HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.

Androgens may regulate the male skeleton either directly by stimulation of the androgen receptor (AR) or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors (ERs). To directly compare the effect of ER activation on bone in vivo with the effect of AR activation, 9-month-old orchidectomized wild-type and ER-inactivated mice were treated with the nonaromatizable androgen 5␣-dihydrotestosterone, 17␤-estradiol, or vehicle. Both ER␣ and AR but not ER␤ activation preserved the amount of trabecular bone. ER␣ activation resulted both in a preserved thickness and number of trabeculae. In contrast, AR activation exclusively preserved the number of trabeculae, whereas the thickness of the trabeculae was unaffected. Furthermore, the effects of 17␤-estradiol could not be mediated by the AR, and the effects of 5␣-dihydrotestosterone were increased rather than decreased in ER-inactivated mice. ER␣, but not AR or ER␤, activation resulted in preserved thickness, volumetric density, and mechanical strength of the cortical bone. ER␣ activation increased serum levels of insulin-like growth factor I, which were positively correlated with all the cortical and trabecular bone parameters that were specifically preserved by ER␣ activation but not by AR activation, suggesting that insulin-like growth factor I might mediate these effects of ER␣ activation. Thus, the in vivo bone-sparing effect of ER␣ activation is distinct from the bone-sparing effect of AR activation in adult male mice. Because these two pathways are clearly distinct from each other, one may speculate that a combined treatment of selective ER modulators and selective AR modulators might be beneficial in the treatment of osteoporosis. S ex steroids are important not only for the maintenance of the female skeleton, but also for the male skeleton. The relative contribution of androgens versus estrogens in the regulation of the male skeleton is unclear. Testosterone replacement therapy increases bone mineral density (BMD) in hypogonadal men (1), but several clinical studies indicate that BMD is correlated more to serum levels of estradiol than to serum levels of testosterone in males (2-4). A previous clinical study, which directly compared estrogen versus testosterone effects on bone, showed that estrogens play the dominant role in the regulation of bone resorption markers, whereas both estrogens and testosterone contribute to the maintenance of markers for bone formation (5).The effects of testosterone can be exerted either directly by means of the androgen receptor (AR) or indirectly by aromatization to estrogens and further by estrogen receptor (ER)␣ and͞or ER␤. All three sex steroid receptors are expressed both in growth-plate cartilage and in bone (6-11). Functional studies using sex steroid receptor-inactivated animal models have demonstrated that ER␣ but not ER␤ is important for the regulation of appendicular longitudinal skeletal growth in male mice (12-14), and a recent report indicates that AR-inactivate...

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Citation:Salmon PL, Ohlsson C, Shefelbine SJ and Doube M (2015) Structure model index (SMI) is widely used to measure rods and plates in trabecular bone. It exploits the change in surface curvature that occurs as a structure varies from spherical (SMI = 4), to cylindrical (SMI = 3) to planar (SMI = 0). The most important assumption underlying SMI is that the entire bone surface is convex and that the curvature differential is positive at all points on the surface. The intricate connections within the trabecular continuum suggest that a high proportion of the surface could be concave, violating the assumption of convexity and producing regions of negative differential. We implemented SMI in the BoneJ plugin and included the ability to measure the amounts of surface that increased or decreased in area after surface mesh dilation, and the ability to visualize concave and convex regions. We measured SMI and its positive (SMI + ) and negative (SMI − ) components, bone volume fraction (BV/TV), the fraction of the surface that is concave (CF), and mean ellipsoid factor (EF) in trabecular bone using 38 X-ray microtomography (XMT) images from a rat ovariectomy model of sex steroid rescue of bone loss, and 169 XMT images from a broad selection of 87 species' femora (mammals, birds, and a crocodile). We simulated bone resorption by eroding an image of elephant trabeculae and recording SMI and BV/TV at each erosion step. Up to 70%, and rarely <20%, of the trabecular surface is concave (CF 0.155-0.700). SMI is unavoidably influenced by aberrations induced by SMI − , which is strongly correlated with BV/TV and CF. The plate-to-rod transition in bone loss is an erroneous observation resulting from the close and artifactual relationship between SMI and BV/TV. SMI cannot discern between the distinctive trabecular geometries typical of mammalian and avian bone, whereas EF clearly detects birds' more plate-like trabeculae. EF is free from confounding relationships with BV/TV and CF. SMI results reported in the literature should be treated with suspicion. We propose that EF should be used instead of SMI for measurements of rods and plates in trabecular bone.