RESUMEN
Exercise training is a key countermeasure used to offset spaceflight-induced multisystem deconditioning. Here, we evaluated the effects of exercise countermeasures on multisystem function in a large cohort (N = 46) of astronauts on long-duration spaceflight missions. We found that during 178 ± 48 d of spaceflight, ~600 min/wk of aerobic and resistance exercise did not fully protect against multisystem deconditioning. However, substantial inter-individual heterogeneity in multisystem response was apparent with changes from pre to postflight ranging from -30% to +5%. We estimated that up to 17% of astronauts would experience performance-limiting deconditioning if current exercise countermeasures were used on future spaceflight missions. These findings support the need for refinement of current countermeasures, adjunct interventions, or enhanced requirements for preflight physiologic and functional capacity for the protection of astronaut health and performance during exploration missions to the moon and beyond.
RESUMEN
Many cancer patients undergoing treatment experience cancer-related fatigue (CRF). Inflammatory markers are correlated with CRF but are not routinely targeted for treatment. We previously demonstrated in an NIH-funded placebo-controlled, double-blind, randomized clinical trial (NCT00878995, closed to follow-up) that seven weekly injections of 100 mg adjunct testosterone preserved lean body mass in cancer patients undergoing standard-of-care treatment in a hospital setting. Because testosterone therapy can reduce circulating proinflammatory cytokines, we conducted an ancillary analysis to determine if this testosterone treatment reduced inflammatory burden and improved CRF symptoms and health-related quality of life. Randomization was computer-generated and managed by the pharmacy, which dispensed testosterone and placebo in opaque syringes to the administering study personnel. A total of 24 patients were randomized (14 placebo, 10 testosterone), and 21 were included in the primary analysis (11 placebo, 10 testosterone). Testosterone therapy did not ameliorate CRF symptoms (placebo to testosterone difference in predicted mean multidimensional fatigue symptom inventory scores: -5.6, 95% CI: -24.6 to 13.3), improve inflammatory markers, or preserve health-related quality of life and functional measures of performance in late-stage cancer patients.
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Neoplasias , Testosterona , Humanos , Testosterona/uso terapéutico , Calidad de Vida , Fatiga/tratamiento farmacológico , Fatiga/etiología , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Composición CorporalRESUMEN
There are marked decreases in plasma concentrations of cortisol and arginine (an essential amino acid for neonates) as well as intestinal citrulline synthesis in piglets during the first 14 days of life. The objective of this study was to test the hypothesis that increasing plasma cortisol concentrations by cortisol administration may prevent the decline in intestinal citrulline and arginine synthesis from proline, thereby possibly increasing plasma arginine concentration in suckling piglets and their growth. Seven-day-old pigs reared by sows received daily intramuscular injections of hydrocortisone 21-acetate (25 mg/kg) or vehicle solution (saline) (n = 10/group). At 14 days of age, piglets were used to prepare jejunal enterocytes. Cells were incubated at 37 °C for 30 min in oxygenated Krebs buffer containing 5 mM glucose, 2 mM [U-14C]proline, and 2 mM glutamine. Cortisol treatment increased plasma cortisol concentration, mitochondrial proline oxidase and N-acetylglutamate synthase activities, cytosolic argininosuccinate lyase activity, and the intracellular concentrations of N-acetylglutamate and carbamoyl phosphate for citrulline and arginine synthesis. However, cortisol treatment induced the expression of intestinal arginase-II for arginine hydrolysis, resulting in no change in plasma arginine concentration. Administration of cortisol had no effect on milk consumption or the whole-body growth rate of piglets, but increased villus height in the jejunum and ileum. Collectively, these results suggest an important role for proline oxidase and N-acetylglutamate in regulating citrulline and arginine synthesis from proline in pig enterocytes. Because proline catabolism plays an important role in modulating protein synthesis, cell proliferation, and arginine production, our findings may have important implications for understanding the role of proline oxidase in the growth and health of the mammalian small intestine.
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Citrulina/metabolismo , Enterocitos/metabolismo , Hidrocortisona/metabolismo , Prolina/metabolismo , Animales , Animales Lactantes/metabolismo , Arginina/metabolismo , Proliferación Celular/fisiología , Glutamina/metabolismo , Íleon/metabolismo , Yeyuno/metabolismo , Masculino , Prolina Oxidasa/metabolismo , Biosíntesis de Proteínas/fisiología , PorcinosRESUMEN
BACKGROUND/OBJECTIVES: Exercise is a front-line countermeasure used to maintain astronaut health during long-duration spaceflight; however, reductions in metabolic health still occur. Accordingly, we evaluated serial changes in metabolic parameters in a spaceflight analog and evaluated the efficacy of exercise with or without the addition of low-dose testosterone treatment on mitigating adverse metabolic changes. SUBJECTS/METHODS: Healthy young (<55 years) men were randomly assigned to one of three groups during 70-days of strict, diet controlled, 6° head-down bed rest: Control (CON, n=9), exercise plus testosterone countermeasure (TEX, n=8), or exercise countermeasure plus placebo (PEX, n=9). Basal metabolic rate (BMR), glucose tolerance, and insulin sensitivity were measured before, during, and after bed rest. Exercise energy expenditure and excess post-exercise oxygen consumption were measured in TEX and PEX subjects during bed rest. RESULTS: Leptin decreased during bed rest (Pre to BR+0 changed from 6.9 ± 5.1, 5.8 ± 4.2, and 4.7 ± 4.1 to 7.9 ±3.6, 6.5 ± 4.6, and 4.1 ±3.0 ug⢠L-1 for CON, PEX, and TEX respectively). Bed rest induced a decrease in BMR (Pre to BR57 changed from 1655 ± 212, 1629 ± 108, and 1706 ± 146 to 1476 ± 166, 1668 ± 142, and 1603 ± 132 kcal ⢠day-1 ± 95%CI for CON, PEX, and TEX respectively). Similarly, bed rest negatively affected glucose metabolism assessed by 2hr OGTT glucose (Pre to BR66 changed from 6.29 ± 0.72, 5.13 ± 0.72, and 5.87 ± 0.73 to 6.62 ± 0.72, 5.83 ± 0.72, and 7.08 ± 0.72 mmol ⢠L-1 ± 95%CI). Reambulation following bed rest positively affected glucose tolerance in CON (2hr OGTT glucose at BR+12: 5.3 ± 0.72, 6.42 ± 0.73, and 6.04 ± 0.73 mmol ⢠L-1 ± 95%CI). Testosterone protected against bed rest induced insulin resistance (HOMA-IR from Pre to BR+66 changed from 1.74 ± 0.54, 1.18 ± 0.55, and 1.45 ± 0.56 to 2.24 ± 0.56, 1.47 ± 0.54, and 1.07 ± 0.54). CONCLUSION: This study confirmed that inactivity during 70 days of head-down bed rest adversely affects metabolic health. The daily exercise countermeasures were beneficial but not completely protective of bed rest induced decrements in metabolic health. Supplementary countermeasures such as testosterone may provide additional benefits not provided by exercise alone.
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Reposo en Cama , Ejercicio Físico/fisiología , Testosterona/uso terapéutico , Simulación de Ingravidez , Adulto , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Pituitary dysfunction with reduced growth hormone (GH) secretion is common in patients following traumatic brain injury (TBI), and these patients often develop chronic symptoms including fatigue and altered cognition. We examined 18 subjects with a history of mild TBI, fatigue, and insufficient GH secretion. Subjects received GH replacement in a year-long, double-blind, placebo-controlled, crossover study, and were assessed for changes in physical performance, body composition, resting energy expenditure, fatigue, sleep, mood, and neuropsychological status. Additionally, magnetic resonance imaging (MRI) was used to assess changes in brain structure and resting state functional connectivity. GH replacement resulted in decreased fatigue, sleep disturbance, and anxiety, as well as increased resting energy expenditure, improved body composition, and altered perception of submaximal effort when performing exercise testing. Associated brain changes included increased frontal cortical thickness and gray matter volume and resting state connectivity changes in regions associated with somatosensory networks. GH replacement altered brain morphology and connectivity and reduced fatigue and related symptoms in mild TBI patients. Additional studies are needed to understand the mechanisms causing TBI-related fatigue and symptom relief with GH replacement.
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Conmoción Encefálica/complicaciones , Encéfalo/efectos de los fármacos , Fatiga/tratamiento farmacológico , Hormona de Crecimiento Humana/farmacología , Adulto , Composición Corporal/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Estudios Cruzados , Método Doble Ciego , Fatiga/diagnóstico por imagen , Femenino , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Sueño/efectos de los fármacosRESUMEN
Patients with chronic traumatic brain injury (TBI) requiring long-term, permanent care suffer a myriad of clinical symptoms (i.e., impaired cognition, fatigue, and other conditions) that persist for years beyond the acute brain injury. In addition to these comorbid clinical symptoms, chronic TBI patients exhibit altered amino acid and hormonal profiles with distinct cytokine patterns suggesting chronic inflammation. This metabolic link suggests a role of the gut-brain axis in chronic TBI. Thus, we utilized a two-site trial to investigate the role of the gut-brain axis in comorbidities of chronic TBI. The fecal microbiome profile of 22 moderate/severe TBI patients residing in permanent care facilities in Texas and California was compared to 18 healthy age-matched control subjects working within the participating facilities. Each fecal microbiome was characterized by 16S(V4) ribosomal RNA (rRNA) gene sequencing and metagenomic genome sequencing approaches followed by confirmatory full 16S rRNA gene sequencing or focused tuf gene speciation and specific quantitative polymerase chain reaction evaluation of selected genera or species. The average chronic TBI patient fecal microbiome structure was significantly different compared to the control cohort, and these differences persisted after group stratification analysis to identify any unexpected confounders. Notably, the fecal microbiome of the chronic TBI cohort had absent or reduced Prevotella spp. and Bacteroidies spp. Conversely, bacteria in the Ruminococcaceae family were higher in abundance in TBI compared to control profiles. Previously reported hypoaminoacidemia, including significantly reduced levels of l-tryptophan, l-sarcosine, ß-alanine, and alanine, positively correlated with the reduced levels of Prevotella spp. in the TBI cohort samples compared to controls. Although the sequelae of gut-brain axis disruption after TBI is not fully understood, characterizing TBI-related alterations in the fecal microbiome may provide biomarkers and therapeutic targets to address patient morbidity.
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Lesiones Traumáticas del Encéfalo/microbiología , Microbioma Gastrointestinal/fisiología , Adulto , Anciano , Bacterias/genética , Bacterias/metabolismo , Heces/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Ribosómico 16S/genética , ARN Ribosómico 16S/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Adjunct testosterone therapy improves lean body mass, quality of life, and physical activity in patients with advanced cancers; however, the effects of testosterone on cardiac morphology and function are unknown. Accordingly, as an ancillary analysis of a randomized, placebo-controlled trial investigating the efficacy of testosterone supplementation on body composition in men and women with advanced cancers, we explored whether testosterone supplementation could prevent or reverse left ventricular (LV) atrophy and dysfunction. METHODS: Men and women recently diagnosed with late stage (≥IIB) or recurrent head and neck or cervical cancer who were scheduled to receive standard of care chemotherapy or concurrent chemoradiation were administered an adjunct 7 week treatment of weekly intramuscular injections of either 100 mg testosterone (T, n = 1 M/5F) or placebo (P, n = 6 M/4F) in a double-blinded randomized fashion. LV morphology (wall thickness), systolic function (ejection fraction, EF), diastolic function (E/A; E'/E), arterial elastance (Ea), end-systolic elastance (Ees), and ventricular-arterial coupling (Ea/Ees) were assessed. RESULTS: No significant differences were observed in LV posterior wall thickness in placebo (pre: 1.10 ± 0.1 cm; post: 1.16 ± 0.2 cm; p = 0.11) or testosterone groups (pre: 0.99 ± 0.1 cm; post: 1.14 ± 0.20 cm; p = 0.22). Compared with placebo, testosterone significantly improved LVEF (placebo: - 1.8 ± 4.3%; testosterone: + 6.2 ± 4.3%; p < 0.05), Ea (placebo: 0.0 ± 0.2 mmHg/mL; testosterone: - 0.3 ± 0.2 mmHg/mL; p < 0.05), and Ea/Ees (placebo: 0.0 ± 0.1; testosterone: - 0.2 ± 0.1; p < 0.05). CONCLUSIONS: In patients with advanced cancers, testosterone was associated with favorable changes in left ventricular systolic function, arterial elastance, and ventricular-arterial coupling. Given the small sample size, the promising multisystem benefits of testosterone warrants further evaluation in a definitive randomized trial. TRIAL REGISTRATION: This study was prospectively registered on ClinicalTrials.gov (NCT00878995; date of registration: April 9, 2009).
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Corazón/efectos de los fármacos , Neoplasias/fisiopatología , Testosterona/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Ecocardiografía , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Calidad de Vida , Testosterona/administración & dosificación , Testosterona/efectos adversos , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
INTRODUCTION: Long-term head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-term space flight. Agents such as testosterone, in addition to regular exercise, are effective countermeasures for reducing loss of skeletal muscle mass and function. OBJECTIVE: We investigated the skeletal muscle proteome of healthy men in response to long term HDBR alone (CON) and to HDBR with exercise (PEX) or exercise plus testosterone (TEX) countermeasures. METHOD: Biopsies were performed on the vastus lateralis before (pre) HDBR and on HDBR days 32 (mid) and 64 (post). Extracted proteins from these skeletal muscle biopsies were subjected to 2-dimensional gel electrophoresis (2DE), stained for phosphoproteins (Pro-Q Diamond dye) and total proteins (Sypro Ruby dye). Proteins showing significant fold differences (t-test p ≤ 0.05) in abundance or phosphorylation state at mid or post were identified by mass spectroscopy (MS). RESULTS: From a total of 932 protein spots, 130 spots were identified as potentially altered in terms of total protein or phosphoprotein levels due to HDBR and/or countermeasures, and 59 unique molecules emerged from MS analysis. Top canonical pathways identified through IPA included calcium signaling, actin cytoskeleton signaling, integrin linked kinase (ILK) signaling, and epithelial adherens junction signaling. Data from the pre-HDBR proteome supported the potential for predicting physiological post-HDBR responses such as the individual's potential for loss vs. maintenance of muscle mass and strength. CONCLUSIONS: HDBR resulted in alterations to skeletal muscle abundances and phosphorylation of several structural and metabolic proteins. Inclusion of exercise alone or in combination with testosterone treatment modulated the proteomic responses towards cellular reorganization and hypertrophy, respectively. Finally, the baseline proteome may aid in the development of personalized countermeasures to mitigate health risks in astronauts as related to loss of muscle mass and function.
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Reposo en Cama/efectos adversos , Inclinación de Cabeza/efectos adversos , Músculo Esquelético/fisiopatología , Adulto , Atrofia/tratamiento farmacológico , Ejercicio Físico/fisiología , Terapia por Ejercicio/métodos , Inclinación de Cabeza/fisiología , Voluntarios Sanos , Humanos , Masculino , Fenómenos Fisiológicos Musculoesqueléticos/efectos de los fármacos , Proteómica/métodos , Músculo Cuádriceps/metabolismo , Testosterona/uso terapéutico , Simulación de IngravidezRESUMEN
INTRODUCTION: Prolonged confinement to head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-duration space flight. Exercise countermeasures by themselves have not completely prevented the deleterious losses in muscle mass or function in HDBR or space flight. PURPOSE: The objective was to investigate the safety and efficacy of intermittent, low-dose testosterone treatment in conjunction with NASA exercise (SPRINT) countermeasures during 70 d of 6° HDBR. METHODS: Healthy men (35 ± 8 yr) were randomized into one of three groups that remained inactive (CON) or performed exercise 6 d·wk in addition to receiving either placebo (PEX) or testosterone treatment (TEX, 100 mg·wk). Testosterone/placebo injections were administered once a week for 2 wk, followed by 2 wk off and so on, during HDBR. RESULTS: Total, leg, and trunk lean body mass (LBM) consistently decreased in CON, increased in TEX, and had little or no changes in PEX. Total, leg, and trunk fat mass consistently increased in CON and PEX and decreased in TEX. Leg strength decreased in CON, whereas PEX and TEX were protected against loss in strength. Changes in leg LBM correlated positively with changes in leg muscle strength. CONCLUSIONS: Addition of a testosterone countermeasure enhanced the preventative actions of exercise against body composition changes during long-term HDBR in healthy eugonadal men. This is the first report to demonstrate that cycled, low-dose testosterone treatment increases LBM under conditions of strict exercise control. These results are clinically relevant to the development of safe and effective therapies against muscle atrophy during long-term bed rest, aging, and disease where loss of muscle mass and strength is a risk. The potential space flight applications of such countermeasure combinations deserve further investigations.
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Reposo en Cama , Terapia por Ejercicio , Atrofia Muscular/prevención & control , Testosterona/uso terapéutico , Adulto , Humanos , Masculino , Persona de Mediana Edad , Vuelo Espacial , Estados Unidos , United States National Aeronautics and Space Administration , Simulación de IngravidezRESUMEN
BACKGROUND: Cancer cachexia negatively impacts cancer-related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment. METHODS: A randomized, double-blind, placebo-controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival. RESULTS: A total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0-7%) whereas those receiving placebo lost 3.3% (95% CI, -7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups. CONCLUSIONS: In patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo.
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Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Atrofia Muscular/tratamiento farmacológico , Neoplasias/complicaciones , Testosterona/uso terapéutico , Adulto , Anciano , Biomarcadores , Composición Corporal/efectos de los fármacos , Caquexia/tratamiento farmacológico , Caquexia/etiología , Caquexia/patología , Metabolismo Energético/efectos de los fármacos , Femenino , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/fisiopatología , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatología , Neoplasias/diagnóstico , Neoplasias/terapia , Calidad de Vida , Resultado del TratamientoRESUMEN
PURPOSE: Early and consistent evaluation of cardiac morphology and function throughout an atrophic stimulus is critically important for the design and optimization of interventions. This randomized controlled trial was designed 1) to characterize the time course of unloading-induced morphofunctional remodeling and 2) to examine the effects of exercise with and without low-dose testosterone supplementation on cardiac biomarker, structural, and functional parameters during unloading. METHODS: Twenty-six subjects completed 70 d of head-down tilt bed rest (BR): 9 were randomized to exercise training (Ex), 8 to EX and low-dose testosterone (ExT), and 9 remained sedentary (CONT). Exercise consisted of high-intensity, continuous, and resistance exercise. Cardiac morphology (left ventricular mass [LVM]) and mechanics (longitudinal, radial, and circumferential strain and twist), cardiovascular biomarkers, and cardiorespiratory fitness (VËO2peak) were assessed before, during, and after BR. RESULTS: Sedentary BR resulted in a progressive decline in LVM, longitudinal, radial, and circumferential strain in CONT, whereas Ex and ExT mitigated decreases in LVM and function. Twist was increased throughout BR in sedentary BR, whereas after an initial increase at BR7, there were no further changes in twist in Ex and ExT. HDL cholesterol was significantly decreased in all groups compared with pre-BR (P < 0.007). There were no significant changes in other cardiovascular biomarkers. Change in twist was significantly related to change in VËO2max (R = 0.68, P < 0.01). CONCLUSION: An integrated approach with evaluation of cardiac morphology, mechanics, VËO2peak, and biomarkers provides extensive phenotyping of cardiovascular atrophic remodeling. Exercise training and exercise training with low-dose testosterone supplementation abrogates atrophic remodeling.
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Atrofia/prevención & control , Reposo en Cama , Terapia por Ejercicio , Corazón/fisiopatología , Testosterona/uso terapéutico , Adulto , Biomarcadores/sangre , Presión Sanguínea , Capacidad Cardiovascular , Inclinación de Cabeza , Frecuencia Cardíaca , Humanos , Masculino , Consumo de Oxígeno , Función Ventricular Izquierda , Simulación de IngravidezRESUMEN
CONTEXT: In older adults, loss of mobility due to sarcopenia is exacerbated in men with low serum T. T replacement therapy is known to increase muscle mass and strength, but the effect of weekly (WK) vs monthly (MO) administration on specific fiber types is unknown. OBJECTIVE: To determine the efficacy of WK vs MO T replacement on the size and functional capacity of individual fast and slow skeletal muscle fiber types. DESIGN, SETTING, AND PATIENTS: Subjects were randomized into a 5-month, double-blind, placebo-controlled trial. All subjects (ages, 61-71 y) were community-dwelling men who had T levels < 500 ng/dL. INTERVENTION: Subjects were dosed weekly for 5 months, receiving continuous T (WK, n = 5; 100 mg T enanthate, im injection), monthly cycled T (MO, n = 7; alternating months of T and placebo), or placebo (n = 7). Muscle biopsies of the vastus lateralis were obtained before and after treatment. MAIN OUTCOME MEASURES: Main outcomes for individual slow and fast fibers included fiber diameter, peak force (P0), rate of tension development, maximal shortening velocity, peak power, and Ca(2+) sensitivity. RESULTS: Both treatments increased fiber diameter and peak power, with WK treatment 5-fold more effective than MO in increasing type I fiber P0. WK effects on fiber diameter and force were 1.5-fold higher in slow fibers compared to fast fibers. In fast type II fibers, diameter and P0 increased similarly between treatments. The increased power was entirely due to increased fiber size and force. CONCLUSIONS: In conclusion, T replacement effects were fiber-type dependent, restricted to increases in cell size, P0, and peak power, and dependent on the paradigm selected (WK vs MO).
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Terapia de Reemplazo de Hormonas/métodos , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Sarcopenia/tratamiento farmacológico , Testosterona/administración & dosificación , Anciano , Método Doble Ciego , Esquema de Medicación , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Testosterona/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. METHODS: In this placebo-controlled study, 76 healthy men (21-50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. RESULTS: LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone-binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. CONCLUSIONS: LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations.
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Andrógenos/farmacología , Andrógenos/farmacocinética , Receptores Androgénicos/efectos de los fármacos , Administración Oral , Adulto , Andrógenos/administración & dosificación , Andrógenos/efectos adversos , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Método Doble Ciego , Hormonas Esteroides Gonadales/sangre , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Proteínas Musculares/biosíntesis , Fuerza Muscular/efectos de los fármacos , Especificidad de Órganos , Próstata/efectos de los fármacos , Testosterona/sangre , Adulto JovenRESUMEN
Aging is associated with a gradual decline in skeletal muscle mass and strength leading to increased risk for functional impairments. Although basal rates of protein synthesis and degradation are largely unaffected with age, the sensitivity of older muscle cells to the anabolic actions of essential amino acids appears to decline. The major pathway through which essential amino acids induce anabolic responses involves the mammalian target of rapamycin (mTOR) Complex 1, a signaling pathway that is especially sensitive to regulation by the branched chain amino acid leucine. Recent evidence suggests that muscle of older individuals require increasing concentrations of leucine to maintain robust anabolic responses through the mTOR pathway. While the exact mechanisms for the age-related alterations in nutritional signaling through the mTOR pathway remain elusive, there is increasing evidence that decreased sensitivity to insulin action, reductions in endothelial function, and increased oxidative stress may be underlying factors in this decrease in anabolic sensitivity. Ensuring adequate nutrition, including sources of high quality protein, and promoting regular physical activity will remain among the frontline defenses against the onset of sarcopenia in older individuals.
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Envejecimiento/metabolismo , Aminoácidos Esenciales/metabolismo , Necesidades Nutricionales , Transducción de Señal , Animales , Humanos , Sirolimus/metabolismoRESUMEN
Aging is associated with a loss of sex hormone in both men (andropause) and women (menopause). In men, reductions in testosterone can trigger declines in muscle mass, bone mass, and in physical function. In women, the impact of the loss of sex hormones, such as estradiol, on bone is well elucidated, but evidence is limited on whether the loss of estradiol negatively affects muscle mass and physical function. However, deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons. Thus, consideration should be given as to whether targeted hormone replacement therapies may prove effective at treating clinical conditions, such as age-related sarcopenia, cancer cachexia, and/or acute or chronic illnesses. If initiated carefully in the appropriate clinical population, hormone replacement therapies in men and women may prevent and reverse muscle and bone loss and functional declines and perhaps promote healthy aging and longevity.
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Envejecimiento/fisiología , Andrógenos/metabolismo , Estrógenos/metabolismo , Longevidad/fisiología , Menopausia/fisiología , Anciano , Anciano de 80 o más Años , Envejecimiento/efectos de los fármacos , Andrógenos/deficiencia , Andrógenos/uso terapéutico , Andropausia/efectos de los fármacos , Andropausia/fisiología , Densidad Ósea/efectos de los fármacos , Estrógenos/deficiencia , Estrógenos/uso terapéutico , Femenino , Terapia de Reemplazo de Hormonas/métodos , Humanos , Longevidad/efectos de los fármacos , Masculino , Menopausia/efectos de los fármacos , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Valores de Referencia , Medición de Riesgo , Resultado del TratamientoRESUMEN
The combination of increasing blood flow and amino acid (AA) availability provides an anabolic stimulus to the skeletal muscle of healthy young adults by optimizing both AA delivery and utilization. However, aging is associated with a blunted response to anabolic stimuli and may involve impairments in endothelial function. We investigated whether age-related differences exist in the muscle protein anabolic response to AAs between younger (30 ± 2 yr) and older (67 ± 2 yr) adults when macrovascular and microvascular leg blood flow were similarly increased with the nitric oxide (NO) donor, sodium nitroprusside (SNP). Regardless of age, SNP+AA induced similar increases above baseline (P ≤ 0.05) in macrovascular flow (4.3 vs. 4.4 ml·min(-1)·100 ml leg(-1) measured using indocyanine green dye dilution), microvascular flow (1.4 vs. 0.8 video intensity/s measured using contrast-enhanced ultrasound), phenylalanine net balance (59 vs. 68 nmol·min(-1)·100 ml·leg(-1)), fractional synthetic rate (0.02 vs. 0.02%/h), and model-derived muscle protein synthesis (62 vs. 49 nmol·min(-1)·100 ml·leg(-1)) in both younger vs. older individuals, respectively. Provision of AAs during NO-induced local skeletal muscle hyperemia stimulates skeletal muscle protein metabolism in older adults to a similar extent as in younger adults. Our results suggest that the aging vasculature is responsive to exogenous NO and that there is no age-related difference per se in AA-induced anabolism under such hyperemic conditions.
Asunto(s)
Envejecimiento/metabolismo , Aminoácidos/metabolismo , Hiperemia/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Óxido Nítrico/metabolismo , Adulto , Factores de Edad , Anciano , Aminoácidos/administración & dosificación , Biopsia , Velocidad del Flujo Sanguíneo , Glucemia/metabolismo , Femenino , Humanos , Hiperemia/inducido químicamente , Hiperemia/fisiopatología , Infusiones Intraarteriales , Infusiones Intravenosas , Insulina/sangre , Extremidad Inferior , Masculino , Microcirculación , Microdiálisis , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Donantes de Óxido Nítrico/administración & dosificación , Nitroprusiato/administración & dosificación , Fenilalanina/metabolismo , Flujo Sanguíneo Regional , Factores de TiempoRESUMEN
CONTEXT: Cycling androgens has been reported by athletes to improve physical performance by enhancing muscle mass and strength, a paradigm that has not been studied, and may have clinical value in older men being treated with testosterone. OBJECTIVE: We investigated the efficacy of a monthly cycled testosterone regimen that uses half the testosterone dose as the current standard of care continuous therapy on body composition and muscle strength in older men. DESIGN, SETTING, AND PATIENTS: Twenty-four community-dwelling older men 70 ± 2 yr of age with total testosterone levels below 500 ng/dl were randomized at the Institute for Translational Sciences-Clinical Research Center into a 5-month double-blind placebo-controlled trial. INTERVENTION: Subjects were dosed weekly for 5 months, receiving continuous testosterone (TE, n = 8; 100 mg testosterone enanthate, im injection), monthly cycled testosterone (MO, n = 8; alternating months of testosterone and placebo), or placebo (PL, n = 8). MAIN OUTCOME MEASURES: Main outcomes included body composition by dual-energy x-ray absorptiometry and upper and lower body muscle strength. Secondary outcomes included body weight, serum hormones, and mixed-muscle protein fractional synthesis rate (FSR). RESULTS: Total lean body mass was increased and percent fat was reduced after 5 months in TE and MO (P < 0.05). Upper body muscle strength increased in TE, and lower body muscle strength increased in TE and MO (P < 0.05). FSR increased in TE and MO (P < 0.05) but not in PL. CONCLUSIONS: Cycled testosterone improved body composition and increased muscle strength compared with placebo and increased FSR similarly to continuous testosterone.
Asunto(s)
Andrógenos/administración & dosificación , Composición Corporal/efectos de los fármacos , Terapia de Reemplazo de Hormonas/métodos , Fuerza Muscular/efectos de los fármacos , Testosterona/administración & dosificación , Anciano , Peso Corporal/efectos de los fármacos , Esquema de Medicación , Humanos , Masculino , Músculo Esquelético/efectos de los fármacos , Proyectos Piloto , Testosterona/sangre , Resultado del TratamientoRESUMEN
Aging is associated with a gradual decline in circulating testosterone concentrations and decreased musculature in men. While testosterone administration is often considered when symptoms of hypogonadism are presented, the long-term effects of androgen use on muscle physiology are not yet fully understood. The definition of hypogonadism in men remains obscure but is generally indicated by total testosterone concentrations less than a threshold value of 300-500 ng/dL. Androgen replacement therapy is generally safe in men and women with low endogenous testosterone concentrations. The development of selective androgen receptor modulators (SARMs) may provide additional options in treatment of hypogonadism while lowering the potential of side effects often associated with long-term androgen use. Androgen administration, either alone or in combination with other treatments, can be successful in improving muscle mass by increasing protein anabolism and reducing protein catabolism in men and women. Further research is necessary to optimize the anabolic and anticatabolic properties of androgens for treatment and prevention of muscle loss in men and women.
Asunto(s)
Envejecimiento/metabolismo , Andrógenos/uso terapéutico , Terapia de Reemplazo de Hormonas , Hipogonadismo/tratamiento farmacológico , Músculo Esquelético/metabolismo , Quimioterapia Combinada , Femenino , Humanos , Masculino , Músculo Esquelético/efectos de los fármacos , Receptores Androgénicos/efectos de los fármacos , Testosterona/administración & dosificación , Testosterona/uso terapéuticoRESUMEN
OBJECTIVE: Diagnosis of pre-diabetes and early-stage diabetes occurs primarily by means of an oral glucose tolerance test (OGTT), which requires invasive blood sampling. The aim of this study was to determine whether differences exist in breath (13)CO(2) excretion during a (13)C-labeled OGTT between individuals with normal glucose tolerance (NGT) and individuals with pre-diabetes and early-stage diabetes (PDED) and whether these differences correlated with blood glucose kinetics. RESEARCH DESIGN AND METHODS: Blood and breath samples were collected at baseline and every 30 min for a 10-h period after ingestion of 75 g glucose isotopically labeled with 150 mg [U-(13)C(6)]D-glucose. RESULTS: Age (56 +/- 5 vs. 47 +/- 3 years) and BMI (31 +/- 2 vs. 31 +/- 2 kg/m(2)) were not different between individuals with NGT (n = 10) and PDED (n = 7), respectively. Blood glucose concentrations were significantly higher in those with PDED compared with those with NGT from baseline to 4.5 h after glucose ingestion (P Asunto(s)
Diabetes Mellitus/diagnóstico
, Adulto
, Glucemia/metabolismo
, Dióxido de Carbono/análisis
, Diabetes Mellitus/sangre
, Femenino
, Prueba de Tolerancia a la Glucosa
, Humanos
, Insulina/sangre
, Resistencia a la Insulina
, Masculino
, Persona de Mediana Edad
, Sensibilidad y Especificidad