scholarly journals PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity

2010 ◽  
Vol 299 (2) ◽  
pp. E145-E161 ◽  
Author(s):  
Vitor A. Lira ◽  
Carley R. Benton ◽  
Zhen Yan ◽  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Mitochondrial Biogenesis ◽  
Therapeutic Potential ◽  
Fiber Type ◽  
Acid Oxidation ◽  
Physiological Limits ◽  
Exercise Induced

The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α (PGC-1α) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1α in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1α. To these ends, the following questions are addressed. 1) How is PGC-1α regulated, 2) what adaptations are indeed dependent on PGC-1α action, 3) is PGC-1α altered in insulin resistance, and 4) are PGC-1α-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca2+-dependent pathways, reactive oxygen species (ROS), nitric oxide (NO), AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other adaptations. However, the p38γ MAPK/PGC-1α regulatory axis has been confirmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulin-sensitizing role of PGC-1α, human studies on type 2 diabetes suggest that PGC-1α and its target genes are only modestly downregulated (≤34%). However, studies in PGC-1α-knockout or PGC-1α-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1α does not have an insulin-sensitizing role. In contrast, a modest (∼25%) upregulation of PGC-1α, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38γ MAPK-PGC-1α regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1α, within physiological limits, have revealed its insulin-sensitizing effects.

scholarly journals Alteration of Mitochondrial Function and Insulin Sensitivity in Primary Mouse Skeletal Muscle Cells Isolated From Transgenic and Knockout Mice: Role of OGG1

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2640-2649 ◽  
Author(s):  
Larysa V. Yuzefovych ◽  
A. Michele Schuler ◽  
Jemimah Chen ◽  
Diego F. Alvarez ◽  
Lars Eide ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Repair ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Mitochondrial Dysfunction ◽  
Knockout Mice ◽  
Repair Enzyme ◽  
Mitochondrial Mass ◽  
Mtdna Damage

Abstract Recent evidence has linked mitochondrial dysfunction and DNA damage, increased oxidative stress in skeletal muscle, and insulin resistance (IR). The purpose of this study was to determine the role of the DNA repair enzyme, human 8-oxoguanine DNA glycosylase/apurinic/apyrimidinic lyase (hOGG1), on palmitate-induced mitochondrial dysfunction and IR in primary cultures of skeletal muscle derived from hind limb of ogg1−/− knockout mice and transgenic mice, which overexpress human (hOGG1) in mitochondria (transgenic [Tg]/MTS-hOGG1). Following exposure to palmitate, we evaluated mitochondrial DNA (mtDNA) damage, mitochondrial function, production of mitochondrial reactive oxygen species (mtROS), mitochondrial mass, JNK activation, insulin signaling pathways, and glucose uptake. Palmitate-induced mtDNA damage, mtROS, mitochondrial dysfunction, and activation of JNK were all diminished, whereas ATP levels, mitochondrial mass, insulin-stimulated phosphorylation of Akt (Ser 473), and insulin sensitivity were increased in primary myotubes isolated from Tg/MTS-hOGG1 mice compared to myotubes isolated from either knockout or wild-type mice. In addition, both basal and maximal respiratory rates during mitochondrial oxidation on pyruvate showed a variable response, with some animals displaying an increased respiration in muscle fibers isolated from the transgenic mice. Our results support the model that DNA repair enzyme OGG1 plays a pivotal role in repairing mtDNA damage, and consequently, in mtROS production and regulating downstream events leading to IR in skeletal muscle.

PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivityThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 307-314 ◽  
Author(s):  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Oxidation ◽  
Insulin Signalling ◽  
Metabolic Effects ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Exercise Induced

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a nuclear encoded transcriptional coactivator, increases the expression of many genes in skeletal muscle, including those involved with fatty acid oxidation and oxidative phosphorylation. Exercise increases the expression of PGC-1α, and the exercise-induced upregulation of many genes is attributable, in part, to the preceding activation and upregulation of PGC-1α. Indeed, PGC-1α overexpression, like exercise training, increases exercise performance. PGC-1α reductions in humans have been observed in type 2 diabetes, while, in cell lines, PGC-1α mimics the exercise-induced improvement in insulin sensitivity. However, unexpectedly, in mammalian muscle, PGC-1α overexpression contributed to the development of diet-induced insulin resistance. This may have been related to the massive overexpression of PGC-1α, which induced the upregulation of the fatty acid transporter FAT/CD36 and led to an increase in intramuscular lipids, which interfere with insulin signalling. In contrast, when PGC-1α was overexpressed modestly, within physiological limits, mitochondrial fatty acid oxidation was increased, GLUT4 expression was upregulated, and insulin-stimulated glucose transport was increased. More recently, similar PGC-1α-induced improvements in the insulin-resistant skeletal muscle of obese Zucker rats have been observed. These studies suggest that massive PGC-1α overexpression, but not physiologic PGC-1α overexpression, induces deleterious metabolic effects, and that exercise-induced improvements in insulin sensitivity are induced, in part, by the exercise-induced upregulation of PGC-1α.

PGC-1α-mediated regulation of gene expression and metabolism: implications for nutrition and exercise prescriptions

2008 ◽  
Vol 33 (5) ◽  
pp. 843-862 ◽  
Author(s):  
Carley R. Benton ◽  
David C. Wright ◽  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Regulation Of Gene Expression ◽  
Acid Oxidation ◽  
Molecular Tools ◽  
Nutritional Factors ◽  
Physiological Limits ◽  
High Fat Diets ◽  
Fat Diets

The discovery 10 years ago of PGC-1α represented a major milestone towards understanding of the molecular processes regulating energy metabolism in many tissues, including skeletal muscle. PGC-1α orchestrates a metabolic program regulating oxidative lipid metabolism and insulin sensitivity. This is essentially the same metabolic program that is activated by exercise and down-regulated by sedentary lifestyles and high-fat diets, as well as in cases of obesity and type 2 diabetes. The present review examines the evidence in support of the key role for PGC-1α regulation of substrate metabolism and mitochondrial biogenesis in skeletal muscle. Surprisingly, studies with PGC-1α null and transgenic mice have revealed unexpected pathologies when PGC-1α is completely repressed (KO animals) or is massively overexpressed. In contrast, PGC-1α overexpression within normal physiological limits results in marked improvements in fatty acid oxidation and insulin-stimulated glucose transport. Exercise, sedentary lifestyles, and nutritional factors can regulate PGC-1α expression. We speculate that optimal targeting of PGC-1α upregulation, whether by diet, exercise, or a combination of both, could represent effective prophylactic or therapeutic means to improve insulin sensitivity. Indeed, using modern molecular tools, it may indeed be possible to prescribe optimally individualized nutrition and exercise programs.

scholarly journals PGC-1α plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis but not fiber-type transformation in mouse skeletal muscle

2010 ◽  
Vol 298 (3) ◽  
pp. C572-C579 ◽  
Author(s):  
Tuoyu Geng ◽  
Ping Li ◽  
Mitsuharu Okutsu ◽  
Xinhe Yin ◽  
Jyeyi Kwek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Exercise ◽  
Mitochondrial Biogenesis ◽  
Knockout Mice ◽  
Functional Role ◽  
Fiber Type ◽  
Mitochondrial Morphology ◽  
Mouse Skeletal Muscle ◽  
Type Transformation ◽  
Exercise Induced

Endurance exercise stimulates peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression in skeletal muscle, and forced expression of PGC-1α changes muscle metabolism and exercise capacity in mice. However, it is unclear if PGC-1α is indispensible for endurance exercise-induced metabolic and contractile adaptations in skeletal muscle. In this study, we showed that endurance exercise-induced expression of mitochondrial enzymes (cytochrome oxidase IV and cytochrome c) and increases of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31)-positive endothelial cells in skeletal muscle, but not IIb-to-IIa fiber-type transformation, were significantly attenuated in muscle-specific Pgc-1α knockout mice. Interestingly, voluntary running effectively restored the compromised mitochondrial integrity and superoxide dismutase 2 (SOD2) protein expression in skeletal muscle in Pgc-1α knockout mice. Thus, PGC-1α plays a functional role in endurance exercise-induced mitochondrial biogenesis and angiogenesis, but not IIb-to-IIa fiber-type transformation in mouse skeletal muscle, and the improvement of mitochondrial morphology and antioxidant defense in response to endurance exercise may occur independently of PGC-1α function. We conclude that PGC-1α is required for complete skeletal muscle adaptations induced by endurance exercise in mice.

scholarly journals Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle

2011 ◽  
Vol 110 (1) ◽  
pp. 264-274 ◽  
Author(s):  
Zhen Yan ◽  
Mitsuharu Okutsu ◽  
Yasir N. Akhtar ◽  
Vitor A. Lira
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Fiber Type ◽  
Genetically Engineered ◽  
Type Transformation ◽  
Muscle Adaptations ◽  
Exercise Induced ◽  
Skeletal Muscle Adaptations ◽  
Muscle Contractile

Skeletal muscle exhibits superb plasticity in response to changes in functional demands. Chronic increases of skeletal muscle contractile activity, such as endurance exercise, lead to a variety of physiological and biochemical adaptations in skeletal muscle, including mitochondrial biogenesis, angiogenesis, and fiber type transformation. These adaptive changes are the basis for the improvement of physical performance and other health benefits. This review focuses on recent findings in genetically engineered animal models designed to elucidate the mechanisms and functions of various signal transduction pathways and gene expression programs in exercise-induced skeletal muscle adaptations.

TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice

2012 ◽  
Vol 302 (7) ◽  
pp. E896-E902 ◽  
Author(s):  
Hitoshi Iwasaki ◽  
Ayano Naka ◽  
Kaoruko Tada Iida ◽  
Yoshimi Nakagawa ◽  
Takashi Matsuzaka ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Transgenic Mice ◽  
Glycogen Synthase ◽  
Bhlh Transcription Factor ◽  
Endurance Capacity ◽  
Glycogen Stores

The role of transcription factor E3 (TFE3), a bHLH transcription factor, in immunology and cancer has been well characterized. Recently, we reported that TFE3 activates hepatic IRS-2 and hexokinase, participates in insulin signaling, and ameliorates diabetes. However, the effects of TFE3 in other organs are poorly understood. Herein, we examined the effects of TFE3 on skeletal muscle, an important organ involved in glucose metabolism. We generated transgenic mice that selectively express TFE3 in skeletal muscles. These mice exhibit a slight acceleration in growth prior to adulthood as well as a progressive increase in muscle mass. In TFE3 transgenic muscle, glycogen stores were more than twofold than in wild-type mice, and this was associated with an upregulation of genes involved in glucose metabolism, specifically glucose transporter 4, hexokinase II, and glycogen synthase. Consequently, exercise endurance capacity was enhanced in this transgenic model. Furthermore, insulin sensitivity was enhanced in transgenic mice and exhibited better improvement after 4 wk of exercise training, which was associated with increased IRS-2 expression. The effects of TFE3 on glucose metabolism in skeletal muscle were different from that in the liver, although they did, in part, overlap. The potential role of TFE3 in regulating metabolic genes and glucose metabolism within skeletal muscle suggests that it may be used for treating metabolic diseases as well as increasing endurance in sport.

Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle

2013 ◽  
Vol 441 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Shin-ichi Ikeda ◽  
Yoshifumi Tamura ◽  
Saori Kakehi ◽  
Kageumi Takeno ◽  
Minako Kawaguchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Mouse Skeletal Muscle ◽  
Exercise Induced

scholarly journals Fast skeletal muscle-specific expression of a quail troponin I gene in transgenic mice.

1988 ◽  
Vol 8 (12) ◽  
pp. 5072-5079 ◽  
Author(s):  
P L Hallauer ◽  
K E Hastings ◽  
A C Peterson
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Troponin I ◽  
Fiber Type ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Mrna Levels ◽  
Fast Skeletal Muscle ◽  
Specific Expression ◽  
Exon 2

We have produced seven lines of transgenic mice carrying the quail gene encoding the fast skeletal muscle-specific isoform of troponin I (TnIf). The quail DNA included the entire TnIf gene, 530 base pairs of 5'-flanking DNA, and 1.5 kilobase pairs of 3'-flanking DNA. In all seven transgenic lines, normally initiated and processed quail TnIf mRNA was expressed in skeletal muscle, where it accumulated to levels comparable to that in quail muscle. Moreover, in the three lines tested, quail TnIf mRNA levels were manyfold higher in a fast skeletal muscle (gastrocnemius) than in a slow skeletal muscle (soleus). We conclude that the cellular mechanisms directing muscle fiber type-specific TnIf gene expression are mediated by cis-regulatory elements present on the introduced quail DNA fragment and that they control TnIf expression by affecting the accumulation of TnIf mRNA. These elements have been functionally conserved since the evolutionary divergence of birds and mammals, despite the major physiological and morphological differences existing between avian (tonic) and mammalian (twitch) slow muscles. In lines of transgenic mice carrying multiple tandemly repeated copies of the transgene, an aberrant quail TnIf transcript (differing from normal TnIf mRNA upstream of exon 2) also accumulated in certain tissues, particularly lung, brain, spleen, and heart tissues. However, this aberrant transcript was not detected in a transgenic line which carries only a single copy of the quail gene.

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