Advantage of ostarine over raloxifene and their combined treatments for muscle of estrogen-deficient rats.
Bone
Muscle
Ovariectomized rat model
Selective androgen receptor modulators (SARMs)
Selective estrogen receptor modulators (SERMs)
Journal
Journal of endocrinological investigation
ISSN: 1720-8386
Titre abrégé: J Endocrinol Invest
Pays: Italy
ID NLM: 7806594
Informations de publication
Date de publication:
06 Sep 2023
06 Sep 2023
Historique:
received:
06
07
2023
accepted:
24
08
2023
medline:
6
9
2023
pubmed:
6
9
2023
entrez:
6
9
2023
Statut:
aheadofprint
Résumé
Selective androgen (ostarine, OST) and estrogen (raloxifene, RAL) receptor modulators with improved tissue selectivity have been developed as alternatives to hormone replacement therapy. We investigated the combined effects of OST and RAL on muscle tissue in an estrogen-deficient rat model of postmenopausal conditions. Three-month-old Sprague Dawley rats were divided into groups: (1) untreated non-ovariectomized rats (Non-OVX), (2) untreated ovariectomized rats (OVX), (3) OVX rats treated with OST, (4) OVX rats treated with RAL, (5) OVX rats treated with OST and RAL. Both compounds were administered in the diet. The average dose received was 0.6 ± 0.1 mg for OST and 11.1 ± 1.2 mg for RAL per kg body weight/day. After thirteen weeks, rat activity, muscle weight, structure, gene expression, and serum markers were analyzed. OST increased muscle weight, capillary ratio, insulin-like growth factor 1 (Igf-1) expression, serum phosphorus, uterine weight. RAL decreased muscle weight, capillary ratio, food intake, serum calcium and increased Igf-1 and Myostatin expression, serum follicle stimulating hormone (FSH). OST + RAL increased muscle nucleus ratio, uterine weight, serum phosphorus, FSH and luteinizing hormone and decreased body and muscle weight, serum calcium. Neither treatment changed muscle fiber size. OVX increased body and muscle weight, decreased uterine weight, serum calcium and magnesium. OST had beneficial effects on muscle in OVX rats. Side effects of OST on the uterus and serum electrolytes should be considered before using it for therapeutic purposes. RAL and RAL + OST had less effect on muscle and showed endocrinological side effects on pituitary-gonadal axis.
Identifiants
pubmed: 37672168
doi: 10.1007/s40618-023-02188-z
pii: 10.1007/s40618-023-02188-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SE 1966/6-1
Organisme : Deutsche Forschungsgemeinschaft
ID : KO 4646/3-1
Informations de copyright
© 2023. The Author(s).
Références
Ikeda K, Horie-Inoue K, Inoue S (2019) Functions of estrogen and estrogen receptor signaling on skeletal muscle. J Steroid Biochem Mol Biol 191:105375
pubmed: 31067490
doi: 10.1016/j.jsbmb.2019.105375
Hernlund E, Svedbom A, Ivergard M et al (2013) Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos. 8:136
pubmed: 24113837
pmcid: 3880487
doi: 10.1007/s11657-013-0136-1
Cruz-Jentoft AJ, Bahat G, Bauer J et al (2019) Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48(1):16–31
pubmed: 30312372
doi: 10.1093/ageing/afy169
Barbonetti A, D’Andrea S, Francavilla S (2020) Testosterone replacement therapy. Andrology 8(6):1551–1566
pubmed: 32068334
doi: 10.1111/andr.12774
Palacios S, Mejias A (2015) An update on drugs for the treatment of menopausal symptoms. Expert Opin Pharmacother 16(16):2437–2447
pubmed: 26395223
doi: 10.1517/14656566.2015.1085508
Stuenkel CA (2015) Menopausal hormone therapy: current considerations. Endocrinol Metab Clin North Am 44(3):565–585
pubmed: 26316244
doi: 10.1016/j.ecl.2015.05.006
Huang L-T, Wang J-H (2021) The therapeutic intervention of sex steroid hormones for sarcopenia. Front Med. https://doi.org/10.3389/fmed.2021.739251
doi: 10.3389/fmed.2021.739251
pubmed: 34792736
pmcid: 8302972
Rossouw JE, Anderson GL, Prentice RL et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333
pubmed: 12117397
doi: 10.1001/jama.288.3.321
Bhasin S, Calof OM, Storer TW et al (2006) Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2(3):146–159
pubmed: 16932274
pmcid: 2072878
doi: 10.1038/ncpendmet0120
Christiansen AR, Lipshultz LI, Hotaling JM, Pastuszak AW (2020) Selective androgen receptor modulators: the future of androgen therapy? Transl Androl Urol 9(Suppl 2):S135–S148
pubmed: 32257854
pmcid: 7108998
doi: 10.21037/tau.2019.11.02
Roch PJ, Henkies D, Carstens JC et al (2020) Ostarine and ligandrol improve muscle tissue in an ovariectomized rat model. Front Endocrinol (Lausanne) 11:556581
pubmed: 33042018
doi: 10.3389/fendo.2020.556581
Roch PJ, Wolgast V, Gebhardt MM et al (2022) Combination of selective androgen and estrogen receptor modulators in orchiectomized rats. J Endocrinol Invest 45(8):1555–1568
pubmed: 35429299
pmcid: 9270269
doi: 10.1007/s40618-022-01794-7
Crawford J, Prado CM, Johnston MA et al (2016) Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials). Curr Oncol Rep 18(6):37
pubmed: 27138015
pmcid: 4853438
doi: 10.1007/s11912-016-0522-0
Dalton JT, Barnette KG, Bohl CE et al (2011) The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle 2(3):153–161
pubmed: 22031847
pmcid: 3177038
doi: 10.1007/s13539-011-0034-6
Dobs AS, Boccia RV, Croot CC et al (2013) Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol 14(4):335–345
pubmed: 23499390
pmcid: 4898053
doi: 10.1016/S1470-2045(13)70055-X
Jacobsen DE, Samson MM, Emmelot-Vonk MH, Verhaar HJ (2010) Raloxifene and body composition and muscle strength in postmenopausal women: a randomized, double-blind, placebo-controlled trial. Eur J Endocrinol 162(2):371–376
pubmed: 19884264
doi: 10.1530/EJE-09-0619
Wu B, Shah SN, Lu P et al (2018) Long-term treatment of tamoxifen and raloxifene alleviates dystrophic phenotype and enhances muscle functions of FKRP dystroglycanopathy. Am J Pathol 188(4):1069–1080
pubmed: 29571322
doi: 10.1016/j.ajpath.2017.12.011
Stuermer EK, Sehmisch S, Tezval M et al (2009) Effect of testosterone, raloxifene and estrogen replacement on the microstructure and biomechanics of metaphyseal osteoporotic bones in orchiectomized male rats. World J Urol 27(4):547–555
pubmed: 19221760
pmcid: 2720581
doi: 10.1007/s00345-009-0373-5
Komrakova M, Rechholtz C, Pohlmann N et al (2019) Effect of alendronate or 8-prenylnaringenin applied as a single therapy or in combination with vibration on muscle structure and bone healing in ovariectomized rats. Bone Rep 11:100224
pubmed: 31516917
pmcid: 6728878
doi: 10.1016/j.bonr.2019.100224
Paylor R, Spencer CM, Yuva-Paylor LA, Pieke-Dahl S (2006) The use of behavioral test batteries, II: effect of test interval. Physiol Behav 87(1):95–102
pubmed: 16197969
doi: 10.1016/j.physbeh.2005.09.002
Andersen P (1975) Capillary density in skeletal muscle of man. Acta Physiol Scand 95(2):203–205
pubmed: 127508
doi: 10.1111/j.1748-1716.1975.tb10043.x
Horak V (1983) A successive histochemical staining for succinate dehydrogenase and “reversed”-ATPase in a single section for the skeletal muscle fibre typing. Histochemistry 78(4):545–553
pubmed: 6225754
doi: 10.1007/BF00496207
Stein KH, Flenker H, Medizin DVTAid. Basiswissen Histologie und Zytologie: Lehr- und Arbeitsbuch ; mit 12 Tabellen: Hoppenstedt Zeitschriften; 2004.
Peter JB, Barnard RJ, Edgerton VR, Gillespie CA, Stempel KE (1972) Metabolic profiles of three fiber types of skeletal muscle in guinea pigs and rabbits. Biochemistry 11(14):2627–2633
pubmed: 4261555
doi: 10.1021/bi00764a013
Schwartz-Giblin S, Rosello L, Pfaff DW (1983) A histochemical study of lateral longissimus muscle in rat. Exp Neurol 79(2):497–518
pubmed: 6217980
doi: 10.1016/0014-4886(83)90229-7
Armstrong RB, Phelps RO (1984) Muscle fiber type composition of the rat hindlimb. Am J Anat 171(3):259–272
pubmed: 6517030
doi: 10.1002/aja.1001710303
Staron RS, Kraemer WJ, Hikida RS, Fry AC, Murray JD, Campos GE (1999) Fiber type composition of four hindlimb muscles of adult Fisher 344 rats. Histochem Cell Biol 111(2):117–123
pubmed: 10090572
doi: 10.1007/s004180050341
Saul D, Harlas B, Ahrabi A et al (2018) Effect of strontium ranelate on the muscle and vertebrae of ovariectomized rats. Calcif Tissue Int 102(6):705–719
pubmed: 29242963
doi: 10.1007/s00223-017-0374-0
Spandidos A, Wang X, Wang H, Seed B. PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res. 2010;38(Database issue):D792–9.
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408
pubmed: 11846609
doi: 10.1006/meth.2001.1262
Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (1997) Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology 138(11):4613–4621
pubmed: 9348186
doi: 10.1210/endo.138.11.5496
Murata Y, Robertson KM, Jones ME, Simpson ER (2002) Effect of estrogen deficiency in the male: the ArKO mouse model. Mol Cell Endocrinol 193(1–2):7–12
pubmed: 12160996
doi: 10.1016/S0303-7207(02)00090-4
Rochira V, Kara E, Carani C (2015) The endocrine role of estrogens on human male skeleton. Int J Endocrinol 2015:165215
pubmed: 25873947
pmcid: 4383300
doi: 10.1155/2015/165215
Hoffmann DB, Komrakova M, Pflug S et al (2019) Evaluation of ostarine as a selective androgen receptor modulator in a rat model of postmenopausal osteoporosis. J Bone Miner Metab 37(2):243–255
pubmed: 29785666
doi: 10.1007/s00774-018-0929-9
Komrakova M, Furtwangler J, Hoffmann DB, Lehmann W, Schilling AF, Sehmisch S (2020) The selective androgen receptor modulator ostarine improves bone healing in ovariectomized rats. Calcif Tissue Int 106(2):147–157
pubmed: 31531719
doi: 10.1007/s00223-019-00613-1
Butera PC (2010) Estradiol and the control of food intake. Physiol Behav 99(2):175–180
pubmed: 19555704
doi: 10.1016/j.physbeh.2009.06.010
Kearbey JD, Gao W, Narayanan R et al (2007) Selective Androgen Receptor Modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharm Res 24(2):328–335
pubmed: 17063395
doi: 10.1007/s11095-006-9152-9
Hoyt JA, Fisher LF, Swisher DK, Byrd RA, Francis PC (1998) The selective estrogen receptor modulator, raloxifene: reproductive assessments in adult male rats. Reprod Toxicol 12(3):223–232
pubmed: 9628547
doi: 10.1016/S0890-6238(98)00004-5
Simitsidellis I, Esnal-Zuffiaure A, Kelepouri O, O’Flaherty E, Gibson DA, Saunders PTK (2019) Selective androgen receptor modulators (SARMs) have specific impacts on the mouse uterus. J Endocrinol 242(3):227–239
pubmed: 31319382
pmcid: 6690265
doi: 10.1530/JOE-19-0153
Kadi F, Karlsson C, Larsson B et al (2002) The effects of physical activity and estrogen treatment on rat fast and slow skeletal muscles following ovariectomy. J Muscle Res Cell Motil 23(4):335–339
pubmed: 12630708
doi: 10.1023/A:1022071114344
Wade GN (1972) Gonadal hormones and behavioral regulation of body weight. Physiol Behav 8(3):523–534
pubmed: 4556652
doi: 10.1016/0031-9384(72)90340-X
Furuya K, Yamamoto N, Ohyabu Y et al (2013) Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479. Biol Pharm Bull 36(3):442–451
pubmed: 23449329
doi: 10.1248/bpb.b12-00885
Schmidt A, Kimmel DB, Bai C et al (2010) Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology. J Biol Chem 285(22):17054–17064
pubmed: 20356837
pmcid: 2878020
doi: 10.1074/jbc.M109.099002
Grese TA, Sluka JP, Bryant HU et al (1997) Molecular determinants of tissue selectivity in estrogen receptor modulators. Proc Natl Acad Sci U S A 94(25):14105–14110
pubmed: 9391160
pmcid: 28440
doi: 10.1073/pnas.94.25.14105
Leciejewska N, Kolodziejski PA, Sassek M, Nogowski L, Malek E, Pruszynska-Oszmalek E (2022) Ostarine-induced myogenic differentiation in C2C12, L6, and rat muscles. Int J Mol Sci 23(8):4404
pubmed: 35457222
pmcid: 9031805
doi: 10.3390/ijms23084404
Dorchies OM, Reutenauer-Patte J, Dahmane E et al (2013) The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy. Am J Pathol 182(2):485–504
pubmed: 23332367
doi: 10.1016/j.ajpath.2012.10.018
Shen HH, Yang CY, Kung CW et al (2019) Raloxifene inhibits adipose tissue inflammation and adipogenesis through Wnt regulation in ovariectomized rats and 3 T3–L1 cells. J Biomed Sci 26(1):62
pubmed: 31470850
pmcid: 6717377
doi: 10.1186/s12929-019-0556-3
Komrakova M, Hoffmann DB, Nuehnen V et al (2016) The effect of vibration treatments combined with teriparatide or strontium ranelate on bone healing and muscle in ovariectomized rats. Calcif Tissue Int 99(4):408–422
pubmed: 27272029
doi: 10.1007/s00223-016-0156-0
Tesch PA, Wright JE, Vogel JA, Daniels WL, Sharp DS, Sjodin B (1985) The influence of muscle metabolic characteristics on physical performance. Eur J Appl Physiol Occup Physiol 54(3):237–243
pubmed: 4065107
doi: 10.1007/BF00426139
Wagner PD (2011) The critical role of VEGF in skeletal muscle angiogenesis and blood flow. Biochem Soc Trans 39(6):1556–1559
pubmed: 22103486
doi: 10.1042/BST20110646
Komrakova M, Werner C, Wicke M et al (2009) Effect of daidzein, 4-methylbenzylidene camphor or estrogen on gastrocnemius muscle of osteoporotic rats undergoing tibia healing period. J Endocrinol 201(2):253–262
pubmed: 19273502
doi: 10.1677/JOE-08-0521
Schiefer S. Einfluss der Ganzkörpervibration in Kombination mit Östrogen und Raloxifen auf die Skelettmuskulatur der ovarektomierten Ratte (Influence of whole-body vibration in combination with estrogen and raloxifene on the skeletal muscles of the ovariectomized rat) [Doctoral Thesis]. Göttingen: Universität Göttingen, Medizinische Fakultät; 2018.
Bhasin S, Jasuja R (2009) Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care 12(3):232–240
pubmed: 19357508
pmcid: 2907129
doi: 10.1097/MCO.0b013e32832a3d79
Musaro A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N (1999) IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400(6744):581–585
pubmed: 10448862
doi: 10.1038/23060
Tsai WJ, McCormick KM, Brazeau DA, Brazeau GA (2007) Estrogen effects on skeletal muscle insulin-like growth factor 1 and myostatin in ovariectomized rats. Exp Biol Med (Maywood) 232(10):1314–1325
pubmed: 17959844
doi: 10.3181/0704-RM-92
Jasuja R, LeBrasseur NK (2014) Regenerating skeletal muscle in the face of aging and disease. Am J Phys Med Rehabil 93(11 Suppl 3):S88-96
pubmed: 24879554
doi: 10.1097/PHM.0000000000000118
Roth SM, Walsh S (2004) Myostatin: a therapeutic target for skeletal muscle wasting. Curr Opin Clin Nutr Metab Care 7(3):259–263
pubmed: 15075916
doi: 10.1097/00075197-200405000-00004
de Araujo LF, Grozovsky R, de Campos PM, de Carvalho JJ, Vaisman M, Carvalho DP (2008) Raloxifene effects on thyroid gland morphology in ovariectomized rats. Fertil Steril 90(4):1211–1214
pubmed: 18178201
doi: 10.1016/j.fertnstert.2007.10.046
Komrakova M, Nagel J, Hoffmann DB, Lehmann W, Schilling AF, Sehmisch S (2020) Effect of selective androgen receptor modulator enobosarm on bone healing in a rat model for aged male osteoporosis. Calcif Tissue Int. https://doi.org/10.1007/s00223-020-00751-x
doi: 10.1007/s00223-020-00751-x
pubmed: 32876707
pmcid: 7593387
Shahida S, Rehman S, Ilyas N et al (2021) Determination of blood calcium and lead concentrations in osteoporotic and osteopenic patients in pakistan. ACS Omega 6(42):28373–28378
pubmed: 34723034
pmcid: 8552473
doi: 10.1021/acsomega.1c04565
Khosla S, Oursler MJ, Monroe DG (2012) Estrogen and the skeleton. Trends Endocrinol Metab 23(11):576–581
pubmed: 22595550
pmcid: 3424385
doi: 10.1016/j.tem.2012.03.008
Moe SM. Disorders involving calcium, phosphorus, and magnesium. Prim Care. 2008;35(2):215–37, v-vi.
Komulainen J, Kytola J, Vihko V (1994) Running-induced muscle injury and myocellular enzyme release in rats. J Appl Physiol 77(5):2299–2304
pubmed: 7868448
doi: 10.1152/jappl.1994.77.5.2299
Davis SR, Lambrinoudaki I, Lumsden M et al (2015) Menopause Nat Rev Dis Primers 1:15004
pubmed: 27188659
doi: 10.1038/nrdp.2015.4
Pinilla L, Gonzalez LC, Tena-Sempere M, Aguilar E (2001) Evidence for an estrogen-like action of raloxifene upon the hypothalamic-pituitary unit: raloxifene inhibits luteinizing hormone secretion and stimulates prolactin secretion in ovariectomized female rats. Neurosci Lett 311(3):149–152
pubmed: 11578816
doi: 10.1016/S0304-3940(01)02104-8
Luderer U, Schwartz NB (1994) Acute changes in pulsatile LH and FSH secretion after ovariectomy in rats: treatment with oestradiol for 24 h suppresses LH, but not FSH, for at least 48 h. J Reprod Fertil 100(2):613–621
pubmed: 8021884
doi: 10.1530/jrf.0.1000613
Gao W, Reiser PJ, Coss CC et al (2005) Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats. Endocrinology 146(11):4887–4897
pubmed: 16099859
doi: 10.1210/en.2005-0572
Bhasin S (2015) Selective androgen receptor modulators as function promoting therapies. J Frailty Aging 4(3):121–122
pubmed: 27030938
pmcid: 6039107
Bhasin S, Storer TW, Berman N et al (1996) The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 335(1):1–7
pubmed: 8637535
doi: 10.1056/NEJM199607043350101