted towards bone/muscle building. I guess it is another way of saying that stress is bad for women's bones/muscles and blocking the stress hormone (estrogen) allowed the females to grow as much as there is food available. I really see no reason why the same would not be true in males and the authors clearly state that blocking estrogen in brain would be therapeutic for both sexes even if this specific study did not find much anabolism for males.
@Blossom @tara @Sheila @AretnaP @Wagner83 @Lokzo @RisingSun @jb116 @tankasnowgod
@opethfeldt
Estrogen signaling in arcuate <i>Kiss1</i> neurons suppresses a sex-dependent female circuit promoting dense strong bones
"...Esr1Nkx2-1Cre females exhibited a sex-dependent change in energy balance that was entirely absent in male mice. The lean mass of mutant females was significantly higher than control floxed (Esr1fl/fl) littermates (Fig. 1d) and was accompanied by decreased physical activity during the dark phase (Fig. 1e and Supplementary Figure 2C). Although highly significant, increased lean mass observed in mutant females failed to change their overall mobility and muscle strength as measured by rotarod and grip strength assays, respectively (Supplementary Figure 2D, E). Blunted BAT thermogenesis was observed in mutant females as evidenced by whitening of BAT and decreased Ucp1 levels; circulating catecholamines were not lower (Fig. 1f and Supplementary Figures 2F, G). Serum leptin levels were also unchanged (Fig. 1g). Thus, these data reveal that central estrogen signaling in this brain region promotes a sex-dependent negative energy state in females in the absence of any change in feeding behavior. This unexpected finding implies that the hyperphagia reported for Esr1POMC-Cre mice might result from selective or ectopic activity of POMC-Cre in non-ARC neurons8."
"...Strikingly, bone mineral density (BMD), as determined by dual X-ray absorptiometry (DEXA), was significantly elevated in Esr1Nkx2-1Crefemales, but not males (Fig. 1h), consistent with the sex-dependent significant increases in lean mass. Further analyses of femoral bone, using three-dimensional high resolution micro-computed tomography (µCT), confirmed a striking increase in trabecular bone mass and microarchitecture in older Esr1Nkx2-1Cre females compared to control littermates (Fig. 2a). Mutant females exhibited a ~500% increase in fractional bone volume in the distal femur, rising from 11 to 52 bone volume/tissue volume (BV/TV) (%) (Fig. 2a). A similar trend was found for vertebral bone (Supplementary Figure 3A). Accompanying structural changes included increases in trabecular number and thickness and reduced trabecular separation (Fig. 2a). Mutant females also exhibited a significant increase in cortical thickness but a modest decrease in tibial and femoral length (Supplementary Figure 3B). This striking skeletal phenotype is sex-dependent, as no changes in bone mass were observed in Esr1Nkx2-1Cre males (Fig. 2b). Further, unlike the 20% increase in femoral bone mass reported for Esr1POMC-Cre and Esr1Nestin-Cre mice that vanishes in OVX females, bone parameters in Esr1Nkx2-1Crefemales remained elevated 5 weeks following ovariectomy (Fig. 2c). In fact, no significant changes in serum sex steroids (E2, T) were detected in 4–5-week-old mutant females when the high bone mass phenotype is clearly present (Fig. 2d, f)."
"...Pituitary and thyroid hormones in mutant females were also unchanged at 7–8 weeks of age (Supplementary Figure 3C). Removing circulating androgens in juvenile Esr1Nkx2-1Cre males by castration failed to elevate their bone mass, implying that male gonadal hormones are unable to account for the lack of high bone mass in Esr1Nkx2-1Cre males (Supplementary Figure 3D). These data imply that while the high BMD in Esr1Nkx2-1Crefemales is partially maintained by ovarian steroids, elevated levels of circulating E2 or pituitary hormones are not the primary drivers of this sex-dependent bone phenotype."
"...Mechanical bone strength tests established that femora and L5 vertebrae in older Esr1Nkx2-1Cre females were substantially stronger than controls (Fig. 2e). The dense skeletal phenotype in Esr1Nkx2-1Cre females observed in femoral and vertebral trabecular bone emerged early and continued to persist in older females (54–74 weeks), exceeding values found for OVX mutant females (Fig. 2c, f, g). Thus, trabecular bone, which becomes porous and more fragile in osteoporosis, is remarkably dense and durable in older Esr1Nkx2-1Cre females. Upregulation of bone metabolism in Esr1Nkx2-1Cre females was not associated with ectopic Cre expression in femoral bone (Supplementary Figure 3F). Representative H&E stained femoral bone sections from juvenile female mice illustrate the striking increase in bone density accompanied by a marked decrease in bone marrow space (Fig. 2h). Despite a narrowing of the bone marrow cavity, no differences in spleen weights were observed in mutant females compared to controls at all ages examined (Supplementary Figure 3E)."
"...Our investigation to understand the complex role of estrogen signaling in the MBH establishes that ERα-expressing Kiss1 ARC neurons are central to restraining a powerful brain–bone axis in female mice. This assertion stems from the sex-dependent, high bone mass phenotype that emerged from three independent, intersectional strategies that target central ERα signaling. When compared with other mouse models that alter bone remodeling, several prominent features emerge from our results. In particular, the only model that, to our knowledge, rivals the magnitude of volumetric bone density increase observed in Esr1Kiss1-Cre and Esr1Nkx2-1Cre females is the sclerostin null (Sost−/−) mouse40,41. However, the Sost−/− bone phenotype is observed in both sexes and the connectivity density is substantially lower40. Moreover, we find that selectively removing ERα in the ARC of older, estrogen depleted females results in an impressive ~50% increase in bone density, indicating a potential therapeutic value in manipulating this female neuroskeletal circuit. Disrupting this neuroskeletal circuit enhances genetic pathways associated with osteogenesis and results in fully functional mature bones with exceptional strength. When considered alongside the well-established role of peripheral estrogen in the prevention of bone loss42, our findings illustrate that the same hypothalamic neurons used to restrain the onset of puberty also inhibit anabolic bone metabolism in females. We speculate that once this female ERα-dependent brain-to-bone pathway is disturbed, energetic resources are funneled into bone and diverted away from reproduction and energy expenditure (Fig. 6f)."
"...Given that prodynorphin, a marker of KNDy ARC neurons is suppressed by estrogen, but not by tamoxifen46, one might also speculate that some of the bone-sparing effects of this selective ERα modulator47 stem from its antagonist activity in the ARC."
"... That sclerostin, a known repressor of bone metabolism is elevated in Esr1Nkx2-1Cre mutants implies that their massive increase in female volumetric bone mass is independent of sclerostin. Thus, we conclude that the high bone mass in our mouse models results from activation of a potent signaling pathway that promotes bone formation by a humoral mechanism and is initiated in the brain."
"...In summary, our work reveals an unprecedented sex-dependent bone phenotype and provides unequivocal proof of brain-to-bone signaling55. Furthermore, our findings demonstrate the importance of central estrogen signaling (which exists in a coregulatory system with peripheral estrogen) in the maintenance of bone homeostasis in females. Breaking this neuroskeletal homeostatic circuit in young and old females promotes anabolic bone metabolism and provides a model for further mechanistic investigations that might eventually provide opportunities to counteract age-related osteoporosis in both women and men."
Estrogen Is NOT Needed For Either Muscle Or Bone Growth / Anabolism
Now, the study below add to the evidence that estrogen is not only not needed for muscle growth and bone health, but blocking its effects (in the brain) leads to such remarkably dense/strong bones in females (mice) that no other known model can even come close to. Simultaneously, the muscle mass of those females also increased dramatically and the authors think the two effects are not a coincidence. I don't know why the effects of blocking estrogen in males were much less pronounced than in females, but I suspect it is due to surges in progesterone activity. Progesterone is highly anabolic in females, but not so much in males. Be that as it may, hopefully this study will lead to serious reconsideration of estrogen therapy in females. The authors think that the anabolism from blocking estrogen in the brain reduces mating and physical activity in the females, and the resulting surplus of energy was diverted towards bone/muscle building. I guess it is another way of saying that stress is bad for women's bones/muscles and blocking the stress hormone (estrogen) allowed the females to grow as much as there is food available. I really see no reason why the same would not be true in males and the authors clearly state that blocking estrogen in brain would be therapeutic for both sexes even if this specific study did not find much anabolism for males.
@Blossom @tara @Sheila @AretnaP @Wagner83 @Lokzo @RisingSun @jb116 @tankasnowgod
@opethfeldt
Estrogen signaling in arcuate <i>Kiss1</i> neurons suppresses a sex-dependent female circuit promoting dense strong bones
"...Esr1Nkx2-1Cre females exhibited a sex-dependent change in energy balance that was entirely absent in male mice. The lean mass of mutant females was significantly higher than control floxed (Esr1fl/fl) littermates (Fig. 1d) and was accompanied by decreased physical activity during the dark phase (Fig. 1e and Supplementary Figure 2C). Although highly significant, increased lean mass observed in mutant females failed to change their overall mobility and muscle strength as measured by rotarod and grip strength assays, respectively (Supplementary Figure 2D, E). Blunted BAT thermogenesis was observed in mutant females as evidenced by whitening of BAT and decreased Ucp1 levels; circulating catecholamines were not lower (Fig. 1f and Supplementary Figures 2F, G). Serum leptin levels were also unchanged (Fig. 1g). Thus, these data reveal that central estrogen signaling in this brain region promotes a sex-dependent negative energy state in females in the absence of any change in feeding behavior. This unexpected finding implies that the hyperphagia reported for Esr1POMC-Cre mice might result from selective or ectopic activity of POMC-Cre in non-ARC neurons8."
"...Strikingly, bone mineral density (BMD), as determined by dual X-ray absorptiometry (DEXA), was significantly elevated in Esr1Nkx2-1Crefemales, but not males (Fig. 1h), consistent with the sex-dependent significant increases in lean mass. Further analyses of femoral bone, using three-dimensional high resolution micro-computed tomography (µCT), confirmed a striking increase in trabecular bone mass and microarchitecture in older Esr1Nkx2-1Cre females compared to control littermates (Fig. 2a). Mutant females exhibited a ~500% increase in fractional bone volume in the distal femur, rising from 11 to 52 bone volume/tissue volume (BV/TV) (%) (Fig. 2a). A similar trend was found for vertebral bone (Supplementary Figure 3A). Accompanying structural changes included increases in trabecular number and thickness and reduced trabecular separation (Fig. 2a). Mutant females also exhibited a significant increase in cortical thickness but a modest decrease in tibial and femoral length (Supplementary Figure 3B). This striking skeletal phenotype is sex-dependent, as no changes in bone mass were observed in Esr1Nkx2-1Cre males (Fig. 2b). Further, unlike the 20% increase in femoral bone mass reported for Esr1POMC-Cre and Esr1Nestin-Cre mice that vanishes in OVX females, bone parameters in Esr1Nkx2-1Crefemales remained elevated 5 weeks following ovariectomy (Fig. 2c). In fact, no significant changes in serum sex steroids (E2, T) were detected in 4–5-week-old mutant females when the high bone mass phenotype is clearly present (Fig. 2d, f)."
"...Pituitary and thyroid hormones in mutant females were also unchanged at 7–8 weeks of age (Supplementary Figure 3C). Removing circulating androgens in juvenile Esr1Nkx2-1Cre males by castration failed to elevate their bone mass, implying that male gonadal hormones are unable to account for the lack of high bone mass in Esr1Nkx2-1Cre males (Supplementary Figure 3D). These data imply that while the high BMD in Esr1Nkx2-1Crefemales is partially maintained by ovarian steroids, elevated levels of circulating E2 or pituitary hormones are not the primary drivers of this sex-dependent bone phenotype."
"...Mechanical bone strength tests established that femora and L5 vertebrae in older Esr1Nkx2-1Cre females were substantially stronger than controls (Fig. 2e). The dense skeletal phenotype in Esr1Nkx2-1Cre females observed in femoral and vertebral trabecular bone emerged early and continued to persist in older females (54–74 weeks), exceeding values found for OVX mutant females (Fig. 2c, f, g). Thus, trabecular bone, which becomes porous and more fragile in osteoporosis, is remarkably dense and durable in older Esr1Nkx2-1Cre females. Upregulation of bone metabolism in Esr1Nkx2-1Cre females was not associated with ectopic Cre expression in femoral bone (Supplementary Figure 3F). Representative H&E stained femoral bone sections from juvenile female mice illustrate the striking increase in bone density accompanied by a marked decrease in bone marrow space (Fig. 2h). Despite a narrowing of the bone marrow cavity, no differences in spleen weights were observed in mutant females compared to controls at all ages examined (Supplementary Figure 3E)."
"...Our investigation to understand the complex role of estrogen signaling in the MBH establishes that ERα-expressing Kiss1 ARC neurons are central to restraining a powerful brain–bone axis in female mice. This assertion stems from the sex-dependent, high bone mass phenotype that emerged from three independent, intersectional strategies that target central ERα signaling. When compared with other mouse models that alter bone remodeling, several prominent features emerge from our results. In particular, the only model that, to our knowledge, rivals the magnitude of volumetric bone density increase observed in Esr1Kiss1-Cre and Esr1Nkx2-1Cre females is the sclerostin null (Sost−/−) mouse40,41. However, the Sost−/− bone phenotype is observed in both sexes and the connectivity density is substantially lower40. Moreover, we find that selectively removing ERα in the ARC of older, estrogen depleted females results in an impressive ~50% increase in bone density, indicating a potential therapeutic value in manipulating this female neuroskeletal circuit. Disrupting this neuroskeletal circuit enhances genetic pathways associated with osteogenesis and results in fully functional mature bones with exceptional strength. When considered alongside the well-established role of peripheral estrogen in the prevention of bone loss42, our findings illustrate that the same hypothalamic neurons used to restrain the onset of puberty also inhibit anabolic bone metabolism in females. We speculate that once this female ERα-dependent brain-to-bone pathway is disturbed, energetic resources are funneled into bone and diverted away from reproduction and energy expenditure (Fig. 6f)."
"...Given that prodynorphin, a marker of KNDy ARC neurons is suppressed by estrogen, but not by tamoxifen46, one might also speculate that some of the bone-sparing effects of this selective ERα modulator47 stem from its antagonist activity in the ARC."
"... That sclerostin, a known repressor of bone metabolism is elevated in Esr1Nkx2-1Cre mutants implies that their massive increase in female volumetric bone mass is independent of sclerostin. Thus, we conclude that the high bone mass in our mouse models results from activation of a potent signaling pathway that promotes bone formation by a humoral mechanism and is initiated in the brain."
"...In summary, our work reveals an unprecedented sex-dependent bone phenotype and provides unequivocal proof of brain-to-bone signaling55. Furthermore, our findings demonstrate the importance of central estrogen signaling (which exists in a coregulatory system with peripheral estrogen) in the maintenance of bone homeostasis in females. Breaking this neuroskeletal homeostatic circuit in young and old females promotes anabolic bone metabolism and provides a model for further mechanistic investigations that might eventually provide opportunities to counteract age-related osteoporosis in both women and men."
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