Context: Inadequate dietary protein intake has been implicated in sarcopenia. Objective and Design: The objectives of this study were to determine whether: 1) chronic essential amino acid (EAA) supplementation improves postabsorptive muscle protein fractional synthesis rate (FSR), lean body mass (LBM), and one-repetition maximum muscle strength, and androgen receptor and IGF-I muscle protein expression; and 2) the acute anabolic response to EAA ingestion is preserved after a 3-month supplementation period. Using a randomized, double-blinded, placebo-controlled design, older women (68 ± 2 yr) were assigned to receive either placebo (n = 7), or 15 g EAA/d [supplemented treatment group (SUP)] (n = 7) for 3 months. Metabolic outcomes were assessed in association with stable isotope studies conducted at 0 and 3 months. Setting: The study was performed at The University of Texas Medical Branch General Clinical Research Center. Results: Ingestion of 7.5 g EAA acutely stimulated FSR in both groups at 0 months (P < 0.05). Basal FSR at 3 months was increased in SUP only. The magnitude of the acute response to EAA was unaltered after 3 months in SUP. LBM increased in SUP only (P < 0.05). One-repetition maximum strength remained unchanged in both groups. Basal IGF-I protein expression increased in SUP after 3 months (P = 0.05), with no changes in androgen receptor or total and phosphorylated Akt, mammalian target of rapamycin, S6 kinase, and 4E-binding protein. Conclusions: EAA improved LBM and basal muscle protein synthesis in older individuals. The acute anabolic response to EAA supplementation is maintained over time and can improve LBM, possibly offsetting the debilitating effects of sarcopenia.

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.

Background: The loss of skeletal muscle mass that occurs with aging, chronic disease or acute injury is clinically important in the health of humans. The mechanisms relating to the synthesis and breakdown of skeletal muscle are now being intensely investigated. Current studies and possible mechanisms for skeletal muscle protein synthesis and degradation will be reviewed with a specific focus on growth hormone and testosterone. Conclusions:Investigation of the mechanisms of action of growth hormone and testosterone in skeletal muscle will likely lead to new therapies to prevent skeletal muscle loss and new awareness of the importance of skeletal muscle in health and disease.

With the progressive aging of the human population, there is an inexorable decline in muscle mass, strength and function. Anabolic supplementation with testosterone has been shown to effectively restore muscle mass in both young and elderly men. In this study, we were interested in identifying serum factors that change with age in two distinct age groups of healthy men, and whether these factors were affected by testosterone supplementation. We measured the protein levels of a number of serum biomarkers using a combination of banked serum samples from older men (60 to 75 years) and younger men (ages 18 to 35), as well as new serum specimens obtained through collaboration. We compared baseline levels of all biomarkers between young and older men. In addition, we evaluated potential changes in these biomarker levels in association with testosterone dose (low dose defined as 125 mg per week or below compared to high dose defined as 300 mg per week or above) in our banked specimens. We identified nine serum biomarkers that differed between the young and older subjects. These age-associated biomarkers included: insulin-like growth factor (IGF1), N-terminal propeptide of type III collagen (PIIINP), monokine induced by gamma interferon (MIG), epithelial-derived neutrophil-activating peptide 78 (ENA78), interleukin 7 (IL-7), p40 subunit of interleukin 12 (IL-12p40), macrophage inflammatory protein 1β (MIP-1β), platelet derived growth factor β (PDGFβ) and interferon-inducible protein 10 (IP-10). We further observed testosterone dose-associated changes in some but not all age related markers: IGF1, PIIINP, leptin, MIG and ENA78. Gains in lean mass were confirmed by dual energy X-ray absorptiometry (DEXA). Results from this study suggest that there are potential phenotypic biomarkers in serum that can be associated with healthy aging and that some but not all of these biomarkers reflect gains in muscle mass upon testosterone administration.

The promoter/regulatory region of the porcine P-450 cholesterol side chain cleavage (P450scc) gene was cloned from a porcine genomic library. This gene contains a GC-rich region (-130-100) that mediates insulin-like growth factor I (IGF-I) and cAMP stimulation of gene expression in porcine granulosa cells. Stimulation of gene expression by cAMP occurs in 6 h, while IGF-I stimulation occurs in 24-48 h. This region is also responsive to insulin but not fibroblast growth factor. The effects of IGF-I and cAMP on gene expression in porcine granulosa cells are additive. In Y1 adrenal cells, the same region is responsive to cAMP but not to IGF-I. Gel shift assays using an oligonucleotide of this region and nuclear extract protein from porcine granulosa and Y1 adrenal cells identified three DNA-protein complexes (C1-C3). The binding activity of the complexes did not change with IGF-I or forskolin treatment of granulosa cells. Mutational analysis results were consistent with IGF-I regulating gene expression through the C2 DNA protein complex. Moreover, this complex binds differently in gel shift assay to mutant oligonucleotides with porcine and Y1 and nuclear extract protein. We conclude that IGF-I stimulates porcine P450scc gene expression through a distinct, cell-specific protein complex binding to a GC-rich domain.

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.