Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake

2008 ◽  
Vol 104 (5) ◽  
pp. 1304-1312 ◽  
Author(s):  
Jennifer A. Calvo ◽  
Thomas G. Daniels ◽  
Xiaomei Wang ◽  
Angelika Paul ◽  
Jiandie Lin ◽  
...  
Keyword(s):  
Oxygen Uptake ◽  
Exercise Performance ◽  
Mitochondrial Gene ◽  
Oxidative Capacity ◽  
Peak Oxygen Uptake ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Sprint Training ◽  
Specific Expression

The induction of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a key regulator of mitochondriogenesis, is well-established under multiple physical exercise regimens, including, endurance, resistance, and sprint training. We wanted to determine if increased expression of PGC-1α in muscle is sufficient to improve performance during exercise in vivo. We demonstrate that muscle-specific expression of PGC-1α improves the performance during voluntary as well as forced exercise challenges. Additionally, PGC-1α transgenic mice exhibit an enhanced performance during a peak oxygen uptake exercise test, demonstrating an increased peak oxidative capacity, or whole body oxygen uptake. This increased ability to perform in multiple exercise paradigms is supported by enhanced mitochondrial function as suggested by increased mitochondrial gene expression, mitochondrial DNA, and mitochondrial enzyme activity. Thus this study demonstrates that upregulation of PGC-1α in muscle in vivo is sufficient to greatly improve exercise performance under various exercise paradigms as well as increase peak oxygen uptake.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

Abstract 15445: The Sirtuin SIRT3 Blocks Doxorubicin-induced Cardiac Hypertrophic Response of Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Vinodkumar Pillai ◽  
Sadhana Samant ◽  
Nagalingam Sundaresan ◽  
Gene Kim ◽  
Mahesh P Gupta
Keyword(s):  
Negative Regulator ◽  
Neonatal Rat ◽  
Whole Body ◽  
Wild Type ◽  
Electron Microscopic ◽  
Specific Expression ◽  
Rat Cardiomyocytes ◽  
Fluorescent Intensity ◽  
Hypertrophic Response

Background and objective: Doxorubicin is a chemotherapeutic drug widely used to treat variety of cancers. One of the serious side effects of doxorubicin is its toxicity to the heart. Previously, we have shown that overexpression of SIRT3 blocks the hypertrophic response of the heart to agonist treatments. This study was undertaken to investigate whether SIRT3 can also attenuate the doxorubicin-induced cardiac hypertrophic response in mice. Methods and results: Neonatal rat cardiomyocytes overexpressed with SIRT3 and treated with doxorubicin (10μM) showed 28% reduced mean fluorescent intensity for CM-H 2 DCFDA dye, compared to mock infected control cells treated with doxorubicin, thus suggesting that SIRT3 was capable of blocking doxorubicin-induced ROS synthesis in cardiomyocytes. To examine the cardioprotective effects of SIRT3 in doxorubicin-induced cardiotoxicity in vivo ; we used a cumulative dose of 15mg/kg of doxorubicin for two different time points. One group of mice was treated intraperitoneally with 5mg/kg doxorubicin or an equal volume of saline every two weeks for a total of three doses. Transgenic mice having cardiac specific expression of SIRT3 (SIRT3-Tg) showed 33% reduced HW/BW ratio compared to control mice. Echocardiographic evaluation of hearts showed significantly reduced fractional shortening in control mice, compared to SIRT3-Tg mice (24.6 vs 34.7 %, P<0.05). SIRT3-Tg mice also showed significantly reduced fetal gene expression for ANF, βMHC and collagen-1 as determined by RT-PCR. Masson’s trichrome staining showed significantly reduced fibrosis in doxorubicin treated SIRT3-Tg mice compared to its control. Furthermore, electron microscopic analysis showed preserved mitochondrial and sarcomeres structures in doxorubicin treated SIRT3-Tg hearts, whereas in wild-type hearts these structures were highly disorganized. Second group of mice that received 15mg/kg dose for two weeks also showed similar results. Contrary to this, whole body SIRT3 knockout mice showed exacerbated cardiac hypertrophic response compared to wild-type mice in response to doxorubicin treatment. Conclusion: These results demonstrated that SIRT3 is an endogenous negative regulator of doxorubicin-induced cardiac hypertrophic response.

scholarly journals Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Pieter de Lange ◽  
Assunta Lombardi ◽  
Elena Silvestri ◽  
Fernando Goglia ◽  
Antonia Lanni ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Oxidative Capacity ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Transcriptional Program ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Metabolic Action

The peroxisome proliferator-activated receptors (PPARs), which are ligand-inducible transcription factors expressed in a variety of tissues, have been shown to perform key roles in lipid homeostasis. In physiological situations such as fasting and physical exercise, one PPAR subtype, PPARδ, triggers a transcriptional program in skeletal muscle leading to a switch in fuel usage from glucose/fatty acids to solely fatty acids, thereby drastically increasing its oxidative capacity. The metabolic action of PPARδ has also been verified in humans. In addition, it has become clear that the action of PPARδ is not restricted to skeletal muscle. Indeed, PPARδ has been shown to play a crucial role in whole-body lipid homeostasis as well as in insulin sensitivity, and it is active not only in skeletal muscle (as an activator of fat burning) but also in the liver (where it can activate glycolysis/lipogenesis, with the produced fat being oxidized in muscle) and in the adipose tissue (by incrementing lipolysis). The main aim of this review is to highlight the central role for activated PPARδ in the reversal of any tendency toward the development of insulin resistance.

scholarly journals High-intensity intermittent exercise training with chlorella intake accelerates exercise performance and muscle glycolytic and oxidative capacity in rats

2017 ◽  
Vol 312 (4) ◽  
pp. R520-R528 ◽  
Author(s):  
Naoki Horii ◽  
Natsuki Hasegawa ◽  
Shumpei Fujie ◽  
Masataka Uchida ◽  
Eri Miyamoto-Mikami ◽  
...  
Keyword(s):  
Exercise Performance ◽  
Oxidative Metabolism ◽  
High Intensity ◽  
Citrate Synthase ◽  
Intermittent Exercise ◽  
Oxidative Capacity ◽  
Monocarboxylate Transporter ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor

The purpose of this study was to investigate the effect of chronic chlorella intake alone or in combination with high-intensity intermittent exercise (HIIE) training on exercise performance and muscle glycolytic and oxidative metabolism in rats. Forty male Sprague-Dawley rats were randomly assigned to the four groups: sedentary control, chlorella intake (0.5% chlorella powder in normal feed), HIIE training, and combination of HIIE training and chlorella intake for 6 wk ( n = 10 each group). HIIE training comprised 14 repeats of a 20-s swimming session with a 10-s pause between sessions, while bearing a weight equivalent to 16% of body weight, 4 days/week. Exercise performance was tested after the interventions by measuring the maximal number of HIIE sessions that could be completed. Chlorella intake and HIIE training significantly increased the maximal number of HIIE sessions and enhanced the expression of monocarboxylate transporter (MCT)1, MCT4, and peroxisome proliferator-activated receptor γ coactivator-1α concomitantly with the activities of lactate dehydrogenase (LDH), phosphofructokinase, citrate synthase (CS), and cytochrome- c oxidase (COX) in the red region of the gastrocnemius muscle. Furthermore, the combination further augmented the increased exercise performance and the enhanced expressions and activities. By contrast, in the white region of the muscle, MCT1 expression and LDH, CS, and COX activities did not change. These results showed that compared with only chlorella intake and only HIIE training, chlorella intake combined with HIIE training has a more pronounced effect on exercise performance and muscle glycolytic and oxidative metabolism, in particular, lactate metabolism.

Voluntary fluid intake, hydration status, and aerobic performance of adolescent athletes in the heat

2010 ◽  
Vol 35 (6) ◽  
pp. 834-841 ◽  
Author(s):  
Boguslaw Wilk ◽  
Brian W. Timmons ◽  
Oded Bar-Or
Keyword(s):  
Body Weight ◽  
Oxygen Uptake ◽  
Exercise Performance ◽  
Fluid Intake ◽  
Tap Water ◽  
Peak Oxygen Uptake ◽  
Adolescent Male ◽  
Aerobic Performance ◽  
Hydration Status ◽  
Time To Exhaustion

We determined whether beverage flavoring and composition would stimulate voluntary drink intake, prevent dehydration, and maintain exercise performance in heat-acclimated adolescent males running in the heat. Eight adolescent (age, 13.7 ± 1.1 years) runners (peak oxygen uptake, 59.5 ± 4.0 mL·kg–1·min–1) underwent at least four 80-min exercise heat-acclimation sessions before completing 3 experimental sessions. All sessions were performed at 30 °C and 60%–65% relative humidity. Each experimental session consisted of five 15-min treadmill runs at a speed eliciting 65% peak oxygen uptake, with a 5 min rest prior to each run. Ten minutes after the final run, a time to exhaustion test was performed at a speed eliciting 90% peak oxygen uptake. Counterbalanced experimental sessions were identical, except for fluid intake, which consisted of tap water (W), flavored water (FW), and FW with 6% carbohydrate and 18 mmol·L–1 NaCl (CNa) consumed ad libitum. Fluid intake and body weight were monitored to calculate dehydration. Voluntary fluid intake was similar to fluid losses in W (1032 ± 130 vs. 1340 ± 246 g), FW (1086 ± 86 vs. 1451 ± 253 g), and CNa (1259 ± 119 vs. 1358 ± 234 g). As a result, significant dehydration was avoided in all trials (–0.45% ± 0.68% body weight in W, –0.66% ± 0.50% body weight in FW, and –0.13% ± 0.71% body weight in CNa). Core temperature increased by ~1 °C during exercise, but was not different between trials. Time to exhaustion was not different between trials and averaged 8.8 ± 1.7 min. Under exercise conditions more closely reflecting real-life situations, heat-acclimatized adolescent male runners can appropriately gauge fluid intake regardless of the type of beverage made available, resulting in consistency in exercise performance.

Downhill treadmill running trains the rat spinotrapezius muscle

2007 ◽  
Vol 102 (1) ◽  
pp. 412-416 ◽  
Author(s):  
S. A. Hahn ◽  
L. F. Ferreira ◽  
J. B. Williams ◽  
K. P. Jansson ◽  
B. J. Behnke ◽  
...  
Keyword(s):  
Citrate Synthase ◽  
Oxidative Capacity ◽  
Peak Oxygen Uptake ◽  
Microscopic Investigation ◽  
Treadmill Running ◽  
Whole Body ◽  
Initial Tension ◽  
Downhill Running ◽  
Health And Disease ◽  
Microcirculatory Function

There are currently no models of exercise that recruit and train muscles, such as the rat spinotrapezius, that are suitable for transmission intravital microscopic investigation of the microcirculation. Recent experimental evidence supports the concept that running downhill on a motorized treadmill recruits the spinotrapezius muscle of the rat. Based on these results, we tested the hypothesis that 6 wk of downhill running (−14° grade) for 1 h/day, 5 days/wk, at a speed of up to 35 m/min, would 1) increase whole body peak oxygen uptake (V̇o2 peak), 2) increase spinotrapezius citrate synthase activity, and 3) reduce the fatigability of the spinotrapezius during electrically induced 1-Hz submaximal tetanic contractions. Trained rats ( n = 6) elicited a 24% higher V̇o2 peak (in ml·min−1·kg−1: sedentary 58.5 ± 2.0, trained 72.7 ± 2.0; P < 0.001) and a 41% greater spinotrapezius citrate synthase activity (in μmol·min−1·g−1: sedentary 14.1 ± 0.7, trained 19.9 ± 0.9; P < 0.001) compared with sedentary controls ( n = 6). In addition, at the end of 15 min of electrical stimulation, trained rats sustained a greater percentage of the initial tension than their sedentary counterparts (control 34.3 ± 3.1%, trained 59.0 ± 7.2%; P < 0.05). These results demonstrate that downhill running is successful in promoting training adaptations in the spinotrapezius muscle, including increased oxidative capacity and resistance to fatigue. Since the spinotrapezius muscle is commonly used in studies using intravital microscopy to examine microcirculatory function at rest and during contractions, our results suggest that downhill running is an effective training paradigm that can be used to investigate the mechanisms for improved microcirculatory function following exercise training in health and disease.

Effect of metformin on substrate utilization after exercise training in adults with impaired glucose tolerance

2013 ◽  
Vol 38 (4) ◽  
pp. 427-430 ◽  
Author(s):  
Steven K. Malin ◽  
Barry Braun
Keyword(s):  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Exercise Training ◽  
Glucose Tolerance ◽  
Oxygen Uptake ◽  
Indirect Calorimetry ◽  
Substrate Utilization ◽  
Peak Oxygen Uptake ◽  
Whole Body ◽  
Glucose Kinetics

Metformin attenuates the higher insulin sensitivity that occurs with exercise training. Sixteen people with prediabetes trained for 10 weeks while taking metformin (n = 8) or placebo (n = 8). Substrate utilization was assessed using glucose kinetics and indirect calorimetry. After training, exercise whole-body fat oxidation was higher and glycogen use lower (p < 0.05), with no differences between groups. Blood glucose use was unchanged. Training-induced enhancement of insulin sensitivity (clamp) correlated with higher peak oxygen uptake (r = 0.70; p < 0.05), but was independent of glucose kinetic and substrate metabolism.

scholarly journals Skeletal Muscle-Specific Expression of PGC-1α-b, an Exercise-Responsive Isoform, Increases Exercise Capacity and Peak Oxygen Uptake

PLoS ONE ◽  
2011 ◽  
Vol 6 (12) ◽  
pp. e28290 ◽  
Author(s):  
Miki Tadaishi ◽  
Shinji Miura ◽  
Yuko Kai ◽  
Yutaka Kano ◽  
Yuichi Oishi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Uptake ◽  
Exercise Capacity ◽  
Peak Oxygen Uptake ◽  
Specific Expression

scholarly journals Adult expression of PGC-1α and -1β in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity

2016 ◽  
Vol 311 (6) ◽  
pp. E928-E938 ◽  
Author(s):  
Christopher Ballmann ◽  
Yawen Tang ◽  
Zachary Bush ◽  
Glenn C. Rowe
Keyword(s):  
Skeletal Muscle ◽  
Exercise Performance ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adult Skeletal Muscle ◽  
Training Response ◽  
Exercise Induced ◽  
Transport Complex ◽  
Specific Deletion

Exercise has been shown to be the best intervention in the treatment of many diseases. Many of the benefits of exercise are mediated by adaptions induced in skeletal muscle. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators has emerged as being key mediators of the exercise response and is considered to be essential for many of the adaptions seen in skeletal muscle. However, the contribution of the PGC-1s in skeletal muscle has been evaluated by the use of either whole body or congenital skeletal muscle-specific deletion. In these models, PGC-1s were never present, thereby opening the possibility to developmental compensation. Therefore, we generated an inducible muscle-specific deletion of PGC-1α and -1β (iMyo-PGC-1DKO), in which both PGC-1α and -β can be deleted specifically in adult skeletal muscle. These iMyo-PGC-1DKO animals were used to assess the role of both PGC-1α and -1β in adult skeletal muscle and their contribution to the exercise training response. Untrained iMyo-PGC-1DKO animals exhibited a time-dependent decrease in exercise performance 8 wk postdeletion, similar to what was observed in the congenital muscle-specific PGC-1DKOs. However, after 4 wk of voluntary training, the iMyo-PGC-1DKOs exhibited an increase in exercise performance with a similar adaptive response compared with control animals. This increase was associated with an increase in electron transport complex (ETC) expression and activity in the absence of PGC-1α and -1β expression. Taken together these data suggest that PGC-1α and -1β expression are not required for training-induced exercise performance, highlighting the contribution of PGC-1-independent mechanisms.

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