Evaluation of early biomarkers of muscle anabolic response to testosterone.
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ABSTRACT:
SUBMITTER: Chen F
PROVIDER: S-EPMC3063869 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Loss of muscle mass and strength with aging, also termed sarcopenia, results in a loss of mobility and independence. Exercise, particularly resistance training, has proven to be beneficial in counteracting the aging-associated loss of skeletal muscle mass and function. However, the anabolic response to exercise in old age is not as robust, with blunted improvements in muscle size, strength, and function in comparison to younger individuals. This review provides an overview of several physiological changes which may contribute to age-related loss of muscle mass and decreased anabolism in response to resistance training in the elderly. Additionally, the following supplemental therapies with potential to synergize with resistance training to increase muscle mass are discussed: nutrition, creatine, anti-inflammatory drugs, testosterone, and growth hormone (GH). Although these interventions hold some promise, further research is necessary to optimize the response to exercise in elderly patients.
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Project description:Leucine (Leu), an essential amino acid, is known to stimulate protein synthesis in the skeletal muscle via mTOR complex 1 (mTORC1) activation. However, the intrinsic contribution of other amino acids to Leu-mediated activation of mTORC1 signaling remains unexplored. This study aimed to identify amino acids that can promote mTORC1 activity in combination with Leu and to assess the effectiveness of these combinations in vitro and in vivo. We found that tyrosine (Tyr) enhanced Leu-induced phosphorylation of S6 kinase (S6K), an indicator of mTORC1 activity, although it exerted no such effect individually. This booster effect was observed in C2C12 cells, isolated murine muscle, and the skeletal muscles of mice orally administered the amino acids. To explore the molecular mechanisms underlying this Tyr-mediated booster effect, the expression of the intracellular Leu sensors, Sestrin1 and 2, was suppressed, and the cells were treated with Leu and Tyr. This suppression enabled Tyr alone to induce S6K phosphorylation and enhanced the booster effect, suggesting that Tyr possibly contributes to mTORC1 activation when Sestrin-GAP activity toward Rags 2 (GATOR2) is dissociated through Sestrin knockdown or the binding of Sestrins to Leu. Collectively, these results indicate that Tyr is a key regulator of Leu-mediated protein synthesis.
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Project description:BACKGROUND: Immobilization-induced loss of muscle mass is a complex phenomenon with several parallels to sarcopenic and cachectic muscle loss. Muscle is a large organ with a protein turnover that is orders of magnitude larger than most other tissues. Thus, we hypothesize that muscle loss and regain is reflected by peptide biomarkers derived from type VI collagen processing released in the circulation. METHODS: In order to test this hypothesis, we set out to develop an ELISA assay against an type VI collagen N-terminal globular domain epitope (IC6) and measured the levels of IC6 and an MMP-generated degradation fragment of collagen 6, (C6M) in a human immobilization-remobilization study setup with young (n?=?11) and old (n?=?9) men. They were subjected to 2 weeks of unilateral lower limb immobilization followed by 4 weeks of remobilization including thrice weekly resistance training, using the contralateral leg as internal controls. Subjects were sampled for strength, quadriceps muscle volume and blood at baseline (PRE), post-immobilization (2W), and post-remobilization (4W). Blood were subsequently analyzed for levels of the C6M and IC6 biomarkers. We subsequently tested if there was any correlation between C6M, IC6, or the C6M/IC6 ratio and muscle mass or strength at baseline. We also tested whether there was any relation between these biomarkers and changes in muscle mass or strength with immobilization or remobilization. RESULTS: The model produced significant loss of muscle mass and strength in the immobilized leg. This loss was bigger in young subjects than in elderly, but whereas the young recovered almost fully, the elderly had limited regrowth of muscle. We found a significant correlation between IC6 and muscle mass at baseline in young subjects (R (2)?=?0.6563, p?=?0.0045), but none in the elderly. We also found a significant correlation between C6M measured at the 4W time point and the change in muscle mass during remobilization, again only manifesting in the young men(R (2)?=?0.6523, p?=?0.0085). This discrepancy between the young and the elderly may be caused in part by much smaller changes in muscle mass in the elderly and partly by the relative small sample size. CONCLUSION: While we cannot rule out the possibility that these biomarkers in part stem from other tissues, our results strongly indicate that these markers represent novel biomarkers of muscle mass or change in muscle mass in young men.
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Project description:BackgroundThe ginsenoside Rg1 has been shown to exert various pharmacological activities with health benefits. Previously, we have reported that Rg1 promoted myogenic differentiation and myotube growth in C2C12 myoblasts. In this study, the in vivo effect of Rg1 on fiber-type composition and oxidative metabolism in skeletal muscle was examined.MethodsTo examine the effect of Rg1 on skeletal muscle, 3-month-old mice were treated with Rg1 for 5 weeks. To assess muscle strength, grip strength tests were performed, and the lower hind limb muscles were harvested, followed by various detailed analysis, such as histological staining, immunoblotting, immunostaining, and real-time quantitative reverse transcription polymerase chain reaction. In addition, to verify the in vivo data, primary myoblasts isolated from mice were treated with Rg1, and the Rg1 effect on myotube growth was examined by immunoblotting and immunostaining analysis.ResultsRg1 treatment increased the expression of myosin heavy chain isoforms characteristic for both oxidative and glycolytic muscle fibers; increased myofiber sizes were accompanied by enhanced muscle strength. Rg1 treatment also enhanced oxidative muscle metabolism with elevated oxidative phosphorylation proteins. Furthermore, Rg1-treated muscles exhibited increased levels of anabolic S6 kinase signaling.ConclusionRg1 improves muscle functionality via enhancing muscle gene expression and oxidative muscle metabolism in mice.
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Project description:Anabolic resistance to a mechanical stimulus may contribute to the loss of skeletal muscle mass observed with age. In this study, young and aged mice were injected with saline or human LM-111 (1 mg/kg). One week later, the myotendinous junction of the gastrocnemius muscle was removed via myotenectomy (MTE), thus placing a chronic mechanical stimulus on the remaining plantaris muscle for 2 weeks. LM-111 increased α7B integrin protein expression and clustering of the α7B integrin near DAPI+ nuclei in aged muscle in response to MTE. LM-111 reduced CD11b+ immune cells, enhanced repair, and improved the growth response to loading in aged plantaris muscle. These results suggest that LM-111 may represent a novel therapeutic approach to prevent and/or treat sarcopenia.
| S-EPMC8011696 | biostudies-literature
Project description:Context:Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. Objective:To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone. Design:Double-blind, placebo-controlled trial. Setting:Twelve academic medical centers in the United States. Participants:In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Intervention:Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcome Measures:Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Results:Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, -6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, -2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, -2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, -1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, -0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo. Conclusions and Relevance:Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes.
| S-EPMC5800829 | biostudies-literature
Project description:Purpose of reviewICU survivors frequently suffer significant, prolonged physical disability. 'ICU Survivorship', or addressing quality-of-life impairments post-ICU care, is a defining challenge, and existing standards of care fail to successfully address these disabilities. We suggest addressing persistent catabolism by treatment with testosterone analogues combined with structured exercise is a promising novel intervention to improve 'ICU Survivorship'.Recent findingsOne explanation for lack of success in addressing post-ICU physical disability is most ICU patients exhibit severe testosterone deficiencies early in ICU that drives persistent catabolism despite rehabilitation efforts. Oxandrolone is an FDA-approved testosterone analogue for treating muscle weakness in ICU patients. A growing number of trials with this agent combined with structured exercise show clinical benefit, including improved physical function and safety in burns and other catabolic states. However, no trials of oxandrolone/testosterone and exercise in nonburn ICU populations have been conducted.SummaryCritical illness leads to a catabolic state, including severe testosterone deficiency that persists throughout hospital stay, and results in persistent muscle weakness and physical dysfunction. The combination of an anabolic agent with adequate nutrition and structured exercise is likely essential to optimize muscle mass/strength and physical function in ICU survivors. Further research in ICU populations is needed.
| S-EPMC8367823 | biostudies-literature
Project description:BACKGROUND:Altering the temporal distribution of energy intake (EI) and introducing periods of intermittent fasting (IF) exert important metabolic effects. Restricting EI to earlier in the day [early time-restricted feeding (eTRF)] is a novel type of IF. OBJECTIVES:We assessed the chronic effects of eTRF compared with an energy-matched control on whole-body and skeletal muscle insulin and anabolic sensitivity. METHODS:Sixteen healthy males (aged 23 ± 1 y; BMI 24.0 ± 0.6 kg·m-2) were assigned to 2 groups that underwent either 2 wk of eTRF (n = 8) or control/caloric restriction (CON:CR; n = 8) diet. The eTRF diet was consumed ad libitum and the intervention was conducted before the CON:CR, in which the diet was provided to match the reduction in EI and body weight observed in eTRF. During eTRF, daily EI was restricted to between 08:00 and 16:00, which prolonged the overnight fast by ?5 h. The metabolic responses to a carbohydrate/protein drink were assessed pre- and post-interventions following a 12-h overnight fast. RESULTS:When compared with CON:CR, eTRF improved whole-body insulin sensitivity [between-group difference (95% CI): 1.89 (0.18, 3.60); P = 0.03; ?2p = 0.29] and skeletal muscle uptake of glucose [between-group difference (95% CI): 4266 (261, 8270) ?mol·min-1·kg-1·180 min; P = 0.04; ?2p = 0.31] and branched-chain amino acids (BCAAs) [between-group difference (95% CI): 266 (77, 455) nmol·min-1·kg-1·180 min; P = 0.01; ?2p = 0.44]. eTRF caused a reduction in EI (?400 kcal·d-1) and weight loss (-1.04 ± 0.25 kg; P = 0.01) that was matched in CON:CR (-1.24 ± 0.35 kg; P = 0.01). CONCLUSIONS:Under free-living conditions, eTRF improves whole-body insulin sensitivity and increases skeletal muscle glucose and BCAA uptake. The metabolic benefits of eTRF are independent of its effects on weight loss and represent chronic adaptations rather than the effect of the last bout of overnight fast. This trial was registered at clinicaltrials.gov as NCT03969745.
| S-EPMC7528549 | biostudies-literature
Project description:Biomarkers that predict response to anabolic therapies could expedite the development of function promoting anabolic drugs. This study aimed to identify serum biomarkers that are responsive to testosterone administration and associated with increases in fat-free mass (FFM). Serum samples were obtained from the 5α-Reductase Trial, a randomized trial that compared the effects of graded doses of testosterone enanthate for 20-weeks in healthy men randomized to placebo or dutasteride (dual SRD5A inhibitor). Testosterone's effects on FFM or strength measures did not differ between placebo vs dutasteride groups. Accordingly, 54 subjects treated with testosterone plus placebo were included in the Discovery Cohort, and 48 randomized to dutasteride were included in the Validation Cohort. 1162 biomarkers were evaluated using pre-specified criteria. In the Discovery Cohort, testosterone administration increased PRO-C3 and PRO-C6 levels in a dose- and concentration-dependent manner; increases in these biomarkers from baseline to week-12 were associated with changes in FFM from baseline to week-20 (PRO-C3: r2=0.437, p<0.001; PRO-C6: r2=0.434, p<0.001). Changes in PRO-C3 and PRO-C6 levels were significantly associated with changes in chest press strength (PRO-C3: r2=0.394, p<0.001; PRO-C6: r2=0.530, p<0.001). In the SOMAscan, changes in insulin-like growth factor binding protein-6 (IGFBP6) and Glypican 3 (GPC3) were associated with changes in total and free testosterone levels and FFM. These findings were replicated in the Validation Cohort. PRO-C3, PRO-C6, IGFBP6 and GPC3 fulfilled the pre-specified criteria for biomarkers of testosterone-induced muscle anabolism: changes in these biomarkers were associated with changes in total and free testosterone concentrations and with testosterone-induced gains in FFM.
| S-EPMC6656422 | biostudies-literature
Project description:Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone's adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone's promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without ?-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone's effects on prostate, but did not affect testosterone's anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.
| S-EPMC4331775 | biostudies-literature