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[Guidelines for drug therapy of postmenopausal osteoporosis].

Osteoporosis is known as a condition characterized by low bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and a consequent susceptibility to fracture. Osteoporosis has its highest rate of occurrence in postmenopausal women, and in Western countries it has been estimated that for white women aged fifty, the life-time risk of developing an osteoporotic fracture is nearly 40%. Given the consequences of osteoporosis, the most important goal of therapy is to prevent fractures. In Austria, several pharmacologic options for treatment of osteoporosis are available, including bisphosphonates (alendronate, etidronate, risedronate), selective estrogen receptor modulators (raloxifene), calcitonins (salm-calcitonin, elcatonin), fluorides (sodium-fluoride, monofluorophosphate), anabolic steroids (nandrolone-decanoate), steroid derivates (tibolone), estrogen and hormone replacement therapy. An evidence-based evaluation of these treatment options clearly indicates that alendronate, risedronate and raloxifene sufficiently reduce the risk of vertebral fractures. There is less evidence for reduction of vertebral fracture risk for etidronate, calcitonin, estrogen replacement therapy or hormone replacement therapy. Only alendronate and risedronate have been shown to reduce the risk of hip fractures. Calcium and vitamin D are useful adjuncts to any specific treatment for osteoporosis, particularly when Calcium and vitamin D deficiencies have been diagnosed. Also, there is good evidence that in women with Calcium and vitamin D deficiency, a combination of Calcium and vitamin D may reduce the risk of non-vertebral fractures. There is no evidence so far that a combination therapy of antiresorptive drugs would result in reduced fracture risk.

Adult↗

Assessment of hormonally active agents in the reproductive tract of female nonhuman primates.

Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks-3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fibrosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents.

Animals↗

Combination treatment of osteoporosis: a clinical review.

OBJECTIVE: Because of the limited efficacy of available agents and to limit toxicity, there is considerable interest in combination pharmacotherapy for osteoporosis. METHODS: A search was performed for randomized controlled trials in MEDLINE (1966-present) using the keywords osteoporosis treatment and combination. RESULTS: Twenty-four randomized controlled trials evaluated osteoporosis medications in combination. Study duration ranged from 1 to 4 years. No serious adverse events were definitively attributable to study drugs. Fracture reduction outcome is not shown for any combination regimen. The literature was mixed regarding bone density augmentation. Combinations of nandrolone decanoate plus calcitonin, calcitonin plus growth hormone (GH), or pamidronate plus GH may be contradictory or detrimental to bone mineral density (BMD). For postmenopausal osteoporosis or osteopenia, four combinations appear to increase hip and lumbar BMD: 10 mg alendronate with 0.625 mg conjugated equine estrogens (CEE), cyclic etidronate with 0.625mg CEE, 10 mg alendronate with 2 mg estradiol (E(2)), and tibolone with fluoride. For steroid-related osteoporosis, intermittent etidronate with fluoride increases lumbar BMD. CONCLUSIONS: The few trials including Food and Drug Administration (FDA)-approved medications suggest that 10 mg/day alendronate with estrogen (equivalent of 0.625 mg CEE daily) can increase BMD moreso than each medication given singly in postmenopausal osteoporotic women. Estrogen dose and type must be controlled in future trials. Long-term safety data are lacking. The utility of these combinations rests on whether bone density changes will translate into decreased fracture rates.

Alendronate↗

Intravenous erythropoietin (rHuEPO) administration increases plasma endothelin and blood pressure in hemodialysis patients.

The correction of anemia in end stage renal disease with recombinant human erythropoietin (rHuEPO) is associated with hypertension in about a third of hemodialysis patients. In the present study, we investigated the role of endothelin (ET-1) on rHuEPO associated hypertension and the effect of the rHuEPO administration route on plasma ET-1 levels. We studied 50 stable chronic hemodialysis patients who were divided into three groups: 26 patients received rHuEPO intravenously (IV) and 21 subcutaneously (SC). The control group was nine patients who were treated with nandrolone decanoate (ND). Prehemodialysis ET-1 plasma levels were correlated with mean arterial pressure (MAP), hematocrit (Hct), time on dialysis, and rHuEPO doses. The antihypertensive therapeutic index (ATI) was used to determine the changes in blood pressure medication intake. We observed that the ET-1 levels were significantly higher in the IV group (19.3 +/- 2) than the SC (5.0 +/- 0.6) or ND groups (3.6 +/- 0.4 pg/mL) (P < 0.001, IV v SC or ND). After IV rHuEPO treatment, there were increases in both MAP (pre- v post-rHuEPO, P < .001) and in ATI (pre- v post-rHuEPO, P < .001). In the SC group, the increases in MAP and ATI were not significant. Only the IV group showed a significant correlation between MAP and ET-1 levels (r = .05, P = .02). To accomplish the same Hct, the IV group received higher rHuEPO doses than those of the SC (180 +/- 15 v 87 +/- 12 U/kg/week) (P < .001). No significant correlations were found between the plasma ET-1 levels and Hct, time on dialysis and rHuEPO doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Over-the-counter delta5 anabolic steroids 5-androsen-3,17-dione; 5-androsten-3beta, 17beta-diol; dehydroepiandrosterone; and 19-nor-5-androsten-3,17-dione: excretion studies in men.

Studies of urinary steroids were performed in males after oral administration of 5-androsten-3,17-dione; 5-androsten-3beta,17beta-diol; dehydroepiandrosterone; and 19-nor-5-androsten-3,17-dione. 5-Androsten-3,17-dione; 5-androsten-3beta,17beta-diol; and dehydroepiandrosterone amplify most endogenous steroids, but to a lesser extent than their delta4 analogues do. Especially affected are androsterone, etiocholanolone, dehydroandrosterone, dehydroepiandrosterone, and isomeric 5-androstendiols. 5-Androsten-3,17-dione; 5-androsten-3beta,17beta-diol; and dehydroepiandrosterone elevate the urinary testosterone to epitestosterone (T/E) ratio by a factor of 2-3 a few hours after administration. This may cause a positive T/E test (> 6) for individuals with normal T/E ratios higher than 2. Most of the steroids return to their original concentrations in less than 24 h. Etiocholanolone and 5beta-androstan-3alpha,17beta-diol remain elevated for several days. A reduced androsterone to etiocholanolone (A/E) ratio may be an indication of delta5 steroids abuse. 19-Nor-5-androsten-3,17-dione has a similar effect, except that all metabolites in urine are 19-nor exogenous steroids. Identification criteria for 19-nor-5-androsten-3,17-dione may be the same as nandrolone, that is, detection of 19-norandrosterone and 19-noretiocholanolone. Specific abundant metabolites of 19-nor-5-androsten-3,17-dione are 19-nordehydroandrosterone and 19-nordehydroepiandrosterone. In the later stages of excretion, higher concentration of 1 9-noreticholanolone relative to 19-norandrosterone specifically indicates administration of 19-nor delta5 steroids.

Adult↗

Corneal wound healing in the rabbit eye: activity of a fibronectin-splitting product.

The corneal wound-healing properties of fibronectin (FN) and a fibronectin hydrolysate (FNH) have been evaluated in comparison with commonly used drugs. Nonpenetrating bilateral surgical keratectomy was performed in male albino rabbits. The left eye was treated with the active product, whereas the right eye served as a control (vehicle). The healing area was measured by planimetry after fluorescein staining at 0, 24, 48, and 72 h after keratectomy. Histological and immunohistochemical analysis of the healing process was also performed. Results were as follows: (a) Nandrolone (p < 0.005) and asiaticoside (p < 0.001), both at 10 mg/ml, in eyedrops delayed the healing process. (b) An ointment containing vitamin A and amino acids also delayed the process but at the limit of statistical significance (p = 0.055). (c) FNH (20-80 mg prot/ml) significantly improved the quality and shortened the time of the healing process at 60 mg prot/ml and above. (d) Human FN (100-800 micrograms/ml) did not affect the healing process. Immunohistochemical analysis demonstrated that FNH accelerated the appearance of endogenous FN in the damaged cornea earlier than in the control eyes. It is concluded that FNH may be useful in the management of corneal wounds, whereas the effectiveness of FN is doubtful.

Animals↗

Treatment of intractable pruritus in drug induced cholestasis with albumin dialysis: a report of two cases.

Cholestatic liver injury can be caused by a variety of drugs and is difficult to treat. We report two patients, a 22 year old male and a 55 year old female, with drug induced cholestasis caused by anabolic-androgenic steroids (silabolin and nandrolone) and by fluoxetine, respectively. Both patients presented with massive jaundice and severe pruritus resulting in sleep deprivation and suicide ideation. Laboratory examination revealed signs of cholestasis. Medical treatment was ineffective; therefore, extracorporeal albumin dialysis using the molecular adsorbent recirculating system (MARS) was started. Three treatments with a mean duration of 16 hours were performed in each patient. The procedure was well tolerated by the patients and resulted in a sustained relief of pruritus as well as in a decline of plasma bilirubin and serum 3alpha-hydroxy bile acid levels. The mean plasma bilirubin concentration decreased from 25.27 mg/dl to 10.7 mg/dl; the mean serum 3alpha-hydroxy bile acid concentration decreased from 299 micromol/L to 88 micromol/L. After 2 months, the pruritus had nearly vanished in both patients, and there was a further decline of bilirubin levels after discharge from hospital. In conclusion, extracorporeal albumin dialysis appears to be a therapeutic option in severe drug induced cholestasis refractory to medical treatment.

Adult↗

Nutritional treatment of bone fracture.

PURPOSE OF REVIEW: Osteoporosis and sarcopenia are nutrition-related risk factors for bone fracture and delayed recuperation from fracture. The purpose of this review was to summarize recent studies that evaluated the effect of the nutritional or anabolic treatment of patients with osteoeporotic, e.g. hip, fractures. RECENT FINDINGS: Four short-term supplementation trials reported trends for improved nutritional and functional status. A high dropout rate and low compliance contributed to negative deductions. The latest Cochrane update on hip fracture aftercare sticks to its previous conclusion that multinutrient feeds reduce the incidence of unfavourable outcomes, i.e. mortality and complications combined. Nandrolone in combination with liquid supplementation improved lean body mass, activities of daily living function and quality of life, effects reported to be partly similar for growth hormone treatment. Bone resorption decreased on 12 months' liquid supplementation in community dwelling osteoporotic individuals. A high protein intake was associated with a lower risk of hip fracture. Calcium and vitamin D supplementation remain the basic prevention for osteoporotic fractures. SUMMARY: Recent supplementation studies appeared to be underpowered or suffered logistic problems, but previous recommendations for multinutrient feeding in hip fracture aftercare remain. Supplementation trials of higher scientific quality are needed, and enteral feeding, anabolic treatment and multimodal approaches need to be evaluated further.

Anabolic Agents↗

Corticoids and cultured human epidermal keratinocytes: specific intracellular binding and clinical efficacy.

Cytosol of cultured human epidermal keratinocytes contains macromolecules, that bind corticoids with high affinity. Binding constants were in the same range for cultured keratinocytes originating from different individuals and did not change during serial cell cultivation. At 0 degree C and using 3H-triamcinolone acetonide as ligand, we obtained the following values; apparent Bmax = 160- 250 fmoles/mg protein and Kdiss = 3.1-5.0 nM; with 3H-dexamethasone Bmax = 200-350 fmoles/mg protein, Kdiss = 6.0-11.1 nM, and with 3H-hydrocortisone Bmax = 140-220 fmoles/mg protein, Kdiss = 17-25 nM. There was an indication that the binding capacity of the receptor system is higher the younger the age of the skin donor. A number of steroids and corticoids commonly used in dermatological practice were tested with respect to displacement of 3H-triamcinolone acetonide, 3H-dexamethasone, and 3H-hydrocortisone from binding sites in cytosol. Good correlation between clinical efficacy and specific binding was observed for all 3 ligands. Other steroids such as 17-beta estradiol and nandrolone did not show any affinity for the corticoid binding system. Progesterone displace 3H-corticoids from their binding sites, but the IC50 was of one order of magnitude larger.

Adrenal Cortex Hormones↗

Therapeutic drug monitoring of atazanavir: surveillance of pharmacotherapy in the clinic.

BACKGROUND: Therapeutic failure with antiretroviral therapy (ART) is a substantial issue where viral rebound, viral resistance and drug-related toxicity remain serious concerns. Drug exposure-response relationships have been described for the protease inhibitors, pharmacokinetic variability is substantial for this class of drugs and drug interactions can also alter ART exposure. Given this background we established a therapeutic drug monitoring (TDM) service to monitor atazanavir (ATV) plasma concentrations early after the therapy was made available to treatment-experienced people infected with HIV who were managed in a clinical setting. METHODS: This was a prospective observational study which evaluated plasma samples from 110 highly treatment-experienced people with HIV using TDM and applied pharmacokinetic analysis over a five month period. RESULTS: ATV trough concentrations exhibited substantial intersubject variability (<25-2108 microg l(-1)). A substantial number of subjects (50%,13/26) who received ATV400 mg daily had low exposure to ATV. Serum bilirubin concentrations correlated significantly with higher ATV trough concentrations (rho = 0.803; P < 0.001) and 55% (29/53) of subjects who received ATV300/100 mg RTV daily had plasma concentrations above a proposed target concentration associated with elevated bilirubin concentrations. This study confirmed low ATV exposure in eight subjects with HIV receiving ATV 400 mg daily. Reasons for low ATV exposure in this cohort include administration of interacting drugs, including a possible interaction with ritonavir, fluticasone and ATV, impaired ATV absorption secondary to suspected achlorhydria and potential interactions with colchicine and nandrolone. Viral load remained undetectable in most of these subjects with low ATV exposure. CONCLUSIONS: TDM and targeted pharmacokinetic studies should be viewed as fundamental tools in the development and clinical application of ART, to improve pharmacotherapy for people with HIV.

Adult↗

Androstane therapy to treat aplastic anaemia in adults: an uncontrolled pilot study.

During the past 9 years, 43 adult patients with severe aplastic anaemia have been treated with a combination of 3 alpha etiocholanolone and nandrolone decanoate in an uncontrolled pilot study. Eleven patients were considered acute and the remainder as chronic severe aplasia. 50% (22 patients) had a haematopoietic recovery and 40% have had a sustained remission varying from 1.5 to 8 years. Three patients who did not respond to 3 alpha etiocholanolone had a haematologic response when treated with the isomer 3 beta etiocholanolone. The recovery did not appear to be associated with age or duration of marrow aplasia. In view of the reproducible chemical structure of these androstanes, we believe this group of steroids should be evaluated further in the treatment of severe aplastic anaemia.

Acute Disease↗

Correction of anaemia and thrombocytopenia in a case of adult type I osteopetrosis with recombinant human erythropoietin (rHuEPO).

A case of adult osteopetrosis Type I was diagnosed in a 22-year-old female. She presented for investigation of anaemia with 'myelophthisic' characteristics and extramedullary haemopoiesis which was resistant to haematinics, nandrolone and low-dose corticosteroids. She became progressively transfusion-dependent with gradually worsening thrombocytopenia. She was successfully treated with recombinant erythropoietin. Anaemia as well as thrombocytopenia were corrected. There appeared to be a synergistic action of erythropoietin with steroids.

Adult↗

Hormonal adjuvants for the treatment of renal anaemia.

Hormonal adjuvants, besides being erythropoietic agents, broaden the spectrum of therapeutic options for the treatment of the anaemia of chronic kidney disease (CKD). Lowering elevated parathyroid hormone levels by oral calcium supplementation and phosphate restriction, by varying dialysate calcium concentrations, by administration of vitamin D3 derivatives and, in the near future, by treatment with calcimimetics may prove efficient in some patients to fight extensive requirements of erythropoietic agents. Clinical evidence for a principal role of secondary hyperparathyroidism in resistance to erythropoietin, however, is lacking. Active vitamin D3 derivatives, in addition to their beneficial effects on secondary hyperparathyroidism, appear to exert a direct, stimulatory action on erythroid precursor cells and possibly also an inhibitory action on collagen synthesis by bone marrow stromal cells. Growth hormone (GH) induces insulin-like growth factor (IGF)-1, which in turn counteracts apoptosis similarly to erythropoietin, and fosters proliferation of burst- and colony-forming units-erythroid (BFU-E, CFU-E). If erythropoietic agents improve survival of CKD patients, a similar benefit should apply for strategies that increase synthesis and bioavailabilty of IGF-1. The latter appears to be reduced in CKD patients, and zinc supplementation potentially enhances it via an increase in free IGF-1. Finally, androgens also exert anti-anaemic effects. Nandrolone decanoate constitutes the only androgen currently applicable for selected male dialysis patients over the age of 50 years. It should not be given to women, however, because of serious side effects. Collectively, hormonal interventions offer the potential to reduce requirements of erythropoietic agents, and some may also improve physical performance.

Adjuvants, Pharmaceutic↗

Abnormality of platelet size and T-lymphocyte proliferation in an autosomal recessive form of dyskeratosis congenita.

Dyskeratosis congenita (DC) is a rare familial hematologic disorder that has various modes of inheritance. We have studied 2 siblings with DC. 1 sibling had thrombocytopenia, which responded to therapy with nandrolone decanoate and oxymetholone. Platelets were abnormally small, which indicates that a qualitatively abnormal megakaryocytopoiesis is a feature of DC. Myeloid and erythroid progenitors in specimens of the blood and bone marrow from both siblings were either absent or greatly reduced in numbers. The qualitatively abnormal megakaryocytopoiesis, and the quantitative abnormality of hematopoietic progenitor cells committed to myelopoiesis and erythropoiesis, indicates involvement of the pluripotent stem cell in DC. Cytogenetic studies of the bone marrow and peripheral blood lymphocytes from these patients showed normal karyotypes, a normal sister chromatid exchange frequency, and a rapid proliferation of peripheral T lymphocytes, a feature of the disorder that has not been reported previously.

Blood Platelets↗

Anabolic steroids alter the haemodynamic effects of endurance training and deconditioning in rats.

The haemodynamic effects of endurance training with or without anabolic steroid treatment (nandrolone decanoate, 5.0 mg kg-1 week-1) were studied before and after a six-week sedentary period in anaesthetized, open-chest rats during isoproterenol and CaCl2 loads. In comparison to the control group (CG I, n = 13) endurance training (TG I, n = 10) increased the resting stroke index significantly, end-diastolic pressure and during CaCl2 infusion the end-diastolic and end-systolic volumes. Peripheral resistance decreased in TG I during both inotropic loads but increased in CG I (P less than 0.01 between the groups). After combined endurance training and anabolic steroid treatment (TSG I, n = 16) the haemodynamic state was similar to that in CG I except peripheral resistance which was even higher than in CG I. The heart weight to body weight ratio was significantly greater both in TG I and TSG I than in CG I. After a six-week deconditioning period the haemodynamic values were essentially similar in endurance trained (TG II, n = 10) and in control rats (CG II, n = 12). After the sedentary period, in the simultaneously trained and anabolic steroid-treated group (TSG II, n = 13) stroke index and end-diastolic volume decreased more during isoproterenol load when compared with TG II or CG II (P less than 0.05 between the groups). Peripheral resistance was higher in the TSG II than in the two other groups. In conclusion, the enhanced pumping performance of the heart by increased left ventricular diastolic filling after endurance training is attenuated by simultaneous anabolic steroid treatment which further increases the peripheral resistance. Detraining reversed the main training effects in six weeks and simultaneous anabolic steroid treatment led to a decreased left ventricular filling and to elevated peripheral resistance after the sedentary period.

Anabolic Agents↗

Significance of 19-norandrosterone in athletes' urine samples.

Nandrolone and other 19-norsteroid potent anabolic steroids have been prohibited in sports for 30 years. The detection of the main urinary metabolite--19-norandrosterone--in amounts greater than 2 ng/ml constitutes an adverse analytical finding. The presence in nutritional sport supplements of steroids not listed on the label has undoubtedly resulted in positive tests, but inadvertent consumption of meat containing residues of hormonal treatment should not realistically cause apprehension. Although highly improbable, athletes should prudently avoid meals composed of pig offal in the hours preceding the test since the consumption of edible parts of a non-castrated pig, containing 19-nortestosterone, has been shown to results in the excretion of 19-norandrosterone in the following hours. Norsteroid metabolites are formed during pregnancy and excreted as minor metabolites of norethisterone, and minute amounts have been identified in some male and female samples when using more sensitive techniques of detection. Whereas exercise does not seem to be a significant factor in 19-norandrosterone excretion, some rare urine samples were found to be a suitable medium for in situ 19-demethylation of urinary metabolites.

Animals↗

Novel attributes of an androgenic steroid-mediated increase in cardiac end diastolic stiffness in rats.

Although cardiac early and mid-diastolic stiffness constants are well accepted as being modulated by alterations in myocyte active processes, increments in left ventricular end diastolic (LVED) stiffness (LVED k; g x cm(-2)) in classical pathological models of a reduced LVED k (e.g., diabetes mellitus (DM) and hypertension) are determined largely by the properties of the myocardial extracellular matrix (ECM). As such, increases in LVED k in the latter cardiac pathologies are insensitive to acute changes in cardiac load, heart rate, and contractility. We examined whether the same attributes that apply to changes in LVED k in DM and in spontaneously hypertensive rats (SHRs) also apply to an androgenic steroid (nandrolone decanoate; 5 mg x kg(-1) biweekly) induced increase in LVED k. Myocardial collagen (ECM) characteristics and the capacity of acute verapamil-mediated changes in cardiac dynamics to impact on LVED k were evaluated after 3 months of steroid treatment to rats, 4 months of DM in rats, and in 45-week-old SHRs. Chronic steroid administration increased LVED k (steroid = 42 +/- 4, control = 25 +/- 2; p < 0.01). An acute infusion of verapamil to steroid-treated rats decreased LVED k to values not different from controls (29 +/- 3; p < 0.05 as compared with LVED k at baseline). Measures of myocardial collagen concentrations, phenotype ratios, and cross-linking were unchanged following steroid administration. Verapamil failed to alter the increased LVED k that occurs in either rats with DM or in SHRs, despite similar effects on cardiac dynamics as those noted in steroid-treated rats. The increased LVED k in the former animal models was associated with alterations in the ECM. In conclusion, the unique lack of association of the androgenic steroid-induced increase in LVED k with alterations in the myocardial ECM and the novel sensitivity of the steroid-mediated increment in LVED k to acute alterations in cardiac dynamics further supports the notion that changes in LVED k should not be considered to be a reflection of ECM characteristics in all cardiac conditions.

Androgens↗

Regulation of androgen receptor expression at the onset of functional overload in rat plantaris muscle.

Skeletal muscle androgen receptor (AR) expression at the onset of functional overload (OV) has not been well described. It is also not known if overload and/or anabolic steroid differentially regulate AR expression. The purpose of this study was to examine AR gene expression at the onset of functional OV in rat plantaris muscle with and without nandrolone decanoate (ND) administration. The functional significance of AR protein induction was examined using skeletal alpha-actin promoter activity in transiently transfected CV-1 fibroblast cells. Male Sprague-Dawley rats ( approximately 125 g) were functionally overloaded for 1, 3, 7, or 21 days. A subset of animals was given an ND (6 mg/kg) injection at day 0 and then overloaded for 3 days. Control animals underwent sham surgeries. AR protein concentration increased 106 and 279% after 7 and 21 days of OV, respectively. AR mRNA increased 430% after 7 days of OV. AR protein expression in C2C12 murine myotubes subjected to 1% chronic radial stretch for 18 h was elevated 101% compared with control. ND treatment increased AR protein concentration 1,300% compared with controls, and there was no additional effect when ND and OV were combined. ND with 3 days of OV treatment increased AR mRNA expression 50% compared with control. AR overexpression in transiently transfected CV-1 fibroblast cells increased -424 bp skeletal alpha-actin promoter activity 80 to 1,800% in a dose-dependent fashion. Co-overexpression of either serum response factor (SRF) or active RhoA with AR overexpression induced a synergistic 36- and 28-fold induction of skeletal alpha-actin promoter. Cotransfection of AR, SRF, and active RhoA induced 180-fold increase in skeletal alpha-actin promoter activity. In conclusion, AR protein expression is increased after 7 days of functional OV, and this induction is regulated pretranslationally. AR induction in conjunction with SRF and RhoA signaling may be an important regulator of gene expression during overload-induced muscle growth.

Actins↗