Skeletal muscle and beyond: the role of exercise as a mediator of systemic mitochondrial biogenesis

2011 ◽  
Vol 36 (5) ◽  
pp. 598-607 ◽  
Author(s):  
Jonathan P. Little ◽  
Adeel Safdar ◽  
Carley R. Benton ◽  
David C. Wright
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Enzyme ◽  
Mitochondrial Content ◽  
Enzyme Content ◽  
Wide Range ◽  
Underlying Mechanisms

It has been known for more than 4 decades that exercise causes increases in skeletal muscle mitochondrial enzyme content and activity (i.e., mitochondrial biogenesis). Increasing evidence now suggests that exercise can induce mitochondrial biogenesis in a wide range of tissues not normally associated with the metabolic demands of exercise. Perturbations in mitochondrial content and (or) function have been linked to a wide variety of diseases, in multiple tissues, and exercise may serve as a potent approach by which to prevent and (or) treat these pathologies. In this context, the purpose of this review is to highlight the effects of exercise, and the underlying mechanisms therein, on the induction of mitochondrial biogenesis in skeletal muscle, adipose tissue, liver, brain, and kidney.

scholarly journals Regulation of PPARγCoactivator-1αFunction and Expression in Muscle: Effect of Exercise

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Giulia Uguccioni ◽  
Donna D'souza ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Posttranslational Modifications ◽  
Mitochondrial Proteins ◽  
Mitochondrial Content ◽  
Brown Adipose ◽  
Muscle Adaptations ◽  
Genes Encoding ◽  
Skeletal Muscle Adaptations

PPARγcoactivator-1α(PGC-1α) is considered to be a major regulator of mitochondrial biogenesis. Though first discovered in brown adipose tissue, this coactivator has emerged as a coordinator of mitochondrial biogenesis in skeletal muscle via enhanced transcription of many nuclear genes encoding mitochondrial proteins. Stimuli such as exercise provoke the activation of signalling cascades that lead to the induction of PGC-1α. Posttranslational modifications also regulate the function of PGC-1α, with a multitude of upstream molecules targeting the protein to modify its activity and/or expression. Previous research has established a positive correlation between resistance to fatigue and skeletal muscle mitochondrial content. Recently, studies have begun to elucidate the specific role of PGC-1αin exercise-related skeletal muscle adaptations, with several studies identifying it as a dominant regulator of organelle synthesis. This paper will highlight the function, regulation, and expression of PGC-1α, as well as the role of the coactivator during exercise adaptations.

Inter-Tissue and Intra-Tissue Co-Expression Networks in Human Metabolism: Morphological Evaluation of the Link Between Transcription Factors ERβ and NFAT in Morbid Obesity

2020 ◽  
Vol 17 (1) ◽  
pp. 63-80
Author(s):  
Athina Chasapi ◽  
Kostas Balampanis ◽  
Eleni Kourea ◽  
Fotios Kalfaretzos ◽  
Vaia Lambadiari ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Adipose Tissue ◽  
Clinicopathological Parameters ◽  
Morbidly Obese ◽  
Human Metabolism ◽  
Activated T Cells ◽  
Alcoholic Fatty Liver ◽  
Morphological Evaluation ◽  
Underlying Mechanisms

Background: Estrogen receptor β (ERβ) plays an important role in human metabolism and some of its metabolic actions are mediated by a positive “cross-talk” with Nuclear Factor of Activated T cells (NFAT) and the key metabolic transcriptional coregulator Transcriptional Intermediary Factor 2 (TIF2). Introduction: Our study is an “in situ” morphological evaluation of the communication between ERβ, NFAT and TIF2 in morbid obesity. Potential correlations with clinicopathological parameters and with the presence of diabetes and non-alcoholic fatty liver disease (NAFLD) were also explored. The aim of the present study was to determine the role of ERβ and NFAT in the underlying pathophysiology of obesity and related comorbidities. We have investigated the expression of specific proteins using immunochemistry methodologies. Methods: Our population consists of 50 morbidly obese patients undergoing planned bariatric surgery, during which biopsies were taken from visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver and the differential protein expression was evaluated by immunohistochemistry. Results: We demonstrated an extensive intra- and inter-tissue co-expression network, which confirms the tissue-specific and integral role of each one of the investigated proteins in morbid obesity. Moreover, a beneficial role of ERβ and NFATc1 against NAFLD is implicated, whereas the distinct roles of TIF2 still remain an enigma. Conclusions: We believe that our findings will shed light on the complex underlying mechanisms and that the investigated biomarkers could represent future targets for the prevention and therapy of obesity and its comorbidities.

Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exerciseThis 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. 315-322 ◽  
Author(s):  
Gregory R. Steinberg
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Moderate Intensity ◽  
Amp Activated Protein Kinase

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

Abstract 112: A Pathological Role of Endothelial p53 in the Regulation of Endothelial Function and Glucose Metabolism

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Masataka YOKOYAMA ◽  
Yoshio KOBAYASHI ◽  
Tohru MINAMINO
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cell ◽  
Glucose Metabolism ◽  
Endothelial Function ◽  
Mitochondrial Biogenesis ◽  
Glucose Transporter ◽  
Diabetic Patients ◽  
Glucose Transporter 1 ◽  
P53 Activation

Cellular senescence is a state of irreversible growth arrest induced by various stresses such as oncogenic stimuli. This response is controlled by negative regulators of the cell cycle like the p53 tumor suppressor protein. Accumulating evidence has suggested a role of p53 activation in various age-associated conditions including atherosclerosis, heart failure and diabetes. Here we show that endothelial p53 activation plays a pathological role in the regulation of endothelial function and glucose metabolism under diabetic conditions. Endothelial expression of p53 was markedly up-regulated in a streptozotocin-induced diabetes model. Endothelial function such as acetylcholine-dependent vasodilatation was markedly impaired in this model. Although hyperglycemia was not altered, impairment of endothelial function was significantly improved in mice with endothelial cell-specific p53 deficiency. In same way, p53 was markedly activated in ischemic vessels, and endothelial p53 deficiency enhanced ischemia-induced angiogenesis. Mechanistically, endothelial p53 up-regulated the expression of PTEN that negatively regulated the Akt-eNOS pathway, and therefore disruption of p53 improved endothelial dysfunction. We also found that endothelial p53 was markedly activated, and the Akt-eNOS pathway was attenuated in a diet-induced obesity model. Disruption of endothelial p53 activation improved dietary inactivation of eNOS that up-regulated the expression of PGC-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Consequently, mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 negatively regulates endothelium-dependent vasodilatation, ischemia-induced angiogenesis, and mitochondrial biogenesis by inhibiting the Akt-eNOS pathway and suggest that inhibition of endothelial p53 could be a novel therapeutic target in diabetic patients.

scholarly journals Dietary Manipulations Concurrent to Endurance Training

2018 ◽  
Vol 3 (3) ◽  
pp. 41 ◽  
Author(s):  
Jeffrey Rothschild ◽  
Conrad Earnest
Keyword(s):  
Endurance Athlete ◽  
Training Session ◽  
Food Type ◽  
Mitochondrial Enzyme ◽  
High Fat ◽  
Mitochondrial Content ◽  
The Past ◽  
Metabolic Adaptations ◽  
Fasted State

The role of an athlete’s dietary intake (both timing and food type) goes beyond simply providing fuel to support the body’s vital processes. Nutritional choices also have an impact on the metabolic adaptations to training. Over the past 20 years, research has suggested that strategically reducing carbohydrate (CHO) availability during an athlete’s training can modify the metabolic responses in lieu of simply maintaining a high CHO diet. Several methods have been explored to manipulate CHO availability and include: Low-carb, high-fat (LCHF) diets, performing two-a-day training without glycogen restoration between sessions, and a “sleep-low” approach entailing a glycogen-depleting session in the evening without consuming CHO until after a morning training session performed in an overnight fasted state. Each of these methods can confer beneficial metabolic adaptations for the endurance athlete including increases in mitochondrial enzyme activity, mitochondrial content, and rates of fat oxidation, yet data showing a direct performance benefit is still unclear.

scholarly journals Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue

2020 ◽  
Vol 21 (16) ◽  
pp. 5738
Author(s):  
Xiong Weng ◽  
De Lin ◽  
Jeffrey T. J. Huang ◽  
Roland H. Stimson ◽  
David H. Wasserman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Resistant ◽  
Global View ◽  
Novel Association ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes.

Postprandial leg uptake of triglyceride is greater in women than in men

2002 ◽  
Vol 283 (6) ◽  
pp. E1192-E1202 ◽  
Author(s):  
Tracy J. Horton ◽  
S. Renee Commerford ◽  
Michael J. Pagliassotti ◽  
Daniel H. Bessesen
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Test Meal ◽  
Dietary Fat ◽  
Nutritional State ◽  
Lipid Uptake ◽  
Postprandial Metabolism ◽  
Men And Women ◽  
Main Effect

The postprandial excursion of plasma triglyceride (TG) concentration is greater in men than in women. In this study, the disposition of dietary fat was examined in lean healthy men and women ( n = 8/group) in either the overnight-fasted or fed (4.5 h after breakfast) states. A [14C]oleate tracer was incorporated into a test meal, providing 30% of total daily energy requirements. After ingestion of the test meal, measures of arteriovenous differences in TG and14C across the leg were combined with needle biopsies of skeletal muscle and adipose tissue and respiratory gas collections to define the role of skeletal muscle in the clearance of dietary fat. The postprandial plasma TG and14C tracer excursions were lower ( P = 0.04) in women than in men in the overnight-fasted and fed states. Women, however, had significantly greater limb uptake of total TG compared with men on both the fasted (3,849 ± 846 vs. 528 ± 221 total μmol over 6 h) and fed (4,847 ± 979 vs. 1,571 ± 334 total μmol over 6 h) days. This was also true for meal-derived14C lipid uptake.14C content of skeletal muscle tissue (μCi/g tissue) was significantly greater in women than in men 6 h after ingestion of the test meal. In contrast,14C content of adipose tissue was not significantly different between men and women at 6 h. The main effect of nutritional state, fed vs. fasted, was to increase the postmeal glucose ( P = 0.01) excursion (increase from baseline) and decrease the postmeal TG excursion ( P = 0.02). These results support the notion that enhanced skeletal muscle clearance of lipoprotein TG in women contributes to their reduced postprandial TG excursion. Questions remain as to the mechanisms causing these sex-based differences in skeletal muscle TG uptake and metabolism. Furthermore, nutritional state can significantly impact postprandial metabolism in both men and women.

scholarly journals The role of protein-mediated transport in regulating mitochondrial long-chain fatty acid oxidation

2008 ◽  
Vol 33 (1) ◽  
pp. 141-142
Author(s):  
Graham Paul Holloway
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Muscle Contraction ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Mitochondrial Content ◽  
Palmitate Oxidation ◽  
Long Chain

This thesis is an investigation of the role of fatty acid translocase (FAT/CD36), plasma membrane associated fatty acid binding protein (FABPpm), and carnitine palmitoyltransferase I (CPTI) in transporting long-chain fatty acids (LCFAs) across mitochondrial membranes. Maximal CPTI activity, as well as the sensitivity of CPTI for its substrate palmitoyl-CoA (P-CoA) and its inhibitor malonyl-CoA (M-CoA), were measured in mitochondria isolated from human vastus lateralis muscles at rest and following muscle contraction. Exercise did not alter maximal CPTI activity or the sensitivity of CPTI for P-CoA. In contrast, exercise progressively attenuated the ability of M-CoA to inhibit CPTI activity. Mitochondrial FAT/CD36 protein content was also measured at rest, during, and following 2 h of cycling at ~60% maximal oxygen uptake. Exercise progressively increased the content of mitochondrial FAT/CD36 (+59%), which was significantly (p < 0.05) correlated with palmitate oxidation during exercise (r = 0.52), while palmitate oxidation was inhibited ~80% by the administration of a specific FAT/CD36 inhibitor. These data suggest that alterations in CPTI M-CoA sensitivity and increases in mitochondrial FAT/CD36 coordinate exercise-induced increases in fatty acid oxidation. FABPpm, another plasma membrane transport protein, has identical amino acid sequence to mitochondrial aspartate aminotransferase (mAspAT). Since FABPpm contributes to plasma membrane fatty acid transport, the role of FABPpm with respect to mitochondrial LCFA transport was investigated. However, unlike FAT/CD36, muscle contraction did not induce an increase in mitochondrial FABPpm protein in rat or human skeletal muscle. In addition, electrotransfecting FABPpm cDNA into rat skeletal muscle upregulated this protein in mitochondria by 80% without altering mitochondrial palmitate oxidation. In contrast, electrotransfection increased mAspAT activity  by 90%, and this was correlated (r = 0.75; p < 0.01) with FABPpm protein. These data suggest that FABPpm does not contribute to the regulation of mitochondrial LCFA transport. Previously, it has been suggested that mitochondria from obese individuals contain an inherent dysfunction to oxidize LCFAs. In age-matched lean (BMI = 23.3 ± 0.7 kg·m–2) and obese (BMI = 37.6 ± 2.2 kg·m–2) individuals, isolated mitochondrial palmitate oxidation was not altered. In addition, mitochondrial FAT/CD36 content was not different in lean and obese individuals. In contrast, citrate synthase and β-hydroxyacyl-CoA dehydrogenase, common markers of total mitochondrial content, were decreased with obesity. Therefore, the decrease in mitochondrial content appeared to account for the observed reductions in whole-muscle LCFA oxidation.

Effects of low-dose leucine supplementation on gastrocnemius muscle mitochondrial content and protein turnover in tumor-bearing mice

2019 ◽  
Vol 44 (9) ◽  
pp. 997-1004 ◽  
Author(s):  
Harold W. Lee ◽  
Ella Baker ◽  
Kevin M. Lee ◽  
Aaron M. Persinger ◽  
William Hawkins ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Mitochondrial Biogenesis ◽  
Protein Turnover ◽  
C2c12 Myotubes ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Mitochondrial Content ◽  
Leucine Supplementation ◽  
Tumor Bearing

Many forms of cancer are associated with loss of lean body mass, commonly attributed to decreased protein synthesis and stimulation of proteolytic pathways within the skeletal muscle. Leucine has been shown to improve protein synthesis, insulin signaling, and mitochondrial biogenesis, which are key signaling pathways influenced by tumor signaling. The purpose of this study was to examine the effects of leucine supplementation on mitochondrial biogenesis and protein turnover in tumor-bearing mice. Twenty male C57BL/6 mice were divided into 4 groups (n = 5): Chow, leucine (Leu), Lewis lung carcinoma (LLC) implant, and LLC+Leu. At 9–10 weeks of age, mice were inoculated and supplemented with 5% leucine (w/w) in the diet. C2C12 myotubes were treated with 2.5 mmol/L leucine and 25% LLC conditioned media to further elucidate the direct influence of the tumor and leucine on the muscle. Measures of protein synthesis, mitochondrial biogenesis, and inflammation in the gastrocnemius were assessed via Western blot analysis. Gastrocnemius mass was decreased in LLC+Leu relative to LLC (p = 0.040). Relative protein synthesis rate was decreased in LLC mice (p = 0.001). No change in protein synthesis was observed in myotubes. Phosphorylation of STAT3 was decreased in the Leu group relative to the control in both mice (p = 0.019) and myotubes (p = 0.02), but did not significantly attenuate the inflammatory effect of LLC implantation (p = 0.619). LLC decreased markers of mitochondrial content; however, PGC-1α was increased in LLC+Leu relative to LLC (p = 0.001). While leucine supplementation was unable to preserve protein synthesis or mitochondrial content associated with LLC implantation, it was able to increase mitochondrial biogenesis signaling. Novelty This study provides novel insights on the effect of leucine supplementation on mitochondrial biogenesis and protein turnover in tumor-bearing mice. Leucine increased signaling for mitochondrial biogenesis in the skeletal muscle. Leucine supplementation decreased inflammatory signaling in skeletal muscle.

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