RET
Proto-oncogene tyrosine-protein kinase receptor Ret precursor (EC 2.7.10.1) (Cadherin family member 12) (Proto-oncogene c-Ret) [Contains: Soluble RET kinase fragment; Extracellular cell-membrane anchored RET cadherin 120 kDa fragment] [CDHF12] [CDHR16] [PTC] [RET51]
Publications[править]
Regular physical activity has a positive effect on the prevention of cellular aging. The present study investigated the effect of 12-week resistance training (RT) on serum levels of Sirtuin-1 (SIRT1), Sirtuin-3 (SIRT3), Sirtuin-6 (SIRT6), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), and telomerase enzyme in elderly men. For this purpose, 30 elderly men (age 66.23 ± 0.57 years) were randomly divided into two groups: resistance training group (RET, n = 15) and control group (CTR, n = 15). Participants in RET performed RT protocols with intensity of 60% one-repetition maximum (3×/week, 4 sets of the six exercise circuits). Body composition, physical functioning and, blood samples were assessed before (pre-test) and after (post-test) a 12-week intervention. The results showed that there was a significant increase in serum levels of SIRT1 (P = 0.001), SIRT3 (P = 0.001), SIRT6 (P = 0.02), PGC1-α (P = 0.001), and telomerase enzyme (P = 0.001) in RET. Also, we found a significant difference between the RET and CTR in serum levels of SIRT1 (P = 0.001), SIRT3 (P = 0.001), SIRT6 (P = 0.037), PGC1-α (P = 0.007), and telomerase enzyme (P = 0.001). 12-Week RT increased the levels of proteins associated with the biological aging process in elderly men. It seems that the RT may have beneficial effects on cellular senescence and also improved impaired mitochondrial protein and enzymatic functional induced aging.
Keywords
- Cellular senescence
- Elderly
- Resistance training
Resistance exercise training (RET) has proven effective at reducing the risk of chronic disease in older populations, and it appears to regulate redox homeostasis. To determine the effects of RET on redox homeostasis in older people. A systematic review and meta-analysis of randomized clinical trials identified by searching MEDLINE, Web of Science, EMBASE, Sportdiscus, LILACS, CENTRAL and CINAHL. We included studies of subjects aged 65 years or older, with or without pathologies, and including RET metrics with quantified molecular oxidation and antioxidant capacity outcomes. Fifteen studies were included in this review. Agreement between reviewers reached a kappa value of 0.725. There were a total of 614 participants, with an average age of 68.1 years. Five (for molecular oxidation markers) and three (for antioxidant capacity markers) studies included data that quantified the effects of RET on homeostasis redox. The results of the meta-analysis showed that there were no differences in the molecular oxidation markers (SMD = -0.26; 95% CI = -0.57 to 0.05; P = 0.10; I2 = 0%) and antioxidant capacity markers (SMD = 0.53; 95% CI = -0.20 to 1.26; P = 0.16; I2 = 71.5%) in healthy older people after a RET of 8-24 weeks compared to non-intervention. Based on a small number of studies of low methodological quality, this systematic review with meta-analysis suggests that RET is not effective at reducing molecular oxidation markers in healthy older people. More research is needed on the effects of RET on redox homeostasis in older people. CRD42019121529.
Keywords
- Aging
- Antioxidants
- Exercise
- Oxidative stress
- Resistance exercise training
The present study examined 8 weeks of resistance training and its effects on muscle quality measures, plantar flexor muscle strength, muscle thickness and functional capacity in older women. Moreover, we tested if changes in muscle quality were associated with functional capacity. Twenty-four older women (66.3 ± 5.8 years; 69.0 ± 3.0 kg; 25.3 ± 1.4 kg·m ) were recruited to the study. After completion of the baseline assessment, participants were randomly assigned to either the resistance training (RET, n = 12) or an active control group (CTR, n = 12). Muscle quality was evaluated through muscle echo intensity (MQ ) and specific tension (MQ ). Muscle thickness, unilateral plantar flexor muscle strength and functional tests were evaluated at baseline and after the training period. After 8 weeks, both MQ and MQ did not respond to the intervention. Furthermore, significant changes in stair climb performance (P < 0.05) were not associated with plantar flexor-derived muscle quality (P > 0.05). Finally, significant gains in muscle hypertrophy were observed in the RET group (P < 0.01), while muscle strength failed to change significantly (P > 0.05). In conclusion, a resistance training program provided significant benefits in the stair climb test, unrelated to plantar flexor-derived muscle quality measures as previously demonstrated in quadriceps femoris.
Keywords
- Aging
- Muscle echo intensity
- Muscle quality
- Physical function
- Resistance training
Aging induces physiological decline in human skeletal muscle function and morphology, including type II fiber atrophy and an increase in type I fiber frequency. Resistance exercise training (RET) is an effective strategy to overcome muscle mass loss and improve strength, with a stronger effect on type II fibers. In the present study, we sought to determine the effect of a 12-wk progressive RET program on the fiber type-specific skeletal muscle hypertrophic response in older adults. Nineteen subjects [10 men and 9 women (71.1 ± 4.3 yr)] were studied before and after the 12-wk program. Immunohistochemical analysis was used to quantify myosin heavy chain (MyHC) isoform expression, cross-sectional area (CSA), satellite cell abundance, myonuclear content, and lipid droplet density. RET induced an increase in MyHC type II fiber frequency and a concomitant decrease in MyHC type I fiber frequency. Mean CSA increased significantly only in MyHC type II fibers ( 23.3%, [i]P[/i] < 0.05), but myonuclear content increased only in MyHC type I fibers ([i]P[/i] < 0.05), with no change in MyHC type II fibers. Satellite cell content increased ~40% in both fiber types ([i]P[/i] > 0.05). RET induced adaptations to the capillary supply to satellite cells, with the distance between satellite cells and the nearest capillary increasing in type I fibers and decreasing in type II fibers. Both fiber types showed similar decrements in intramuscular lipid density with training ([i]P[/i] < 0.05). Our data provide intriguing evidence for a fiber type-specific response to RET in older adults and suggest flexibility in the myonuclear domain of type II fibers during a hypertrophic stimulus. In older adults, progressive resistance exercise training (RET) increased skeletal muscle fiber volume and cross-sectional area independently of myonuclear accretion, leading to an expansion of the myonuclear domain. Fiber type-specific analyses illuminated differential adaptation; type II fibers underwent hypertrophy and exhibited myonuclear domain plasticity, whereas myonuclear accretion occurred in type I fibers in the absence of a robust hypertrophic response. RET also augmented satellite cell-capillary interaction and reduced intramyocellular lipid density to improve muscle quality.
Keywords
- aging
- hypertrophy
- myonuclear domain
- skeletal muscle
Adequate muscle perfusion supports the transport of nutrients, oxygen and hormones into muscle fibers. Aging is associated with a substantial decrease in skeletal muscle capillarization, fiber size and oxidative capacity, which may be improved with regular physical activity. The aim of this study was to investigate the relationship between muscle capillarization and indices of muscle hypertrophy (i.e. lean mass; fiber cross sectional area (CSA)) in older adults before and after 12 weeks of progressive resistance exercise training (RET). Interventional study SETTING AND PARTICIPANTS: 19 subjects (10 male and 9 female; 71.1 ± 4.3 years; 27.6 ± 3.2 BMI) were enrolled in the study and performed a whole body RET program for 12 weeks. Subjects where then retrospectively divided into a LOW or HIGH group, based on their pre-RET capillary-to-fiber perimeter exchange index (CFPE). Physical activity level, indices of capillarization (capillaries-to-fiber ratio, C:Fi; CFPE index and capillary-to-fiber interface, LC-PF index), muscle hypertrophy, muscle protein turnover and mitochondrial function were assessed before and after RET. Basal capillarization (C:Fi; CFPE and LP-CF index) correlates with daily physical activity level (C:Fi, r = 0.57, p = 0.019; CFPE index, r = 0.55, p = 0.024; LC-PF index, r = 0.56, p = 0.022) and CFPE and LC-PF indices were also positively associated with oxidative capacity (respectively r = 0.45, p = 0.06; r = 0.67, p = 0.004). Following RET, subjects in the HIGH group underwent hypertrophy with significant improvements in muscle protein synthesis and muscle fiber CSA (p < 0.05). However, RET did not promote muscle hypertrophy in the LOW group, but RET significantly increased muscle capillary density (p < 0.05). Muscle fiber capillarization before starting an exercise training program may be predictive of the muscle hypertrophic response to RET in older adults. Increases in muscle fiber size following RET appear to be blunted when muscle capillarization is low, suggesting that an adequate initial capillarization is critical to achieve a meaningful degree of muscle adaptation to RET.
MeSH Terms
- Adaptation, Physiological
- Aged
- Capillaries
- Citrate (si)-Synthase
- Exercise
- Female
- Humans
- Hypertrophy
- Male
- Muscle Fibers, Skeletal
- Muscle Proteins
- Muscle, Skeletal
- Resistance Training
- Sarcopenia
- Ubiquitin-Protein Ligases
Keywords
- Aging
- Capillary
- Fiber cross-sectional area
- Muscle hypertrophy
- Muscle protein synthesis
Age is a primary risk factor for a number of chronic diseases including mobility disability, cardiovascular disease (CVD), type 2 diabetes (T2D), and cancer. Most physical activity guidelines emphasize the performance of 150 min of moderate-to-vigorous or 75 min of vigorous aerobic exercise training (AET) weekly for reduction of chronic disease risk. Nonetheless, there is an emerging body of evidence showing that resistance exercise training (RET) appears to be as effective as AET in reducing risk of several chronic diseases. It may also be that RET is more effective than AET in some regards; the converse is likely also true. We posit that the perceived divergent exercise mode-dependent health benefits of AET and RET are likely small in most cases. In this short review, our aim is to examine evidence of associations between the performance of RET and chronic health disease risk (mobility disability, T2D, CVD, cancer). We also postulate on how RET may be influencing chronic disease risk and how it is a critical component for healthy aging. Accumulating evidence points to RET as a potent and robust preventive strategy against a number of chronic diseases traditionally associated with the performance of AET, but evidence favors RET as a potent countermeasure against declines in mobility. On the basis of this review we propose that the promotion of RET should assume a more prominent position in exercise guidelines particularly for older persons.
Keywords
- aging
- cancer
- cardiovascular disease
- chronic disease risk
- physical mobility
- resistance training
- sarcopenia
- type 2 diabetes
In this study, the change in the physical, chemical, microstructural, and rheological properties of a road bitumen modified with reactive terpolymer (Elvaloy RET) was investigated. For this purpose, four different Elvaloy RET percentages (0%, 0.4%, 0.8%, and 1.2% by wt.) were mixed with B 160/220 bitumen. Firstly, the obtained samples were subjected to a short and long-term aging process using a rotating thin-film oven test and pressurized aging vessel, respectively. Then, the engineering characteristics of the samples were investigated using X-ray diffraction, scanning electron microscopy, and conventional and Superpave bitumen tests. The results showed that Elvaloy RET reacted with the main macromolecular groups in the bitumen, and that the modified bitumens behaved as a homogenous single phase structure as a result of this reaction. Conventional tests showed that Elvaloy RET-modified bitumens were much harder than pure bitumen and had better aging resistance. Furthermore, the penetration classes of these bitumens changed and their temperature sensitivities decreased significantly. Rheological tests showed that the Elvaloy RET additive increased the resistance of the bitumen against fatigue cracking and particularly permanent deformation. Moreover, the high temperature performance class of the bitumen also increased. However, parallel to the hardening of the bitumen, a reduction in its resistance to cracking at low temperature was observed.
Keywords
- aging
- bitumen
- microstructure
- reactive terpolymer
- rheological property
- stiffness
We recently demonstrated that citrulline (CIT) reduced the expression of inflammatory genes in cultured explants from retroperitoneal (RET) white adipose tissue (WAT) from young (2-4 months) but not old (25 months) rats. Here we show that in RET WAT from old rats and high-fat-diet-fed (HFD) young rats, the basal expression of the leptin gene was increased (275-345%) whereas that of the adiponectin gene was decreased (48-60%), when compared to those from control-diet-fed (CD) young rats. We show also that in RET WAT from old rats, a diet supplemented with CIT for 3 months reduced macrophage (F4/80, CD68) and inflammation (interleukin-6, tumor necrosis factor-α) marker genes 23-97%. CIT supplementation lowered leptin mRNA 62% and increased adiponectin mRNA 232%. In cultured explants of RET WAT from 4 month-old CD, 4 month-old HFD and 25-month-old CD rats, the exposure to 2.5 mmol/L CIT for 24 h up-regulated adiponectin gene expression 151%, 362% and 216% respectively. In contrast, leptin gene expression was down-regulated 66% selectively in CIT-treated explants from 25-month-old CD rats. These results further support the proposed beneficial effect of CIT to counteract the deleterious effects of aging and overweight on the metabolic, inflammatory and endocrine functions of WAT.
Keywords
- ASL, argininosuccinate lyase
- ASS, argininosuccinate synthase
- Adiponectin
- Adipose tissue
- Aging
- CD, control diet
- CIT, citrulline
- Citrulline
- HFD, high-fat diet
- IL, interleukin
- INFγ, interferon gamma
- Leptin
- NFκB, nuclear factor κ B
- NOS, nitric oxide synthase
- Obesity
- RET, retroperitoneal
- TNF-α, tumor necrosis factor alpha
- UCP1, uncoupling protein 1
- WAT, white adipose tissue
Despite the fact that manganese (Mn) is known to be a neurotoxic element relevant to age-related disorders, the risk of oral exposure to Mn for age-related hearing loss remains unclear. In this study, we orally exposed wild-type young adult mice to Mn (Mn-exposed WT-mice) at 1.65 and 16.50 mg/L for 4 weeks. Mn-exposed WT-mice showed acceleration of age-related hearing loss. Mn-exposed WT-mice had neurodegeneration of spiral ganglion neurons (SGNs) with increased number of lipofuscin granules. Mn-exposed WT-mice also had increased hypoxia-inducible factor-1 alpha (Hif-1α) protein with less hydroxylation at proline 564 and decreased c-Ret protein in SGNs. Mn-mediated acceleration of age-related hearing loss involving neurodegeneration of SGNs was rescued in RET-transgenic mice carrying constitutively activated RET. Thus, oral exposure to Mn accelerates age-related hearing loss in mice with Ret-mediated neurodegeneration of SGNs.
MeSH Terms
- Aging
- Animals
- Disease Models, Animal
- Hearing Loss
- Hydroxylation
- Hypoxia-Inducible Factor 1, alpha Subunit
- Manganese
- Mice
- Mice, Transgenic
- Nerve Degeneration
- Phosphorylation
- Proline
- Proto-Oncogene Proteins c-ret
- Spiral Ganglion
- Up-Regulation
Resistance exercise training (RET) is one of the most effective strategies for preventing declines in skeletal muscle mass and strength with age. Hypertrophic responses to RET with age are diminished compared to younger individuals. In response to 6 weeks RET, we found blunted hypertrophic responses with age are underpinned by chronic deficits in long-term muscle protein synthesis. We show this is likely to be the result of multifactorial deficits in anabolic hormones and blunted translational efficiency and capacity. These results provide great insight into age-related exercise adaptations and provide a platform on which to devise appropriate nutritional and exercise interventions on a longer term basis. Ageing is associated with impaired hypertrophic responses to resistance exercise training (RET). Here we investigated the aetiology of 'anabolic resistance' in older humans. Twenty healthy male individuals, 10 younger (Y; 23 ± 1 years) and 10 older (O; 69 ± 3 years), performed 6 weeks unilateral RET (6 × 8 repetitions, 75% of one repetition maximum (1-RM), 3 times per week). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D O (70 atom%; thereafter 50 ml week ), further bilateral VL muscle biopsies were taken at 3 and 6 weeks to quantify muscle protein synthesis (MPS) via gas chromatography-pyrolysis-isotope ratio mass spectrometry. After RET, 1-RM increased in Y ( 35 ± 4%) and O ( 25 ± 3%; P < 0.01), while MVC increased in Y ( 21 ± 5%; P < 0.01) but not O ( 6 ± 3%; not significant (NS)). In comparison to Y, O displayed blunted RET-induced increases in muscle thickness (at 3 and 6 weeks, respectively, Y: 8 ± 1% and 11 ± 2%, P < 0.01; O: 2.6 ± 1% and 3.5 ± 2%, NS). While 'basal' longer term MPS was identical between Y and O (∼1.35 ± 0.1% day ), MPS increased in response to RET only in Y (3 weeks, Y: 1.61 ± 0.1% day ; O: 1.49 ± 0.1% day ). Consistent with this, O exhibited inferior ribosomal biogenesis (RNA:DNA ratio and c-MYC induction: Y: 4 ± 2 fold change; O: 1.9 ± 1 fold change), translational efficiency (S6K1 phosphorylation, Y: 10 ± 4 fold change; O: 4 ± 2 fold change) and anabolic hormone milieu (testosterone, Y: 367 ± 19; O: 274 ± 19 ng dl (all P < 0.05). Anabolic resistance is thus multifactorial.
MeSH Terms
- Adult
- Aged
- Aging
- DNA
- Humans
- Hypertrophy
- Male
- Muscle Proteins
- Protein Biosynthesis
- Quadriceps Muscle
- RNA
- Resistance Training
- Ribosomes
- Young Adult
Keywords
- ageing
- exercise
- hypertrophy
- muscle
- protein synthesis
- ribosomal biogenesis
- signalling
- stable isotope
Whether resistance exercise training (RET) improves skeletal muscle substrate oxidative capacity and reduces mitochondrial production of reactive oxygen species in older adults remains unclear. To address this, 19 older males (≥60 years) were randomized to a RET (n = 11) or to a waitlist control group (n = 8) that remained sedentary for 12 weeks. RET was comprised of three upper body and four lower body movements on resistance machines. One set of 8-12 repetitions to failure of each movement was performed on three nonconsecutive days/week. Improvements in chest press and leg press strength were assessed using a three-repetition maximum (3 RM). Body composition was assessed via dual energy X-ray absorptiometry. Muscle biopsies were obtained from the vastus lateralis muscle at baseline and at both 3 weeks and 12 weeks. Palmitate and pyruvate oxidation rates were measured from the (14)CO2 produced from [1-(14)C] palmitic acid and [U-(14)C] pyruvate, respectively, during incubation of muscle homogenates. PGC-1α, TFAM, and PPARδ levels were quantified using qRT-PCR Citrate synthase (CS) and β-HAD activities were determined spectrophotometrically. Mitochondrial production of reactive oxygen species (ROS) were assessed using the Amplex Red Hydrogen Peroxide/Peroxidase assay. There were no significant changes in body weight or body composition following the intervention. Chest press and leg press strength (3RM) increased ~34% (both P < 0.01) with RET There were no significant changes in pyruvate or fatty acid oxidation or in the expression of target genes with the intervention. There was a modest increase (P < 0.05) in βHAD activity with RET at 12 weeks but the change in CS enzyme activity was not significant. In addition, there were no significant changes in ROS production in either group following RET Taken together, the findings of this study suggest that 12 weeks of low volume RET does not increase skeletal muscle oxidative capacity or reduce ROS production in older adults.
MeSH Terms
- Absorptiometry, Photon
- Age Factors
- Aged
- Aging
- Biomarkers
- Biopsy
- Body Composition
- Energy Metabolism
- Gene Expression Regulation
- Humans
- In Vitro Techniques
- Male
- Middle Aged
- Mitochondria, Muscle
- Mitochondrial Proteins
- Muscle Contraction
- Muscle Strength
- Oxidation-Reduction
- Quadriceps Muscle
- Reactive Oxygen Species
- Resistance Training
- Time Factors
Keywords
- Metabolism
- mitochondria
- oxidative damage
- strength
The development of germ cells has not been entirely documented in the cat especially the transition phase of the gonocyte to the spermatogonial stem cell (G/SSC). The aims of study were to examine testicular development and to identify the G/SSC transition in order to isolate and culture SSCs in vitro. Testes were divided into 3 groups according to donor age (I, < 4 months; II, 4-6 months; and III, > 6 months). In Exp. 1, we studied testicular development by histology, transmission electron microscopy and immunohistochemistry. In Exp. 2, we determined the expression of GFRα-1, DDX-4 and c-kit and performed flow cytometry. The SSCs isolated from groups II and III were characterized by RT-PCR and TEM (Exp. 3). Chronological changes in the G/SSC transition were demonstrated. The size, morphology and ultrastructure of SSCs were distinguishable from those of gonocytes. The results demonstrated that group II contained the highest numbers of SSCs per seminiferous cord/tubule (17.66 ± 2.20%) and GFRα-1( ) cells (14.89 ± 5.66%) compared with the other groups. The findings coincided with an increased efficiency of SSC derivation in group II compared with group III (74.33 ± 2.64% vs. 23.33 ± 2.23%). The colonies expressed mRNA for GFRA1, ZBTB16, RET and POU5F1. Our study found that the G/SSC transition occurs at 4-6 months of age. This period is useful for isolation and improves the establishment efficiency of cat SSCs in vitro.
MeSH Terms
- Adult Stem Cells
- Aging
- Animals
- Cats
- Cells, Cultured
- Flow Cytometry
- Immunohistochemistry
- Male
- Microscopy, Electron
- RNA, Messenger
- Spermatogonia
Glial cell-line derived neurotrophic factor (GDNF) and the GFRα co-receptors play a role in the developing enteric nervous system. The co-receptors elicit their action by binding receptor tyrosine kinase RET. This immunohistochemical study reports the presence of GDNF and its specific co-receptor GFRα1 in the cat gastrointestinal apparatus during development, from stage 9 to 22. At stage 9 and 11, immunoreactivity (IR) to GDNF was observed in the cells of mesenchyme of the anterior gut. From stage 14 to 22, GDNF IR was detected in nervous plexuses; moreover, GDNF and GFRα1 IR appeared localized in gastrointestinal endocrine cells. The presence of GDNF in the enteric nervous system and in the endocrine cells suggests an involvement of this neurotrophic factor in the gastrointestinal development. Moreover, the presence of the co-receptor GFRα1 in endocrine cells and its absence in the enteric nervous system seems to indicate a different mode of transduction of GDNF signal. GFRα2 and GFRα3 co-receptors were not detected.
MeSH Terms
- Aging
- Animals
- Cats
- Enteric Nervous System
- Female
- Fetus
- Gastrointestinal Tract
- Glial Cell Line-Derived Neurotrophic Factor
- Glial Cell Line-Derived Neurotrophic Factor Receptors
- Pregnancy
- Receptor Protein-Tyrosine Kinases
- Signal Transduction
Keywords
- Endocrine cells
- Enteric nervous system
- Intestine
- Neurotrophic factor
- Stomach
A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.
MeSH Terms
- Adolescent
- Adrenal Gland Neoplasms
- Child
- Child, Preschool
- DNA, Neoplasm
- Female
- Genetic Predisposition to Disease
- Germ-Line Mutation
- Humans
- Kaplan-Meier Estimate
- Life Expectancy
- Longitudinal Studies
- Male
- Paraganglioma
- Pheochromocytoma
- Sequence Analysis, DNA
Keywords
- germline mutations
- long-term follow-up
- pheochromocytoma
- relapse
Docosahexaenoic acid (DHA) is one of the critical fatty acids for optimal health, which affect the expression of nerve growth factor and brain-derived neurotrophic factor in brain. This study investigates whether DHA supplementation affects lipid peroxidation and activates the glial-derived neurotrophic factor (GDNF)-mitogen-activated protein kinase pathway (MAPK pathway) in hippocampus of natural aged rat. Rats were randomly divided into four groups; DHA was orally administered at 80 and 160 mg/kg/day to 24-month female rats for 50 days. The antioxidant parameters and GDNF-GDNF family receptor α-1 (GFRα1)-tyrosine-protein kinase receptor (RET)-MAPK-cyclic AMP response element-binding protein (CERB) pathway were assayed in natural aged rat's hippocampus. The results demonstrated that DHA supplementation significantly increased the activities of superoxide dismutase (SOD) by 37.39 and 57.69%, glutathione peroxidase (GSH-Px) by 27.62 and 32.57% decreased TBARS level by 28.49 and 49.05%, respectively, but did not significantly affect catalase (CAT), in hippocampus, when compared with the aged group. DHA supplementation in diet resulted in an increase of DHA level in hippocampus. Furthermore, we found that DHA supplementation markedly increased the levels of GDNF and GFRα1 and the phosphorylation of RET, and led to the activation of the MAPK pathway in hippocampus tissue. DHA supplementation can change fatty acids composition, improve antioxidant parameters and activate the GDNF-MAPK pathway in natural aged rat's hippocampus.
MeSH Terms
- Aging
- Animals
- Cyclic AMP Response Element-Binding Protein
- Dietary Supplements
- Docosahexaenoic Acids
- Female
- Glial Cell Line-Derived Neurotrophic Factor
- Glial Cell Line-Derived Neurotrophic Factor Receptors
- Hippocampus
- Lipid Peroxidation
- MAP Kinase Signaling System
- Nerve Tissue Proteins
- Neurons
- Neuroprotective Agents
- Oxidative Stress
- Oxidoreductases
- Phosphorylation
- Protein Processing, Post-Translational
- Random Allocation
- Rats
- Rats, Sprague-Dawley
- Up-Regulation
Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to 28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ~580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4 × 10(-30)). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6 × 10(-13)) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = -2.3; P = 3 × 10(-7))) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent "generic" physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18-78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ~500 genes highly enriched in post-transcriptional processes (P = 1 × 10(-6)) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to the muscle age-related genes. Finally, a number of specific chromosomal loci, including 1q12 and 13q21, contributed by more than chance to the age-related gene list (P = 0.01-0.005), implying possible epigenetic events. We conclude that human muscle age-related molecular processes appear distinct from the processes regulated by those of physical activity.
MeSH Terms
- Adaptation, Physiological
- Adolescent
- Adult
- Aged
- Aging
- Down-Regulation
- Exercise
- Female
- Gene Expression Profiling
- Gene Regulatory Networks
- Humans
- Male
- Middle Aged
- Muscle, Skeletal
- Ribosome Subunits
- Signal Transduction
- TOR Serine-Threonine Kinases
Resistance exercise training (RET) remains the most effective treatment for the loss of muscle mass and strength in elderly people. However, the underlying cellular and molecular mechanisms are not well understood. Recent evidence suggests that autophagic signaling is altered in aged skeletal muscles. This study aimed to investigate if RET affects IGF-1 and its receptors, the Akt/mTOR, and Akt/FOXO3a signaling pathways and regulates autophagy and apoptosis in the gastrocnemius muscles of 18-20 month old rats. The results showed that 9 weeks of RET prevented the loss of muscle mass and improved muscle strength, accompanied by reduced LC3-II/LC3-I ratio, reduced p62 protein levels, and increased levels of autophagy regulatory proteins, including Beclin 1, Atg5/12, Atg7, and the lysosomal enzyme cathepsin L. RET also reduced cytochrome c level in the cytosol but increased its level in mitochondrial fraction, and inhibited cleaved caspase 3 production and apoptosis. Furthermore, RET upregulated the expression of IGF-1 and its receptors but downregulated the phosphorylation of Akt and mTOR. In addition, RET upregulated the expression of total AMPK, phosphorylated AMPK, and FOXO3a. Taken together, these results suggest that the benefits of RET are associated with increased autophagy activity and reduced apoptosis of muscle cells by modulating IGF-1 and its receptors, the Akt/mTOR and Akt/FOXO3a signaling pathways in aged skeletal muscles.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Autophagy
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- Insulin-Like Growth Factor I
- Metabolic Networks and Pathways
- Models, Animal
- Muscle Fibers, Skeletal
- Proto-Oncogene Proteins c-akt
- Rats
- Rats, Sprague-Dawley
- Receptor, IGF Type 1
- Resistance Training
- Signal Transduction
- TOR Serine-Threonine Kinases
Twenty years ago, the groundbreaking discovery that rearranged during transfection (RET) mutations underlie multiple endocrine neoplasia 2 (MEN2) and familial medullary thyroid cancer (FMTC) ushered in the era of personalized medicine. MEN2-associated signs, taking time to manifest, can be subtle. This study sought to clarify to what extent conventional estimates of 1:200 000-500 000 underestimate the incidence of RET mutations in the population. Included in this retrospective investigation were 333 RET carriers born between 1951 and 2000 and operated on at the largest German surgical referral center (286 carriers) or elsewhere (47 carriers). To estimate the incidence of RET mutations, the number of RET carriers born in Germany in five decades (1951-1960, 1961-1970, 1971-1980, 1981-1990, and 1991-2000) was divided by the corresponding number of German live births. Owing to improved diagnosis and capture of FMTC and MEN2 patients, minimum incidence estimates increased over time: overall from 5.0 (1951-1960) to 9.9 (1991-2000) per million live births and year (P=0.008), and by American Thyroid Association/ATA class from 1.7 to 3.7 for ATA class C (P=0.008); from 1.8 to 2.7 for ATA class A (P=0.017); from 1.5 to 2.2 for ATA class B (P=0.20); and from 0 to 1.4 for ATA class D mutations per million live births and year (P=0.008). Based on 1991-2000 incidence estimates the prevalence in Germany is ∼1:80 000 inhabitants. The molecular minimum incidence estimate of ≈1:100 000 was two- to fivefold greater than conventional estimates of 1:200 000-500 000.
MeSH Terms
- Carcinoma, Medullary
- Cohort Studies
- Early Detection of Cancer
- Europe
- Gene Rearrangement
- Germ-Line Mutation
- Heterozygote
- Humans
- Incidence
- Life Expectancy
- Molecular Epidemiology
- Multiple Endocrine Neoplasia Type 2a
- Mutation
- Mutation, Missense
- Prevalence
- Proto-Oncogene Proteins c-ret
- Reproducibility of Results
- Retrospective Studies
- Tertiary Care Centers
- Thyroid Neoplasms
- Transfection