scholarly journals Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone

2014 ◽  
Vol 171 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Stine J Petersson ◽  
Louise L Christensen ◽  
Jonas M Kristensen ◽  
Rikke Kruse ◽  
Marianne Andersen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Lipid Oxidation ◽  
Mitochondrial Biogenesis ◽  
Protein Abundance ◽  
Mrna Levels ◽  
Testosterone Therapy ◽  
Bioavailable Testosterone ◽  
Aging Men

ObjectiveRecent studies have indicated that serum testosterone in aging men is associated with insulin sensitivity and expression of genes involved in oxidative phosphorylation (OxPhos), and that testosterone treatment increases lipid oxidation. Herein, we investigated the effect of testosterone therapy on regulators of mitochondrial biogenesis and markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels.MethodsSkeletal muscle biopsies were obtained before and after treatment with either testosterone gel (n=12) or placebo (n=13) for 6 months. Insulin sensitivity and substrate oxidation were assessed by euglycemic–hyperinsulinemic clamp and indirect calorimetry. Muscle mRNA levels and protein abundance and phosphorylation of enzymes involved in mitochondrial biogenesis, OxPhos, and lipid metabolism were examined by quantitative real-time PCR and western blotting.ResultsDespite an increase in lipid oxidation (P<0.05), testosterone therapy had no effect on insulin sensitivity or mRNA levels of genes involved in mitochondrial biogenesis (PPARGC1A,PRKAA2, andPRKAG3), OxPhos (NDUFS1,ETFA,SDHA,UQCRC1, andCOX5B), or lipid metabolism (ACADVL,CD36,CPT1B,HADH, andPDK4). Consistently, protein abundance of OxPhos subunits encoded by both nuclear (SDHAandUQCRC1) and mitochondrial DNA (ND6) and protein abundance and phosphorylation of AMP-activated protein kinase and p38 MAPK were unaffected by testosterone therapy.ConclusionThe beneficial effect of testosterone treatment on lipid oxidation is not explained by increased abundance or phosphorylation-dependent activity of enzymes known to regulate mitochondrial biogenesis or markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels.

Human skeletal muscle PPARα expression correlates with fat metabolism gene expression but not BMI or insulin sensitivity

2004 ◽  
Vol 286 (2) ◽  
pp. E168-E175 ◽  
Author(s):  
Junlong Zhang ◽  
D. I. W. Phillips ◽  
Chunli Wang ◽  
Christopher D. Byrne
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Few Data

Peroxisome proliferator-activated receptor-α (PPARα) is a key regulator of fatty acid oxidation in skeletal muscle, but few data exist from humans in vivo. To investigate whether insulin sensitivity in skeletal muscle and body mass index (BMI) were associated with skeletal muscle expression of PPARα and with important genes regulating lipid metabolism in humans in vivo, we undertook hyperinsulinemic-euglycemic clamps and measured PPARα mRNA levels and mRNA levels of lipid regulating PPARα response genes in skeletal muscle biopsies. mRNA levels were measured in 16 men, using a novel highly sensitive and specific medium throughput quantitative competitive PCR that allows reproducible measurement of multiple candidate mRNAs simultaneously. mRNA levels of PPARα were positively correlated with mRNA levels of CD36 ( r = 0.77, P = 0.001), lipoprotein lipase ( r = 0.54, P = 0.024), muscle-type carnitine palmitoyltransferase-I ( r = 0.54, P = 0.024), uncoupling protein-2 ( r = 0.63, P = 0.008), and uncoupling protein-3 ( r = 0.53, P = 0.026), but not with measures of insulin sensitivity, BMI, or GLUT4, which plays an important role in insulin-mediated glucose uptake. Thus our data suggest that in humans skeletal muscle PPARα expression and genes regulating lipid metabolism are tightly linked, but there was no association between both insulin sensitivity and BMI with PPARα expression in skeletal muscle.

scholarly journals Testosterone therapy decreases subcutaneous fat and adiponectin in aging men

2012 ◽  
Vol 166 (3) ◽  
pp. 469-476 ◽  
Author(s):  
L Frederiksen ◽  
K Højlund ◽  
D M Hougaard ◽  
T H Mosbech ◽  
R Larsen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fat Mass ◽  
Subcutaneous Fat ◽  
Fat Distribution ◽  
Controlled Study ◽  
Testosterone Therapy ◽  
Testosterone Levels ◽  
Bioavailable Testosterone ◽  
Aging Men ◽  
Total Fat

ObjectiveTestosterone therapy increases lean body mass and decreases total fat mass in aging men with low normal testosterone levels. The major challenge is, however, to determine whether the metabolic consequences of testosterone therapy are overall positive. We have previously reported that 6-month testosterone therapy did not improve insulin sensitivity. We investigated the effect of testosterone therapy on regional body fat distribution and on the levels of the insulin-sensitizing adipokine, adiponectin, in aging men with low normal bioavailable testosterone levels.DesignA randomized, double-blinded, placebo-controlled study on 6-month testosterone treatment (gel) in 38 men, aged 60–78 years, with bioavailable testosterone <7.3 nmol/l, and a waist circumference >94 cm.MethodsCentral fat mass (CFM) and lower extremity fat mass (LEFM) were measured by dual X-ray absorptiometry. Subcutaneous abdominal adipose tissue (SAT), visceral adipose tissue (VAT), and thigh subcutaneous fat area (TFA) were measured by magnetic resonance imaging. Adiponectin levels were measured using an in-house immunofluorometric assay. Coefficients (b) represent the placebo-controlled mean effect of intervention.ResultsLEFM was decreased (b=−0.47 kg, P=0.07) while CFM did not change significantly (b=−0.66 kg, P=0.10) during testosterone therapy. SAT (b=−3.0%, P=0.018) and TFA (b=−3.0%, P<0.001) decreased, while VAT (b=1.0%, P=0.54) remained unchanged. Adiponectin levels decreased during testosterone therapy (b=−1.3 mg/l, P=0.001).ConclusionTestosterone therapy decreased subcutaneous fat on the abdomen and lower extremities, but visceral fat was unchanged. Moreover, adiponectin levels were significantly decreased during testosterone therapy.

Selected Contribution: Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle

2001 ◽  
Vol 90 (1) ◽  
pp. 389-396 ◽  
Author(s):  
Joe W. Gordon ◽  
Arne A. Rungi ◽  
Hidetoshi Inagaki ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Regulatory Protein ◽  
Mrna Levels ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A ◽  
Mitochondrial Transcript

Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is imported into mitochondria and is required for the transcription of mitochondrial DNA (mtDNA). We hypothesized that conditions known to produce mitochondrial biogenesis in skeletal muscle would be preceded by an increase in Tfam expression. Therefore, rat muscle was stimulated (10 Hz, 3 h/day). Tfam mRNA levels were significantly elevated (by 55%) at 4 days and returned to control levels at 14 days. Tfam import into intermyofibrillar (IMF) mitochondria was increased by 52 and 61% ( P < 0.05) at 5 and 7 days, respectively. This corresponded to an increase in the level of import machinery components. Immunoblotting data indicated that IMF Tfam protein content was increased by 63% ( P < 0.05) at 7 days of stimulation. This was associated with a 49% ( P < 0.05) increase in complex formation at the mtDNA promoter and a 65% ( P< 0.05) increase in the levels of a mitochondrial transcript, cytochrome- c oxidase (COX) subunit III. Similarly, COX enzyme activity was elevated by 71% ( P < 0.05) after 7 days of contractile activity. These results indicate that early events in mitochondrial biogenesis include increases in Tfam mRNA, followed by accelerations in mitochondrial import and increased Tfam content, which correspond with increased binding to the mtDNA promoter region. This was accompanied by increased mitochondrial transcript levels and elevated COX activity. These data support the role of Tfam as a regulatory protein involved in contractile activity-induced mitochondrial biogenesis.

Responses of skeletal muscle lipid metabolism in rat gastrocnemius to hypothyroidism and iodothyronine administration: a putative role for FAT/CD36

2012 ◽  
Vol 303 (10) ◽  
pp. E1222-E1233 ◽  
Author(s):  
Assunta Lombardi ◽  
Rita De Matteis ◽  
Maria Moreno ◽  
Laura Napolitano ◽  
Rosa Anna Busiello ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Protein Level ◽  
Oxidation Rate ◽  
Mitochondrial Protein ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Muscle Lipid ◽  
Mitochondrial Fatty Acid ◽  
Skeletal Muscle Lipid

Iodothyronines such as triiodothyronine (T3) and 3,5-diiodothyronine (T2) influence energy expenditure and lipid metabolism. Skeletal muscle contributes significantly to energy homeostasis, and the above iodothyronines are known to act on this tissue. However, little is known about the cellular/molecular events underlying the effects of T3 and T2 on skeletal muscle lipid handling. Since FAT/CD36 is involved in the utilization of free fatty acids by skeletal muscle, specifically in their import into that tissue and presumably their oxidation at the mitochondrial level, we hypothesized that related changes in lipid handling and in FAT/CD36 expression and subcellular redistribution would occur due to hypothyroidism and to T3 or T2 administration to hypothyroid rats. In gastrocnemius muscles isolated from hypothyroid rats, FAT/CD36 was upregulated (mRNA levels and total tissue, sarcolemmal, and mitochondrial protein levels). Administration of either T3 or T2 to hypothyroid rats resulted in 1) little or no change in FAT/CD36 mRNA level, 2) a decreased total FAT/CD36 protein level, and 3) further increases in FAT/CD36 protein level in sarcolemma and mitochondria. Thus, the main effect of each iodothyronine seemed to be exerted at the level of FAT/CD36 cellular distribution. The effect of further increases in FAT/CD36 protein level in sarcolemma and mitochondria was already evident at 1 h after iodothyronine administration. Each iodothyronine increased the mitochondrial fatty acid oxidation rate. However, the mechanisms underlying their rapid effects seem to differ; T2 and T3 each induce FAT/CD36 translocation to mitochondria, but only T2 induces increases in carnitine palmitoyl transferase system activity and in the mitochondrial substrate oxidation rate.

scholarly journals Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle

2014 ◽  
Vol 11 (1) ◽  
pp. 32 ◽  
Author(s):  
Rie Tsutsumi ◽  
Tomomi Yoshida ◽  
Yoshitaka Nii ◽  
Naoki Okahisa ◽  
Shinya Iwata ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Mitochondrial Biogenesis ◽  
Glucose And Lipid Metabolism

scholarly journals Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

2013 ◽  
Vol 219 (2) ◽  
pp. 173-182 ◽  
Author(s):  
P Brandimarti ◽  
J M Costa-Júnior ◽  
S M Ferreira ◽  
A O Protzek ◽  
G J Santos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Secretion ◽  
Alternative Splicing ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Clearance ◽  
Cafeteria Diet ◽  
Mrna Levels ◽  
Insulin Degrading Enzyme ◽  
Diet Induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

Whole body metabolic effects of prolonged endurance training in combination with erythropoietin treatment in humans: a randomized placebo controlled trial

2013 ◽  
Vol 305 (7) ◽  
pp. E879-E889 ◽  
Author(s):  
Britt Christensen ◽  
Birgitte Nellemann ◽  
Mads S. Larsen ◽  
Line Thams ◽  
Peter Sieljacks ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Endurance Training ◽  
Exercise Capacity ◽  
Uncoupling Protein ◽  
Metabolic Effects ◽  
Whole Body ◽  
Mrna Levels ◽  
Healthy Humans ◽  
Ucp2 Mrna

Erythropoietin (Epo) administration improves aerobic exercise capacity and insulin sensitivity in renal patients and also increases resting energy expenditure (REE). Similar effects are observed in response to endurance training. The aim was to compare the effects of endurance training with erythropoiesis-stimulating agent (ESA) treatment in healthy humans. Thirty-six healthy untrained men were randomized to 10 wk of either: 1) placebo ( n = 9), 2) ESA ( n = 9), 3) endurance training ( n = 10), or 4) ESA and endurance training ( n = 8). In a single-blinded design, ESA/placebo was injected one time weekly. Training consisted of biking for 1 h at 65% of wattmax three times per week. Measurements performed before and after the intervention were as follows: body composition, maximal oxygen uptake, insulin sensitivity, REE, and palmitate turnover. Uncoupling protein 2 (UCP2) mRNA levels were assessed in skeletal muscle. Fat mass decreased after training ( P = 0.003), whereas ESA induced a small but significant increase in intrahepatic fat ( P = 0.025). Serum free fatty acid (FFA) levels and palmitate turnover decreased significantly in response to training, whereas the opposite pattern was found after ESA. REE corrected for lean body mass increased in response to ESA and training, and muscle UCP2 mRNA levels increased after ESA ( P = 0.035). Insulin sensitivity increased only after training ( P = 0.011). In conclusion: 1) insulin sensitivity is not improved after ESA treatment despite improved exercise capacity, 2) the calorigenic effects of ESA may be related to increased UCP2 gene expression in skeletal muscle, and 3) training and ESA exert opposite effects on lipolysis under basal conditions, increased FFA levels and liver fat fraction was observed after ESA treatment.

Leptin, skeletal muscle lipids, and lipid-induced insulin resistance

2007 ◽  
Vol 293 (2) ◽  
pp. R642-R650 ◽  
Author(s):  
John J. Dube ◽  
Bankim A. Bhatt ◽  
Nikolas Dedousis ◽  
Arend Bonen ◽  
Robert M. O'Doherty
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Lipid Metabolites

Leptin-induced increases in insulin sensitivity are well established and may be related to the effects of leptin on lipid metabolism. However, the effects of leptin on the levels of lipid metabolites implicated in pathogenesis of insulin resistance and the effects of leptin on lipid-induced insulin resistance are unknown. The current study addressed in rats the effects of hyperleptinemia (HL) on insulin action and markers of skeletal muscle (SkM) lipid metabolism in the absence or presence of acute hyperlipidemia induced by an infusion of a lipid emulsion. Compared with controls (CONT), HL increased insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (∼15%), and increased SkM Akt (∼30%) and glycogen synthase kinase 3α (∼52%) phosphorylation. These improvements in insulin action were associated with decreased SkM triglycerides (TG; ∼61%), elevated ceramides (∼50%), and similar diacylglycerol (DAG) levels in HL compared with CONT. Acute hyperlipidemia in CONT decreased insulin sensitivity (∼25%) and increased SkM DAG (∼33%) and ceramide (∼60%) levels. However, hyperlipidemia did not induce insulin resistance or SkM DAG and ceramide accumulation in HL. SkM total fatty acid transporter CD36, plasma membrane fatty acid binding protein, acetyl Co-A carboxylase phosphorylation, and fatty acid oxidation were similar in HL compared with CONT. However, HL decreased SkM protein kinase Cθ (PKCθ), a kinase implicated in mediating the detrimental effects of lipids on insulin action. We conclude that increases in insulin sensitivity induced by HL are associated with decreased levels of SkM TG and PKCθ and increased SkM insulin signaling, but not with decreases in other lipid metabolites implicated in altering SkM insulin sensitivity (DAG and ceramide). Furthermore, insulin resistance induced by an acute lipid infusion is prevented by HL.

scholarly journals LMNA Mutations, Skeletal Muscle Lipid Metabolism, and Insulin Resistance

2010 ◽  
Vol 95 (4) ◽  
pp. 1634-1643 ◽  
Author(s):  
Michael Boschmann ◽  
Stefan Engeli ◽  
Cedric Moro ◽  
Angelika Luedtke ◽  
Frauke Adams ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Lipid Oxidation ◽  
Exercise Intolerance ◽  
Intrinsic Defect ◽  
Lamin A ◽  
Glucose Ingestion

Abstract Context: Type 2 familial partial lipodystrophy (FPLD) is an autosomal-dominant lamin A/C-related disease associated with exercise intolerance, muscular pain, and insulin resistance. The symptoms may all be explained by defective metabolism; however, metabolism at the tissue level has not been investigated. Objective: We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect. Patients and Methods: Carbohydrate and lipid metabolism was studied on 10 FPLD patients, one patient with limb-girdle muscular dystrophy (LGMD1B, a different lamin A/C disease), and 10 healthy control subjects before and during an oral glucose tolerance test by indirect calorimetry and im microdialysis. Muscle biopsies were taken for in vitro studies. Results: We observed marked increased skeletal muscle fatty acid β-oxidation rate in vitro and in vivo, even after glucose ingestion in FPLD patients. However, fatty acid oxidation was largely incomplete and accompanied by increased ketogenesis. The lipid oxidation abnormality was associated with impaired glucose disposition through reduction in glucose oxidation, rather than decreased cellular glucose uptake. A microarray showed down-regulation of complex I respiratory chain, glycolysis, and nuclear transport genes. Although not overtly insulin resistant, the LGMD1B patient showed similar metabolic derangements as the FPLD patients. Conclusions: Our study suggests imbalance between lipid oxidation and oxidative glucose metabolism in FPLD and LGMD1B patients. The observation suggests an intrinsic defect in skeletal muscle metabolism due to lamin A/C dysfunction. The metabolic FPLD phenotype likely results from this intrinsic defect combined with lipodystrophic “lipid pressure” due to decreased adipose tissue lipid storage capacity.

Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle

2007 ◽  
Vol 102 (1) ◽  
pp. 314-320 ◽  
Author(s):  
G. D. Wadley ◽  
G. K. McConell
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Acute Exercise ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced ◽  
Edl Muscle ◽  
Oxide Synthase

The purpose of this study was to determine whether nitric oxide synthase (NOS) inhibition decreased basal and exercise-induced skeletal muscle mitochondrial biogenesis. Male Sprague-Dawley rats were assigned to one of four treatment groups: NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, ingested for 2 days in drinking water, 1 mg/ml) followed by acute exercise, no l-NAME ingestion and acute exercise, rest plus l-NAME, and rest without l-NAME. The exercised rats ran on a treadmill for 53 ± 2 min and were then killed 4 h later. NOS inhibition significantly ( P < 0.05; main effect) decreased basal peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) mRNA levels and tended ( P = 0.08) to decrease mtTFA mRNA levels in the soleus, but not the extensor digitorum longus (EDL) muscle. This coincided with significantly reduced basal levels of cytochrome c oxidase (COX) I and COX IV mRNA, COX IV protein and COX enzyme activity following NOS inhibition in the soleus, but not the EDL muscle. NOS inhibition had no effect on citrate synthase or β-hydroxyacyl CoA dehydrogenase activity, or cytochrome c protein abundance in the soleus or EDL. NOS inhibition did not reduce the exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA in the soleus or EDL. In conclusion, inhibition of NOS appears to decrease some aspects of the mitochondrial respiratory chain in the soleus under basal conditions, but does not attenuate exercise-induced mitochondrial biogenesis in the soleus or in the EDL.

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