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ABSTRACT: We sought to evaluate baseline mRNA values and changes in gene expression of myostatin-related factors in postmenopausal women taking hormone therapy (HT) and not taking HT after eccentric exercise. Fourteen postmenopausal women participated including 6 controls not using HT (59 ± 4 years, 63 ± 17 kg) and 8 women using HT (59 ± 4 years, 89 ± 24 kg). The participants performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on a dynamometer. Muscle biopsies from the vastus lateralis were obtained from the exercised leg at baseline and 4 hours after the exercise bout. Gene expression was determined using reverse transcriptase polymerase chain reaction for myostatin, activin receptor IIb (ActRIIb), follistatin, follistatin-related gene (FLRG), follistatin-like-3 (FSTL3), and GDF serum-associated protein-1 (GASP-1). In response to the exercise bout, myostatin and ActRIIb significantly decreased (p < 0.05), and follistatin, FLRG, FSTL3, and GASP-1 significantly increased in both groups (p < 0.05). Significantly greater changes in gene expression of all genes occurred in the HT group than in the control group after the acute eccentric exercise bout (p < 0.05). These data suggest that postmenopausal women using HT express greater myostatin-related gene expression, which may reflect a mechanism by which estrogen influences the preservation of muscle mass. Further, postmenopausal women using HT experienced a profoundly greater myostatin-related response to maximal eccentric exercise.
The Journal of Strength and Conditioning Research 03/2012; 26(5):1374-82. · 1.83 Impact Factor
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E Todd Schroeder,
Jiaxiu He,
Kevin E Yarasheski,
Ellen F Binder,
Carmen Castaneda-Sceppa,
Shalender Bhasin,
Christina M Dieli-Conwright,
Miwa Kawakubo,
Ronenn Roubenoff,
Stanley P Azen, Fred R Sattler
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ABSTRACT: We hypothesized that treatment with testosterone (T) and recombinant human growth hormone (rhGH) would increase lean mass (LM) and muscle strength proportionally and an in a linear manner over 16 weeks. This was a multicenter, randomized, controlled, double-masked investigation of T and rhGH supplementation in older (71 ± 4 years) community-dwelling men. Participants received transdermal T at either 5 or 10 g/day as well as rhGH at 0, 3.0 or 5.0 μg/kg/day for 16 weeks. Body composition was determined by dual-energy X-ray absorptiometry (DEXA) and muscle performance by composite one-repetition maximum (1-RM) strength and strength per unit of lean mass (muscle quality, MQ) for five major muscle groups (upper and lower body) at baseline, week 8 and 17. The average change in total LM at study week 8 compared with baseline was 1.50 ± 1.54 kg (P < 0.0001) in the T only group and 2.64 ± 1.7 (P < 0.0001) in the T + rhGH group and at week 17 was 1.46 ± 1.48 kg (P < 0.0001) in the T only group and 2.14 ± 1.96 kg (P < 0.0001) in the T + rhGH group. 1-RM strength improved modestly in both groups combined (12.0 ± 23.9%, P < 0.0001) at week 8 but at week 17 these changes were twofold greater (24.7 ± 31.0%, P < 0.0001). MQ did not significantly change from baseline to week 8 but increased for the entire cohort, T only, and T + rhGH groups by week 17 (P < 0.001). Despite sizeable increases in LM measurements at week 8, tests of muscle performance did not show substantive improvements at this time point.
Arbeitsphysiologie 07/2011; 112(3):1123-31. · 2.15 Impact Factor
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ABSTRACT: Acute deviations in protein intake before the quantification of protein kinetics in older humans may explain the controversy over the effects of older age on muscle protein synthesis and proteolysis rates.
We hypothesized that an acute decrease in protein intake from the habitual intake is associated with lower muscle protein synthesis and higher proteolysis rates, whereas an acute increase in protein intake from the habitual intake is associated with higher muscle protein synthesis and lower proteolysis rates.
In 112 community-dwelling healthy men aged 65-90 y, we quantified resting whole-body [1,2-(13)C(2)]leucine kinetics, muscle mixed protein fractional synthesis rates (FSRs), and muscle proteasome proteolytic enzyme activities after participants consumed for 3 d controlled research meals (0.9-1.1 g protein · kg(-1) · d(-1)) that contained more or less protein than that habitually consumed and that induced alterations in nitrogen balance.
Protein kinetic parameters were not significantly different between the groups, despite controlled research protein intakes that were lower (-0.2 to -0.3 g · kg(-1) · d(-1)) or higher (+0.2 g · kg(-1) · d(-1)) than habitual intakes and that induced negative (-22 to -25 mg · kg(-1) · d(-1)) or positive (22-25 mg · kg(-1) · d(-1)) nitrogen balance. Within these acutely altered protein intake and nitrogen balance boundaries, a reduction in protein intake from habitual intake and induction of negative nitrogen balance were not associated with higher proteolysis or lower muscle FSR, and an acute increase in protein intake from habitual intake and induction of positive nitrogen balance were not associated with lower proteolysis or higher muscle FSR. A higher quantitative insulin sensitivity check index was associated with lower whole-body proteolysis rates.
The practice of acutely controlling protein intake, even at intakes lower than habitual intakes that induce negative nitrogen balance, before quantifying human protein kinetics does not significantly reduce muscle protein synthesis or increase proteolysis. Factors other than protein intake explain lower muscle protein synthesis rates with advanced age. This trial is registered at clinicaltrials.gov as NCT00183040.
American Journal of Clinical Nutrition 07/2011; 94(1):172-81. · 6.67 Impact Factor
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Fred R. Sattler,
Shalender Bhasin,
Jiaxiu He,
Kevin E. Yarasheski,
Ellen F. Binder,
E. Todd Schroeder,
Carmen Castaneda-Sceppa,
Miwa Kawakubo,
Ronenn Roubenoff,
Matthew Dunn,
Chris Hahn,
Yolanda Stewart,
Carmen Martinez,
Stanley P. Azen
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ABSTRACT: Objectives To determine the durability of anabolic effects and adverse events (AEs) after stopping testosterone and growth hormone supplementation in older men.Design Secondary analysis of a double-masked, randomized controlled trial of testosterone gel (5 or 10 g/daily) plus rhGH (0, 3 or 5 μg/kg/day) with follow-up of outcomes 3 months later.Participants A total of 108 community-dwelling 65- to 90-year-old men.Measurements Testosterone and IGF-1 levels, body composition (DEXA), 1-repetition maximum (1-RM) strength, stair-climbing power, quality-of-life (QOL) and activity questionnaires, AEs.Results Despite improvements in body composition during treatment, residual benefits 3 months later (week 28) were variable. For participants with improvements exceeding their week-17 median changes, benefits were sustained at week 28 for lean body mass (1·45 ± 1·63 kg, 45% of week-17 values, P < 0·0001 vs baseline), appendicular skeletal muscle mass (ASMM, 0·71 ± 1·01 kg, 42%, P < 0·0001), total fat (−1·06 ± 2·18 kg, 40%, P < 0·0001) and trunk fat (−0·89 ± 1·42 kg, 50%, P < 0·0001); retention of ASMM was associated with greater week-16 protein intake (P = 0·01). For 1-RM strength, 39%–43% of week-17 improvements (P ≤ 0·05) were retained and associated with better week-17 strength (P < 0·0001), change in testosterone from week 17-to 28 (P = 0·004) and baseline PASE (P = 0·04). Framingham 10-year cardiovascular risks were low (∼14%), did not worsen and improved by week 28 (P = 0·0002). The hypothalamic-pituitary-gonadal axis recovered completely.Conclusions Durable improvements in muscle mass, strength and fat mass were retained 3 months after discontinuing hormone supplementation in participants with greater than median body composition changes during treatment, but not in others with smaller gains. AEs largely resolved after intervention discontinuation. Additional strategies may be needed to sustain or augment muscle mass and strength gains achieved during short-term hormone therapy.
Clinical Endocrinology 06/2011; 75(1):103 - 111. · 3.17 Impact Factor
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ABSTRACT: Prospective data on factors associated with the non-AIDS-defining cancer (NADC) incidence in HIV-infected individuals are limited.
We examined the NADC incidence in 3,158 antiretroviral treatment (ART)-naïve subjects after ART initiation in AIDS Clinical Trials Group trials; extended follow-up was available for 2,122 subjects. Poisson regression was used to examine the associations between covariates and incident NADC.
At ART initiation, subjects (median age 37 years) were 40% non-Hispanic whites, and 82% were male; 23% had CD4+ T cell count ≤ 50 cells/mm³ and 25% had CD4 >350 cells/mm³. Median follow-up was 3.8 years. Among 64 incident NADCs, the most common were 8 anal cancers, 8 basal cell carcinomas, 8 Hodgkin's disease, and 6 lung cancers. In univariate models, age, smoking and recent (time-updated) CD4 were associated with incident NADC. There was no association between initial ART drug class (protease inhibitor, nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor) and NADC. After adjusting for age, race and sex: smoking [relative risk = 2.12 (95% CI = 1.1-4.08)] and recent CD4 (≤ 50 cells/mm³: 3.58, 1.22-10.45; 51-200 cells/mm³: 2.54, 1.30-5.0; 201-350 cells/mm³: 2.37, 1.32-4.26 vs. >350 cells/mm³) were associated with NADC.
Smoking and lower recent CD4 levels, but not initial ART drug class, were associated with NADC. Strategies for maintaining higher CD4 cell counts and successful smoking cessation may reduce the NADC incidence in the HIV-infected population.
Oncology 05/2011; 80(1-2):42-9. · 2.27 Impact Factor
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Fred R Sattler,
Shalender Bhasin,
Jiaxiu He,
Kevin Yarasheski,
Ellen Binder,
E Todd Schroeder,
Carmen Castaneda-Sceppa,
Miwa Kawakubo,
Ronenn Roubenoff,
Matthew Dunn,
Chris Hahn,
Yolanda Stewart,
Carmen Martinez,
Stanley P Azen
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ABSTRACT: Objectives: Determine the durability of anabolic effects and adverse events (AEs) after stopping testosterone and growth hormone supplementation in older men. Design: Secondary analysis of a double-masked, randomized controlled trial of testosterone gel (5g or 10g/daily) plus rhGH (0, 3, or 5ug/kg/day) with follow-up of outcomes 3-months later. Participants: 108 community-dwelling 65-90 year-old-men. Measurements: Testosterone and IGF-1 levels, body composition (DEXA), 1-repetition maximum (1-RM) strength, stair-climbing power, quality-of-life (QOL) and activity questionnaires, AEs. Results: Despite improvements in body composition during treatment, residual benefits 3-months later (week-28) were variable. For participants with improvements exceeding their week-17 median changes, benefits were sustained at week 28 for lean body mass (LBM, 1.45±1.63kg, 45% of week-17 values, p<0.0001-vs-baseline), appendicular skeletal muscle mass (ASMM, 0.71±1.01kg, 42%, p<0.0001), total fat (-1.06±2.18kg, 40%, p<0.0001,), and trunk fat (-0.89±1.42kg, 50%, p<0.0001,); retention of ASMM was associated with greater week-16 protein intake (p=0.01). For 1-RM strength, 39%-43% of week-17 improvements (p≤0.05) were retained and associated with better week-17 strength (p<0.0001), change in testosterone from week-17-to-28 (p=0.004) and baseline PASE (p=0.04). Framingham 10-year cardiovascular risks were low (∼14%), didn't worsen, and improved by week-28 (p=0.0002). The hypothalamic-pituitary-gonadal axis recovered completely. Conclusions: Durable improvements in muscle mass, strength, and fat mass were retained 3-months after discontinuing hormone supplementation in participants with greater than median body composition changes during treatment, but not in others with smaller gains. AEs largely resolved after intervention discontinuation. Additional strategies may be needed to sustain or augment muscle mass and strength gains achieved during short-term hormone therapy.
Clinical Endocrinology 03/2011; · 3.17 Impact Factor
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The Journal of Infectious Diseases 06/2010; 201(12):1783-5. · 6.41 Impact Factor
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ABSTRACT: The use of hormone replacement therapy (HRT) is a potential treatment to relieve symptoms of menopause in postmenopausal women; however, the effects on skeletal muscle are unclear. Specifically, it is unknown if HRT enhances estrogen receptor (ER) transcriptional activation in skeletal muscle at rest and after resistance exercise.
To evaluate changes in the messenger RNA (mRNA) expression of ER coregulators (steroid receptor coactivator-1 (SRC-1) and silencing mediator of retinoid and thyroid receptors (SMRT)) in postmenopausal women after a maximal eccentric exercise bout.
Fourteen postmenopausal women were divided into two groups: control, women not using HRT (n = 6, 59.2 +/- 4.2 yr, 63.1 +/- 17.4 kg); or HRT, women using traditional HRT (n = 8, 58.5 +/- 3.7 yr, 89.5 +/- 23.7 kg). Participants performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60 degrees .s with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. mRNA expression was determined using real-time polymerase chain reaction for SRC-1 and SMRT.
mRNA expression of SRC-1 significantly increased (P < or = 0.01; 2.4- to 5.2-fold change) and mRNA expression of SMRT significantly decreased (P < or = 0.01; -1.3- to -4.3-fold change) after the exercise bout in both groups. We observed significantly greater changes in mRNA expression of SRC-1 and SMRT (P < or = 0.01) in the HRT group compared with controls after exercise.
A single bout of maximal eccentric exercise enhances ER transcriptional activity with a greater response present in postmenopausal women using HRT.
Medicine and science in sports and exercise 03/2010; 42(3):422-9. · 3.71 Impact Factor
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ABSTRACT: We evaluated changes in myostatin, follistatin, and MyoD messenger RNA (mRNA) gene expression using eccentric exercise (EE) and concentric exercise (CE) as probes to better understand the mechanisms of muscle hypertrophy in young women. Twelve women performed single-leg maximal eccentric (n = 6, 25 +/- 1 years, 59 +/- 7 kg) or concentric (n = 6, 24 +/- 1 years, 65 +/- 7 kg) isokinetic knee extension exercise for 7 sessions. Muscle biopsies were taken from the vastus lateralis at baseline, 8 hours after the first exercise session, and 8 hours after the seventh exercise session. In the EE group, there were no changes in myostatin and follistatin (p > or = 0.17); however, MyoD expression increased after 1 exercise bout (p = 0.02). In the CE group, there were no changes in myostatin, follistatin, or MyoD mRNA gene expression (p > or = 0.07). Differences between the EE and CE groups were not significant (p > or = 0.05). These data suggest that a single bout or multiple bouts of maximal EE or CE may not significantly alter myostatin or follistatin mRNA gene expression in young women. However, MyoD mRNA expression seems to increase only after EE.
The Journal of Strength and Conditioning Research 02/2010; 24(2):522-30. · 1.83 Impact Factor
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Shalender Bhasin,
E Jiaxiu He,
Miwa Kawakubo,
E Todd Schroeder,
Kevin Yarasheski,
Gregory J Opiteck,
Alise Reicin,
Fabian Chen,
Raymond Lam,
Jeffrey A Tsou,
Carmen Castaneda-Sceppa,
Ellen F Binder,
Stanley P Azen, Fred R Sattler
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ABSTRACT: Biomarkers that predict musculoskeletal response to anabolic therapies should expedite drug development. During collagen synthesis in soft lean tissue, N-terminal propeptide of type III procollagen (P3NP) is released into circulation. We investigated P3NP as a biomarker of lean body mass (LBM) and muscle strength gains in response to testosterone and GH.
Community-dwelling older men received GnRH agonist plus 5 or 10 g testosterone gel plus 0, 3, or 5 microg recombinant human GH daily. P3NP levels were measured at baseline and wk 4, 8, 12, and 16. LBM and appendicular skeletal muscle mass (ASM) were measured by dual-energy x-ray absorptiometry.
One hundred twelve men completed treatment; 106 underwent serum P3NP measurements. P3NP levels were higher at wk 4 than baseline (6.61 +/- 2.14 vs. 4.51 +/- 1.05, P < 0.0001) and reached plateau by wk 4 in men receiving testosterone alone. However, wk 8 P3NP levels were higher than wk 4 levels in men receiving testosterone plus recombinant human GH. Increases in P3NP from baseline to wk 4 and 16 were significantly associated with gains in LBM (r = 0.26, P = 0.007; r = 0.53, P < 0.001) and ASM (r = 0.17, P = 0.07; r = 0.40, P < 0.0001). Importantly, for participants receiving only testosterone, P3NP increases at wk 4 and 16 were related to muscle strength gains (r = 0.20, P = 0.056 and r = 0.36, P = 0.04). In stepwise regression, change in P3NP explained 28 and 30% of the change in ASM and LBM, respectively, whereas change in testosterone but not IGF-I and age provided only small improvements in the models.
Early changes in serum P3NP levels are associated with subsequent changes in LBM and ASM during testosterone and GH administration. Serum P3NP may be a useful early predictive biomarker of anabolic response to GH and testosterone.
The Journal of clinical endocrinology and metabolism 11/2009; 94(11):4224-33. · 6.50 Impact Factor
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ABSTRACT: Hormone replacement therapy (HRT) is used in postmenopausal women to relieve symptoms of menopause and prevent osteoporosis. We sought to evaluate changes in mRNA expression of key myogenic factors in postmenopausal women taking and not taking HRT following a high-intensity eccentric resistance exercise. Fourteen postmenopausal women were studied and included 6 control women not using HRT (59 +/- 4 years, 63 +/- 17 kg) and 8 women using traditional HRT (59 +/- 4 yr, 89 +/- 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on a Cybex dynamometer at 60 degrees /s. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined using RT-PCR for follistatin, forkhead box 3A (FOXO3A), muscle atrophy F-box (MAFbx), muscle ring finger-1 (MuRF-1), myogenic differentiation factor (MyoD), myogenin, myostatin, myogenic factor 5 (Myf5), and muscle regulatory factor 4 (MRF4). At rest, the HRT group expressed higher levels of MyoD, myogenin, Myf5, MRF4, and follistatin (P < 0.05). In response to eccentric exercise, follistatin, MyoD, myogenin, Myf5, and MRF4 were significantly increased (P <or= 0.05) and FOXO3A, MAFbx, MuRF-1, and myostatin were significantly decreased in the control and HRT groups (P <or= 0.05). Significantly greater changes in mRNA expression of follistatin, FOXO3A, MAFbx, MuRF-1, MyoD, myogenin, myostatin, Myf5, and MRF4 (p<or=0.05) occurred in the HRT group than in the control group after exercise. These data suggest that postmenopausal women using HRT express higher myogenic regulatory factor gene expression, which may reflect an attempt to preserve muscle mass. Furthermore, postmenopausal women using HRT experienced a greater myogenic response to maximal eccentric exercise.
Journal of Applied Physiology 08/2009; 107(5):1381-8. · 3.75 Impact Factor
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Fred R Sattler,
Carmen Castaneda-Sceppa,
Ellen F Binder,
E Todd Schroeder,
Ying Wang,
Shalender Bhasin,
Miwa Kawakubo,
Yolanda Stewart,
Kevin E Yarasheski,
Jagadish Ulloor,
Patrick Colletti,
Ronenn Roubenoff,
Stanley P Azen
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ABSTRACT: Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat.
We tested the hypothesis that physiological supplementation with testosterone and GH together improves body composition and muscle performance in older men.
One hundred twenty-two community-dwelling men 70.8 +/- 4.2 yr of age with body mass index of 27.4 +/- 3.4 kg/m2, testosterone of 550 ng/dl or less, and IGF-I in lower adult tertile (< or =167 ng/dl) were randomized to receive transdermal testosterone (5 or 10 g/d) during a Leydig cell clamp plus GH (0, 3, or 5 microg/kg . d) for 16 wk.
Body composition by dual-energy x-ray absorptiometry, muscle performance, and safety tests were conducted.
Total lean body mass increased (1.0 +/- 1.7 to 3.0 +/- 2.2 kg) as did appendicular lean tissue (0.4 +/- 1.4 to 1.5 +/- 1.3 kg), whereas total fat mass decreased by 0.4 +/- 0.9 to 2.3 +/- 1.7 kg as did trunk fat (0.5 +/- 0.9 to 1.5 +/- 1.0 kg) across the six treatment groups and by dose levels for each parameter (P < or = 0.0004 for linear trend). Composite maximum voluntary strength of upper and lower body muscles increased by 14 +/- 34 to 35 +/- 31% (P < 0.003 in the three highest dose groups) that correlated with changes in appendicular lean mass. Aerobic endurance increased in all six groups (average 96 +/- 137 sec longer). Systolic and diastolic blood pressure increased similarly in each group with mean increases of 12 +/- 14 and 8 +/- 8 mm Hg, respectively. Other predictable adverse events were modest and reversible.
Supplemental testosterone produced significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation.
The Journal of clinical endocrinology and metabolism 03/2009; 94(6):1991-2001. · 6.50 Impact Factor
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ABSTRACT: HIV patients with wasting are at increased risk of opportunistic complications and fatality.
We hypothesized that augmenting dietary intake with high-biologic-value protein would enhance weight and lean tissue in weight-stable subjects with a prior unintentional weight loss of >3%.
Fifty-nine subjects with HIV RNA concentrations <5000 copies/mL were randomly assigned to receive a 280-kcal supplement containing 40 g whey protein or a matched isocaloric control supplement without added protein twice daily for 12 wk.
Before the study, intake of total energy and protein exceeded estimated requirements (44.3 +/- 12.6 kcal x kg(-1) x d(-1) and 1.69 +/- 0.55 g x kg(-1) x d(-1), respectively). Both supplements failed to increase total energy intake because of decreases in self-selected food intake. Changes in weight (0.8 +/- 2.4 and 0.7 +/- 2.4 kg) and lean body mass (0.3 +/- 1.4 and 0.3 +/- 1.5 kg) did not differ significantly between the whey protein and control groups, respectively. Waist-to-hip ratio improved more with whey protein (-0.02 +/- 0.05) than with the control (0.01 +/- 0.03; P = 0.025) at week 6 but not at week 12. Fasting triacylglycerol increased by 39 +/- 98 mg/dL with the control supplement and decreased by 16 +/- 62 mg/dL with whey protein at week 12 (P = 0.03). CD4 lymphocytes increased by 31 +/- 84 cells/mm(3) with whey protein and decreased by 5 +/- 124 cells/mm(3) with the control supplement at 12 wk (P = 0.03). Gastrointestinal symptoms occurred more often with whey protein.
A whey protein supplement did not increase weight or lean body mass in HIV-positive subjects who were eating adequately, but it did increase CD4 cell counts. The control supplement with rapidly assimilable carbohydrate substituted for protein increased cardiovascular disease risk factors. Careful dietary and weight history should be obtained before starting nutritional supplements in subjects with stable weight loss and good viral control.
American Journal of Clinical Nutrition 11/2008; 88(5):1313-21. · 6.67 Impact Factor
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ABSTRACT: Maximal voluntary muscle strength (MVMS) and leg power are important measures of physical function in older adults. We hypothesized that performing these measures twice within 7-10 days would demonstrate a >5% increase due to learning and familiarization of the testing procedures.
Data were collected from three studies in older adult men (60-87 years) and were divided into two cohorts defined by study site and type of exercise equipment. MVMS was assessed in 116 participants using the one-repetition maximum method at two separate study visits for the chest press, latissimus pull-down, leg press, leg flexion, and leg extension exercises along with unilateral leg extension power.
Test-retest scores were not different and did not exceed 0.8 +/- 9.0% in Cohort 1 or 2.3 +/- 9.8% in Cohort 2, except for leg extension, which improved by 6.6 +/- 14.4% (p <.009) and 3.4 +/- 6.8% (p <.016), respectively. Repeat tests were closely correlated with initial tests (all p <.001). Pearson correlation coefficients ranged from 0.74 for leg extension power to 0.96 for leg press. Coefficients of variation were <10% (4.2%-9.0%) for all exercises except for leg extension power, which was 15.5%.
Our findings demonstrated that test-retest measures of MVMS and power in older adult men do not differ by more than 2.3% except for leg extension, and have relatively low coefficients of variation using data collected from three studies. Moreover, these findings were similar between two study sites using different equipment, which further supports the reliability of MVMS and power testing in older adult men.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2007; 62(5):543-9. · 4.60 Impact Factor
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Kathleen Mulligan,
Robert Zackin,
Jamie H Von Roenn,
Margaret A Chesney,
Merrill J Egorin, Fred R Sattler,
Constance A Benson,
Tun Liu,
Triin Umbleja,
Sharon Shriver,
Richard J Auchus,
Morris Schambelan
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ABSTRACT: Reduced energy intake is a primary factor in HIV-associated wasting. Megestrol acetate (MA) stimulates appetite and weight gain. However, much of the weight gained is fat, possibly as a result of MA-induced hypogonadism.
The objective of the study was to determine whether coadministration of testosterone with MA could enhance lean body mass (LBM) accrual and evaluate the effects of MA, alone or combined with testosterone, on sexual functioning and the hypothalamic-pituitary-adrenal axis.
This was a randomized, double-blind, placebo-controlled, multicenter trial.
Fourteen AIDS Clinical Trials Units in the United States participated in the study.
Seventy-nine HIV-positive men with 5% or more weight loss or body mass index less than 20 kg/m2 took part in the study.
Subjects were randomized to receive MA (800 mg daily) plus testosterone enanthate (200 mg; MA/TE; n = 41) or placebo (MA/PL; n = 38) biweekly for 12 wk.
Weight, body composition (bioelectric impedance analysis), adrenal and gonadal hormones, and sexual functioning (questionnaire) were measured.
Both groups experienced robust increases in weight (median 5.3 and 7.3 kg in MA/TE and MA/PL, respectively), LBM (3.3 and 3.3 kg), and fat (3.0 and 3.8 kg). There were no significant differences between groups in the magnitude or composition of weight gain (P = 0.44, 0.90, and 0.11 for weight, LBM, and fat, respectively). Trough testosterone concentrations decreased to a greater extent in MA/PL (-12.3 vs. -6.1 nmol/liter in MA/TE; P = 0.04). Cortisol levels became nearly undetectable in subjects with plasma MA levels greater than 150 ng/ml. Sexual functioning was preserved with MA/TE but worsened in MA/PL.
MA produced robust weight gain. Coadministration of testosterone preserved sexual functioning but did not enhance LBM accrual.
Journal of Clinical Endocrinology & Metabolism 03/2007; 92(2):563-70. · 6.50 Impact Factor
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E Todd Schroeder,
Carmen Castaneda-Sceppa,
Ying Wang,
Ellen F Binder,
Miwa Kawakubo,
Yolanda Stewart,
Thomas Storer,
Ronenn Roubenoff,
Shalender Bhasin,
Kevin E Yarasheski, Fred R Sattler,
Stanley P Azen
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ABSTRACT: Older persons often lose muscle mass, strength, and physical function. This report describes the challenges of conducting a complex clinical investigation assessing the effects of anabolic hormones on body composition, physical function, and metabolism during aging.
HORMA is a multicenter, randomized double masked study of 65-90-year-old community dwelling men with testosterone levels of 150-550 ng/dL and IGF-1 < 167 ng/dL. Subjects were randomized to transdermal testosterone (5 or 10 g/day) and rhGH (0, 3, or 5 microg/kg/day) for 16 weeks. Outcome measures included body composition by DEXA, MRI, and (2)H(2)O dilution; muscle performance (strength, power, and fatigability), VO2peak, measures of physical function, synthesis/breakdown of myofibrillar proteins, other measures of metabolism, and quality of life.
Major challenges included delay in startup caused by need for 7 institutional contracts, creating a 142-page manual of operations, orientation and training, creating a 121-page CRF; enrollment inefficiencies; scheduling 16 evaluations/ subject; overnight admissions for invasive procedures and isotope infusions; large data and image management and transfer; quality control at multiples sites; staff turnover; and replacement of a clinical testing site. Impediments were largely solved by implementation of a web-based data entry and eligibility verification; electronic scheduling for multiple study visits; availability of research team members to educate and reassure subjects; more frequent site visits to validate all source documents and reliability of data entry; and intensifying quality control in testing and imaging. The study exceeded the target goal of 108 (n = 112) completely evaluable cases. Two interim DSMB meetings confirmed the lack of excessive adverse events, lack of center effects, comparability of subjects, and that distribution of subjects and enrollment will not jeopardize outcomes or generalizability of results.
Flexibility and rapidly solving evolving problems is critical when conducting highly complex multicenter metabolic studies.
Clinical Trials 02/2007; 4(5):560-71. · 1.92 Impact Factor
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ABSTRACT: In older ambulatory persons, exercise strategies that are expected to generate beneficial muscle adaptations with low cardiopulmonary demands are needed.
We hypothesised that eccentric resistance exercise would be less demanding on the cardiovascular and pulmonary systems than bouts of concentric resistance exercise.
The effects of eccentric and concentric resistance exercise were compared during leg squats at a submaximal intensity known to increase muscle mass.
19 Older persons (15 women/four men, age 65 +/- 4 years) and 19 young reference controls (10 women/nine men; age 25 +/- 2 years) were enrolled.
Participants completed eccentric-only and concentric-only exercise bouts 5-7 days apart.
Cardiovascular and pulmonary measures were collected from subjects during bouts consisting of three sequential sets of 10 repetitions at 65% of their voluntary concentric 1-repetition maximum force (68+/-16 kg for older participants and 94 +/- 36 kg for young participants). Peak heart rate (119 +/- 10 versus 155 +/- 16 b.p.m.), systolic blood pressure (129 +/- 18 versus 167 +/- 14 mmHg), cardiac index (7.8 +/- 2.0 versus 9.2 +/- 1.5 l/min/m2) and expired ventilation (20.5 +/- 5.7 versus 29.8 +/- 9.1 l/min) were significantly lower during eccentric than during concentric bouts in the older subjects, respectively (P < 0.001 for all comparisons). Similarly, peak heart rate, systolic blood pressure, cardiac index and expired ventilation were significantly lower during eccentric bouts in the young control subjects.
Eccentric resistance exercise produced less cardiopulmonary demands and may be better suited for older persons with low exercise tolerance and at risk of adverse cardiopulmonary events.
Age and Ageing 06/2006; 35(3):291-7. · 3.09 Impact Factor
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ABSTRACT: We tested the hypothesis that the expansion of satellite cell numbers, 24 h after maximal eccentric knee extensor exercise, is blunted in older men. Muscle biopsies were obtained from the vastus lateralis of 10 young (23-35 years) and 9 older (60-75 years) men. Satellite cells were identified immunohistochemically using an antibody to neural cell adhesion molecule. After 92 maximal eccentric contractions, the mean number of satellite cells per muscle fiber increased to a greater extent among the young men (141%; P < 0.001) than older men (51%; P = 0.002) from preexercise levels. Similar results were obtained when satellite cells were expressed as a proportion of all sublaminar nuclei. We conclude that a single bout of maximal eccentric exercise increases satellite cell numbers in both age groups, with a significantly greater response among the young men. These data suggest that age-related changes in satellite cell recruitment may contribute to muscle regeneration deficits among the elderly.
Muscle & Nerve 02/2006; 33(2):242-53. · 2.37 Impact Factor
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ABSTRACT: The purpose of our study was to assess the early effects of a potent anabolic androgen on muscle mass and strength, lower extremity power, and functional performance in older men.
Thirty-two men 72 +/- 6 years of age were randomized to receive oxandrolone (10 mg twice daily) or matching placebo in a 2:1 manner for 12 weeks. Total and appendicular lean body mass (LBM) were assessed by dual-energy x-ray absorptiometry (DEXA). Lower extremity muscle volume was determined by magnetic resonance imaging to validate DEXA changes.
Total LBM increased by 2.7 +/- 1.6 kg after 6 weeks with oxandrolone (p <.001), which was greater (p <.001) than the decline in LBM (-0.5 +/- 0.9 kg) with placebo. Appendicular LBM increased by 1.2 +/- 0.9 kg after just 6 weeks with oxandrolone (p <.001), which was greater (p <.001) than the decline in LBM (-0.4 +/- 0.5 kg) with placebo. These changes were >90% of the gains in total and appendicular LBM (3.0 +/- 1.5 kg and 1.3 +/- 0.9 kg, respectively) after 12 weeks. Total thigh and hamstring muscle volume increased by 111 +/- 29 mm(3) (p =.001) and 75 +/- 18 mm(3) (p =.001), respectively, after 12 weeks. Maximal strength increased for the leg press 6.3 +/- 5.6% (p =.003), leg curl 6.7 +/- 8.6% (p =.01), chest press 6.9 +/- 6.5% (p =.001), and latissimus pull-down 4.8 +/- 6.3% (p =.009) with oxandrolone after 6 weeks; these increases were different than those with placebo (p <.001) and were 93%, 96%, 74%, and 94% of the respective gains at week 12. There were no improvements in functional measures.
Treatment with a potent anabolic androgen may produce significant increases in muscle mass and strength after only 6 weeks in healthy older men. However, such treatment did not improve leg muscle power or walking speed.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 01/2006; 60(12):1586-92. · 4.60 Impact Factor
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ABSTRACT: Weight loss is associated with accelerated mortality and disease progression in patients with human immunodeficiency virus (HIV) infection. Although studies have examined a variety of anabolic therapies in HIV-infected men, the safety and efficacy of such treatments in women have not been adequately studied.
In this randomized, double-blind, placebo-controlled, multicenter, phase I/II study, 38 HIV-infected women with documented weight loss of 5% or greater in the preceding year or a body mass index of less than 20 kg/m(2) were randomized to receive nandrolone decanoate (100 mg) or an equivalent volume of placebo every other week by intramuscular injection. Subjects received blinded treatment for 12 weeks, followed by open-label therapy for 12 weeks. Lean body mass and fat (bioelectrical impedance analysis) and weight were measured at baseline and at weeks 6, 12, 18, and 24. Biochemical assessments of safety (hematologic analyses, liver function tests, and sex hormone measurements) were performed at these same time points. Clinical signs and symptoms were monitored biweekly.
Subjects randomized to receive nandrolone had significant increases in weight and lean body mass during blinded treatment (4.6 kg [9.0%] and 3.5 kg [8.6%], respectively; P<.001 vs baseline and placebo in each case). Fat mass did not change statistically significantly in either group. Although there were no statistically significant differences between groups in biochemical measures, the number of grade 3 or greater toxicities, or reports of virilizing effects, a full assessment of safety cannot be made in a trial of this size.
Nandrolone decanoate therapy may prove to be generally safe and beneficial in reversing weight loss and lean tissue loss in women with HIV infection and other chronic catabolic diseases.
Archives of Internal Medicine 04/2005; 165(5):578-85. · 11.46 Impact Factor
