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1
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Leitner BP, Siebel S, Akingbesote ND, Zhang X, Perry RJ. Insulin and cancer: a tangled web. Biochem J 2022; 479:583-607. [PMID: 35244142 PMCID: PMC9022985 DOI: 10.1042/bcj20210134] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/13/2022] [Accepted: 02/15/2022] [Indexed: 12/13/2022]
Abstract
For a century, since the pioneering work of Otto Warburg, the interwoven relationship between metabolism and cancer has been appreciated. More recently, with obesity rates rising in the U.S. and worldwide, epidemiologic evidence has supported a link between obesity and cancer. A substantial body of work seeks to mechanistically unpack the association between obesity, altered metabolism, and cancer. Without question, these relationships are multifactorial and cannot be distilled to a single obesity- and metabolism-altering hormone, substrate, or factor. However, it is important to understand the hormone-specific associations between metabolism and cancer. Here, we review the links between obesity, metabolic dysregulation, insulin, and cancer, with an emphasis on current investigational metabolic adjuncts to standard-of-care cancer treatment.
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Affiliation(s)
- Brooks P. Leitner
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Stephan Siebel
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Pediatrics, Yale School of Medicine, New Haven, CT, U.S.A
| | - Ngozi D. Akingbesote
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Xinyi Zhang
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
| | - Rachel J. Perry
- Departments of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, U.S.A
- Departments of Internal Medicine, Yale School of Medicine, New Haven, CT, U.S.A
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2
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The Effect of a Single Bout of Exercise on Vitamin B2 Status Is Not Different between High- and Low-Fit Females. Nutrients 2021; 13:nu13114097. [PMID: 34836352 PMCID: PMC8618623 DOI: 10.3390/nu13114097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 12/05/2022] Open
Abstract
High-fitness individuals have been suggested to be at risk of a poor vitamin B2 (riboflavin) status due to a potentially higher vitamin B2 demand, as measured by the erythrocyte glutathione reductase (EGR) activation coefficient (EGRAC). Longer-term exercise interventions have been shown to result in a lower vitamin B2 status, but studies are contradictory. Short-term exercise effects potentially contribute to discrepancies between studies but have only been tested in limited study populations. This study investigated if vitamin B2 status, measured by EGRAC, is affected by a single exercise bout in females who differ in fitness levels, and that represents long-term physical activity. At baseline and overnight after a 60-min cycling bout at 70% V·O2peak, EGR activity and EGRAC were measured in 31 young female adults, divided into a high-fit (V·O2peak ≥ 47 mL/kg/min, N = 15) and low-fit (V·O2peak ≤ 37 mL/kg/min, N = 16) group. A single exercise bout significantly increased EGR activity in high-fit and low-fit females (Ptime = 0.006). This response was not affected by fitness level (Ptime*group = 0.256). The effect of exercise on EGRAC was not significant (Ptime = 0.079) and not influenced by EGR activity. The exercise response of EGRAC was not significantly different between high-fit and low-fit females (Ptime*group = 0.141). Thus, a single exercise bout increased EGR activity, but did not affect EGRAC, indicating that vitamin B2 status was not affected. The exercise response on EGRAC and EGR did not differ between high-fit and low-fit females.
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3
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Tardo-Dino PE, Taverny C, Siracusa J, Bourdon S, Baugé S, Koulmann N, Malgoyre A. Effect of heat acclimation on metabolic adaptations induced by endurance training in soleus rat muscle. Physiol Rep 2021; 9:e14686. [PMID: 34405575 PMCID: PMC8371354 DOI: 10.14814/phy2.14686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 10/19/2020] [Accepted: 10/29/2020] [Indexed: 11/24/2022] Open
Abstract
Aerobic training leads to well‐known systemic metabolic and muscular alterations. Heat acclimation may also increase mitochondrial muscle mass. We studied the effects of heat acclimation combined with endurance training on metabolic adaptations of skeletal muscle. Thirty‐two rats were divided into four groups: control (C), trained (T), heat‐acclimated (H), and trained with heat acclimation (H+T) for 6 weeks. Soleus muscle metabolism was studied, notably by the in situ measurement of mitochondrial respiration with pyruvate (Pyr) or palmitoyl‐coenzyme A (PCoA), under phosphorylating conditions (V˙max) or not (V˙0). Aerobic performance increased, and retroperitoneal fat mass decreased with training, independently of heat exposure (p < 0.001 and p < 0.001, respectively). Citrate synthase and hydroxyl‐acyl‐dehydrogenase activity increased with endurance training (p < 0.001 and p < 0.01, respectively), without any effect of heat acclimation. Training induced an increase of the V˙0 and V˙max for PCoA (p < .001 and p < .01, respectively), without interference with heat acclimation. The training‐induced increase of V˙0 (p < 0.01) for pyruvate oxidation was limited when combined with heat acclimation (−23%, p < 0.01). Training and heat acclimation independently increased the V˙max for pyruvate (+60% p < 0.001 and +50% p = 0.01, respectively), without an additive effect of the combination. Heat acclimation doubled the training effect on muscle glycogen storage (p < 0.001). Heat acclimation did not improve mitochondrial adaptations induced by endurance training in the soleus muscle, possibly limiting the alteration of carbohydrate oxidation while not facilitating fatty‐acid utilization. Furthermore, the increase in glycogen storage observed after HA combined with endurance training, without the improvement of pyruvate oxidation, appears to be a hypoxic metabolic phenotype.
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Affiliation(s)
- Pierre-Emmanuel Tardo-Dino
- Unité de Physiologie de l'Exercice et des Activités en Conditions Extrêmes, Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France.,Ecole du Val-de-Grâce, Paris, France.,EDISS 205, Université Claude Bernard Lyon 1, Villeurbanne, France.,LBEPS, Université Evry, IRBA, Université Paris-Saclay, Paris, 91025, France
| | - Cindy Taverny
- Unité de Physiologie de l'Exercice et des Activités en Conditions Extrêmes, Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France
| | - Julien Siracusa
- Unité de Physiologie de l'Exercice et des Activités en Conditions Extrêmes, Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France.,LBEPS, Université Evry, IRBA, Université Paris-Saclay, Paris, 91025, France
| | - Stéphanie Bourdon
- Unité de Physiologie de l'Exercice et des Activités en Conditions Extrêmes, Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France.,LBEPS, Université Evry, IRBA, Université Paris-Saclay, Paris, 91025, France
| | - Stéphane Baugé
- Unité de Physiologie de l'Exercice et des Activités en Conditions Extrêmes, Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France.,LBEPS, Université Evry, IRBA, Université Paris-Saclay, Paris, 91025, France
| | - Nathalie Koulmann
- Unité de Physiologie de l'Exercice et des Activités en Conditions Extrêmes, Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France.,Ecole du Val-de-Grâce, Paris, France.,EDISS 205, Université Claude Bernard Lyon 1, Villeurbanne, France.,LBEPS, Université Evry, IRBA, Université Paris-Saclay, Paris, 91025, France
| | - Alexandra Malgoyre
- Unité de Physiologie de l'Exercice et des Activités en Conditions Extrêmes, Département Environnements Opérationnels, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France.,LBEPS, Université Evry, IRBA, Université Paris-Saclay, Paris, 91025, France
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4
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Gonzalez-Franquesa A, Stocks B, Chubanava S, Hattel HB, Moreno-Justicia R, Peijs L, Treebak JT, Zierath JR, Deshmukh AS. Mass-spectrometry-based proteomics reveals mitochondrial supercomplexome plasticity. Cell Rep 2021; 35:109180. [PMID: 34038727 DOI: 10.1016/j.celrep.2021.109180] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/29/2021] [Accepted: 05/04/2021] [Indexed: 11/26/2022] Open
Abstract
Mitochondrial respiratory complex subunits assemble in supercomplexes. Studies of supercomplexes have typically relied upon antibody-based quantification, often limited to a single subunit per respiratory complex. To provide a deeper insight into mitochondrial and supercomplex plasticity, we combine native electrophoresis and mass spectrometry to determine the supercomplexome of skeletal muscle from sedentary and exercise-trained mice. We quantify 422 mitochondrial proteins within 10 supercomplex bands in which we show the debated presence of complexes II and V. Exercise-induced mitochondrial biogenesis results in non-stoichiometric changes in subunits and incorporation into supercomplexes. We uncover the dynamics of supercomplex-related assembly proteins and mtDNA-encoded subunits after exercise. Furthermore, exercise affects the complexing of Lactb, an obesity-associated mitochondrial protein, and ubiquinone biosynthesis proteins. Knockdown of ubiquinone biosynthesis proteins leads to alterations in mitochondrial respiration. Our approach can be applied to broad biological systems. In this instance, comprehensively analyzing respiratory supercomplexes illuminates previously undetectable complexity in mitochondrial plasticity.
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Affiliation(s)
- Alba Gonzalez-Franquesa
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Ben Stocks
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Sabina Chubanava
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Helle B Hattel
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Roger Moreno-Justicia
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Lone Peijs
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Jonas T Treebak
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark
| | - Juleen R Zierath
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden
| | - Atul S Deshmukh
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen 2200, Denmark.
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5
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Just-Borràs L, Cilleros-Mañé V, Hurtado E, Biondi O, Charbonnier F, Tomàs M, Garcia N, Tomàs J, Lanuza MA. Running and Swimming Differently Adapt the BDNF/TrkB Pathway to a Slow Molecular Pattern at the NMJ. Int J Mol Sci 2021; 22:4577. [PMID: 33925507 PMCID: PMC8123836 DOI: 10.3390/ijms22094577] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/29/2022] Open
Abstract
Physical exercise improves motor control and related cognitive abilities and reinforces neuroprotective mechanisms in the nervous system. As peripheral nerves interact with skeletal muscles at the neuromuscular junction, modifications of this bidirectional communication by physical activity are positive to preserve this synapse as it increases quantal content and resistance to fatigue, acetylcholine receptors expansion, and myocytes' fast-to-slow functional transition. Here, we provide the intermediate step between physical activity and functional and morphological changes by analyzing the molecular adaptations in the skeletal muscle of the full BDNF/TrkB downstream signaling pathway, directly involved in acetylcholine release and synapse maintenance. After 45 days of training at different intensities, the BDNF/TrkB molecular phenotype of trained muscles from male B6SJLF1/J mice undergo a fast-to-slow transition without affecting motor neuron size. We provide further knowledge to understand how exercise induces muscle molecular adaptations towards a slower phenotype, resistant to prolonged trains of stimulation or activity that can be useful as therapeutic tools.
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Affiliation(s)
- Laia Just-Borràs
- Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain; (L.J.-B.); (V.C.-M.); (E.H.); (M.T.); (N.G.)
| | - Víctor Cilleros-Mañé
- Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain; (L.J.-B.); (V.C.-M.); (E.H.); (M.T.); (N.G.)
| | - Erica Hurtado
- Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain; (L.J.-B.); (V.C.-M.); (E.H.); (M.T.); (N.G.)
| | - Olivier Biondi
- INSERM UMRS 1124, Université de Paris, CEDEX 06, F-75270 Paris, France; (O.B.); (F.C.)
| | - Frédéric Charbonnier
- INSERM UMRS 1124, Université de Paris, CEDEX 06, F-75270 Paris, France; (O.B.); (F.C.)
| | - Marta Tomàs
- Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain; (L.J.-B.); (V.C.-M.); (E.H.); (M.T.); (N.G.)
| | - Neus Garcia
- Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain; (L.J.-B.); (V.C.-M.); (E.H.); (M.T.); (N.G.)
| | - Josep Tomàs
- Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain; (L.J.-B.); (V.C.-M.); (E.H.); (M.T.); (N.G.)
| | - Maria A. Lanuza
- Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain; (L.J.-B.); (V.C.-M.); (E.H.); (M.T.); (N.G.)
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6
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Karasawa T, Kondo S, Fukazawa A, Koike A, Tsutsui M, Terada S. Effects of Dietary Fat Restriction on Endurance Training-induced Metabolic Adaptations in Rat Skeletal Muscle. J Oleo Sci 2021; 70:253-262. [PMID: 33456007 DOI: 10.5650/jos.ess20248] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Endurance exercise training enhances muscle fat oxidation while concomitantly reducing carbohydrate (glycogen) utilization during exercise, thereby delaying the onset of fatigue. This study examined the effects of dietary fat restriction on endurance training-induced metabolic adaptations in rat skeletal muscle. Male Sprague-Dawley rats were placed on either a control diet (CON: 19.2% protein, 21.6% fat, and 59.2% carbohydrate as a percentage of total energy) or a fat-restricted diet (FR: 21.5% protein, 2.4% fat, and 76.1% carbohydrate as a percentage of total energy) for 4 wks. Half the rats in each dietary group performed daily 6-h swimming exercise (two 3-h sessions separated by 45 min of rest) on 5 days each wk. Endurance training significantly increased the expression of β-hydroxyacyl CoA dehydrogenase (βHAD), a key enzyme of fat oxidation, and pyruvate dehydrogenase kinase 4 (PDK4), an inhibitory regulator of glycolytic flux, in the skeletal muscle of rats fed the CON diet. However, such endurance training-induced increases in muscle βHAD and PDK4 were partially suppressed by the FR diet, suggesting that a FR diet may diminish the endurance training-induced enhancement of fat oxidation and reduction in glycogen utilization during exercise. We then assessed the muscle glycogen utilization rate during an acute bout of swimming exercise in the trained rats fed either the CON or the FR diet and consequently found that rats fed the FR diet had a significantly higher muscle glycogen utilization rate during exercise compared with rats fed the CON diet. In conclusion, dietary fat restriction may attenuate the endurance training-induced metabolic adaptations in skeletal muscle.
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Affiliation(s)
- Takuya Karasawa
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo
| | - Saki Kondo
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo
- Research Fellow of Japan Society for the Promotion of Science
| | - Ayumi Fukazawa
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo
| | - Atsuko Koike
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo
| | - Momoko Tsutsui
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo
| | - Shin Terada
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo
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7
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Arfuso F, Giannetto C, Giudice E, Fazio F, Piccione G. Dynamic Change of Free Serum L-carnitine Concentration in Relation to Age, Sex, and Exercise in Anglo-Arabian Thoroughbred Horses. J Equine Vet Sci 2020; 97:103343. [PMID: 33478765 DOI: 10.1016/j.jevs.2020.103343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 10/22/2022]
Abstract
The physiological role of L-carnitine in equine species is worthy of investigation; however, the systemic content of free L-carnitine and its dynamic change in growing foals as well as in exercising horses are still poorly investigated. In this study, the influence of age and exercise on free serum L-carnitine levels was evaluated in equine species. Ten foals were monitored from 6 up to 18 months of age (group 1), whereas 60 horses were divided in six groups in accordance with their age: group 2, 2-year-old; group 3, 3-year-old; group 4, 4-year-old; group 5, 5-year-old; group 6, 6-year-old; group 7, 7-year-old. To assess the age and sex effect on free serum L-carnitine values, blood samples were collected from foals and horses. Adult horses (groups 2-7) were subjected to a simulate 1,660-m race, and blood samples were collected before the simulate race (TPRE), within 10 minutes (TPOST10) from the end of race, and after 30 minutes (TPOST30) from the end of race. The amino acid levels were influenced by age (P < .0001) in foals and horses. Decreased levels of amino acid were observed at TPOST10 with respect to TPRE and TPOST30. (P < .001). The findings suggest that the biosynthetic pathway of L-carnitine is organizing and adapting to the metabolic needs of skeletal and cardiac muscle tissue in the course of growth. L-carnitine could play a role for the provision of energy to the exercising muscles. Further studies are needed to evaluate possible beneficial effects of L-carnitine during growing phase and on parameters of equine physical performance.
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Affiliation(s)
- Francesca Arfuso
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy.
| | - Claudia Giannetto
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy
| | - Elisabetta Giudice
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy
| | - Francesco Fazio
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy
| | - Giuseppe Piccione
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy
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8
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Abreu P, Kowaltowski AJ. Satellite cell self-renewal in endurance exercise is mediated by inhibition of mitochondrial oxygen consumption. J Cachexia Sarcopenia Muscle 2020; 11:1661-1676. [PMID: 32748470 PMCID: PMC7749620 DOI: 10.1002/jcsm.12601] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 06/07/2020] [Accepted: 06/15/2020] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Skeletal muscle stem cells (satellite cells) are well known to participate in regeneration and maintenance of the tissue over time. Studies have shown increases in the number of satellite cells after exercise, but their functional role in endurance training remains unexplored. METHODS Young adult mice were submitted to endurance exercise training and the function, differentiation, and metabolic characteristics of satellite cells were investigated in vivo and in vitro. RESULTS We found that injured muscles from endurance-exercised mice display improved regenerative capacity, demonstrated through higher densities of newly formed myofibres compared with controls (evidenced by an increase in embryonic myosin heavy chain expression), as well as lower inflammation (evidenced by quantifying CD68-marked macrophages), and reduced fibrosis. Enhanced myogenic function was accompanied by an increased fraction of satellite cells expressing self-renewal markers, while control satellite cells had morphologies suggestive of early differentiation. The beneficial effects of endurance exercise were associated with satellite cell metabolic reprogramming, including reduced mitochondrial respiration (O2 consumption) under resting conditions (absence of muscle injury) and increased stemness. During proliferation or activated states (3 days after injury), O2 consumption was equal in control and exercised cells, while exercise enhanced myogenic colony formation. Surprisingly, inhibition of mitochondrial O2 consumption was sufficient to enhance muscle stem cell self-renewal characteristics in vitro. Moreover, transplanted muscle satellite cells from exercised mice or cells with reduced mitochondrial respiration promoted a significant reduction in inflammation compared with controls. CONCLUSIONS Our results indicate that endurance exercise promotes self-renewal and inhibits differentiation in satellite cells, an effect promoted by metabolic reprogramming and respiratory inhibition, which is associated with a more favourable muscular response to injury.
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Affiliation(s)
- Phablo Abreu
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Alicia J Kowaltowski
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
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9
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Gumà A, Díaz-Sáez F, Camps M, Zorzano A. Neuregulin, an Effector on Mitochondria Metabolism That Preserves Insulin Sensitivity. Front Physiol 2020; 11:696. [PMID: 32655416 PMCID: PMC7324780 DOI: 10.3389/fphys.2020.00696] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/28/2020] [Indexed: 01/06/2023] Open
Abstract
Various external factors modulate the metabolic efficiency of mitochondria. This review focuses on the impact of the growth factor neuregulin and its ErbB receptors on mitochondria and their relationship with several physiopathological alterations. Neuregulin is involved in the differentiation of heart, skeletal muscle, and the neuronal system, among others; and its deficiency is deleterious for the health. Information gathered over the last two decades suggests that neuregulin plays a key role in regulating the mitochondrial oxidative machinery, which sustains cell survival and insulin sensitivity.
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Affiliation(s)
- Anna Gumà
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.,Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
| | - Francisco Díaz-Sáez
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.,Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
| | - Marta Camps
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.,Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
| | - Antonio Zorzano
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.,Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
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10
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The Role of Nutri(epi)genomics in Achieving the Body's Full Potential in Physical Activity. Antioxidants (Basel) 2020; 9:antiox9060498. [PMID: 32517297 PMCID: PMC7346155 DOI: 10.3390/antiox9060498] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022] Open
Abstract
Physical activity represents a powerful tool to achieve optimal health. The overall activation of several molecular pathways is associated with many beneficial effects, mainly converging towards a reduced systemic inflammation. Not surprisingly, regular activity can contribute to lowering the “epigenetic age”, acting as a modulator of risk toward several diseases and enhancing longevity. Behind this, there are complex molecular mechanisms induced by exercise, which modulate gene expression, also through epigenetic modifications. The exercise-induced epigenetic imprint can be transient or permanent and contributes to the muscle memory, which allows the skeletal muscle adaptation to environmental stimuli previously encountered. Nutrition, through key macro- and micronutrients with antioxidant properties, can play an important role in supporting skeletal muscle trophism and those molecular pathways triggering the beneficial effects of physical activity. Nutrients and antioxidant food components, reversibly altering the epigenetic imprint, have a big impact on the phenotype. This assigns a role of primary importance to nutri(epi)genomics, not only in optimizing physical performance, but also in promoting long term health. The crosstalk between physical activity and nutrition represents a major environmental pressure able to shape human genotypes and phenotypes, thus, choosing the right combination of lifestyle factors ensures health and longevity.
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11
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Hagberg JM, Coyle EF, Baldwin KM, Cartee GD, Fontana L, Joyner MJ, Kirwan JP, Seals DR, Weiss EP. The historical context and scientific legacy of John O. Holloszy. J Appl Physiol (1985) 2019; 127:277-305. [PMID: 30730811 PMCID: PMC6732442 DOI: 10.1152/japplphysiol.00669.2018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
John O. Holloszy, as perhaps the world's preeminent exercise biochemist/physiologist, published >400 papers over his 50+ year career, and they have been cited >41,000 times. In 1965 Holloszy showed for the first time that exercise training in rodents resulted in a doubling of skeletal muscle mitochondria, ushering in a very active era of skeletal muscle plasticity research. He subsequently went on to describe the consequences of and the mechanisms underlying these adaptations. Holloszy was first to show that muscle contractions increase muscle glucose transport independent of insulin, and he studied the mechanisms underlying this response throughout his career. He published important papers assessing the impact of training on glucose and insulin metabolism in healthy and diseased humans. Holloszy was at the forefront of rodent studies of caloric restriction and longevity in the 1980s, following these studies with important cross-sectional and longitudinal caloric restriction studies in humans. Holloszy was influential in the discipline of cardiovascular physiology, showing that older healthy and diseased populations could still elicit beneficial cardiovascular adaptations with exercise training. Holloszy and his group made important contributions to exercise physiology on the effects of training on numerous metabolic, hormonal, and cardiovascular adaptations. Holloszy's outstanding productivity was made possible by his mentoring of ~100 postdoctoral fellows and substantial NIH grant funding over his entire career. Many of these fellows have also played critical roles in the exercise physiology/biochemistry discipline. Thus it is clear that exercise biochemistry and physiology will be influenced by John Holloszy for numerous years to come.
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Affiliation(s)
- James M Hagberg
- Department of Kinesiology, University of Maryland School of Public Health, College Park, Maryland
| | - Edward F Coyle
- Department of Kinesiology and Health Education, University of Texas, Austin, Texas
| | - Kenneth M Baldwin
- Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California
| | - Gregory D Cartee
- Muscle Biology Laboratory, School of Kinesiology; Department of Molecular and Integrative Physiology; and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan
| | - Luigi Fontana
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, Italy; and School of Medicine and Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
| | - Michael J Joyner
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
| | - John P Kirwan
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado
| | - Edward P Weiss
- Department of Nutrition and Dietetics, Doisy College of Health Science, St. Louis University, St. Louis, Missouri
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12
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Aslankeser Z, Balcı ŞS. Re-examination of the contribution of substrates to energy expenditure during high-intensity intermittent exercise in endurance athletes. PeerJ 2017; 5:e3769. [PMID: 28894645 PMCID: PMC5591632 DOI: 10.7717/peerj.3769] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 08/16/2017] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND It has been believed that the contribution of fat oxidation to total energy expenditure is becoming negligible at higher exercise intensities (about 85% VO2max). The aim of the present study was to examine the changes in substrate oxidation during high-intensity interval exercise in young adult men. METHODS A total of 18 healthy well-trained (aged 19.60 ± 0.54 years, BMI = 22.19 ± 0.64 kg/m2, n = 10) and untrained (aged 20.25 ± 0.41 years, BMI = 22.78 ± 0.38 kg/m2, n = 8) young men volunteered to participate in this study. After an overnight fast, subjects were tested on a cycle ergometer and completed six 4-min bouts of cycling (at ∼80% VO2max) with 2 min of rests between intervals. Energy expenditure and the substrate oxidation rate were measured during the experiment by using indirect calorimetry. The blood lactate concentration was collected immediately after each interval workout. RESULTS The fat oxidation rate during each workout was significantly different between the untrained and the athlete groups (p < 0.05), and the carbohydrate (CHO) oxidation rate during the experiment was similar between groups (p > 0.05). Moreover, lactate concentration significantly increased in the untrained group (p < 0.05), whereas it did not significantly change in the athlete group during the workouts (p > 0.05). Fat contribution to energy expenditure was significantly higher in the athlete group (∼25%) than in the untrained group (∼2%). CONCLUSIONS The present study indicates that 17 times more fat oxidation was measured in the athlete group compared to the untrained group. However, the athletes had the same CHO oxidation rate as the recreationally active subjects during high-intensity intermittent exercise. Higher fat oxidation rate despite the same CHO oxidation rate may be related to higher performance in the trained group.
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13
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Fan W, Waizenegger W, Lin CS, Sorrentino V, He MX, Wall CE, Li H, Liddle C, Yu RT, Atkins AR, Auwerx J, Downes M, Evans RM. PPARδ Promotes Running Endurance by Preserving Glucose. Cell Metab 2017; 25:1186-1193.e4. [PMID: 28467934 PMCID: PMC5492977 DOI: 10.1016/j.cmet.2017.04.006] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 01/27/2017] [Accepted: 04/09/2017] [Indexed: 10/19/2022]
Abstract
Management of energy stores is critical during endurance exercise; a shift in substrate utilization from glucose toward fat is a hallmark of trained muscle. Here we show that this key metabolic adaptation is both dependent on muscle PPARδ and stimulated by PPARδ ligand. Furthermore, we find that muscle PPARδ expression positively correlates with endurance performance in BXD mouse reference populations. In addition to stimulating fatty acid metabolism in sedentary mice, PPARδ activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels, PPARδ acts to delay the onset of hypoglycemia and extends running time by ∼100 min in treated mice. Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies, and, unavoidably, the enhancement of athletic performance.
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Affiliation(s)
- Weiwei Fan
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Wanda Waizenegger
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Chun Shi Lin
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Vincenzo Sorrentino
- Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Ming-Xiao He
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Christopher E Wall
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Hao Li
- Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia
| | - Ruth T Yu
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Annette R Atkins
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Johan Auwerx
- Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
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14
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Han D, Johnson HS, Rao MP, Martin G, Sancheti H, Silkwood KH, Decker CW, Nguyen KT, Casian JG, Cadenas E, Kaplowitz N. Mitochondrial remodeling in the liver following chronic alcohol feeding to rats. Free Radic Biol Med 2017; 102:100-110. [PMID: 27867097 PMCID: PMC5209270 DOI: 10.1016/j.freeradbiomed.2016.11.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 09/13/2016] [Accepted: 11/10/2016] [Indexed: 02/07/2023]
Abstract
The feeding of alcohol orally (Lieber-DeCarli diet) to rats has been shown to cause declines in mitochondrial respiration (state III), decreased expression of respiratory complexes, and decreased respiratory control ratios (RCR) in liver mitochondria. These declines and other mitochondrial alterations have led to the hypothesis that alcohol feeding causes "mitochondrial dysfunction" in the liver. If oral alcohol feeding leads to mitochondrial dysfunction, one would predict that increasing alcohol delivery by intragastric (IG) alcohol feeding to rats would cause greater declines in mitochondrial bioenergetics in the liver. In this study, we examined the mitochondrial alterations that occur in rats fed alcohol both orally and intragastrically. Oral alcohol feeding decreased glutamate/malate-, acetaldehyde- and succinate-driven state III respiration, RCR, and expression of respiratory complexes (I, III, IV, V) in liver mitochondria, in agreement with previous results. IG alcohol feeding, on the other hand, caused a slight increase in glutamate/malate-driven respiration, and significantly increased acetaldehyde-driven respiration in liver mitochondria. IG feeding also caused liver mitochondria to experience a decline in succinate-driven respiration, but these decreases were smaller than those observed with oral alcohol feeding. Surprisingly, oral and IG alcohol feeding to rats increased mitochondrial respiration using other substrates, including glycerol-3-phosphate (which delivers electrons from cytoplasmic NADH to mitochondria) and octanoate (a substrate for beta-oxidation). The enhancement of glycerol-3-phosphate- and octanoate-driven respiration suggests that liver mitochondria remodeled in response to alcohol feeding. In support of this notion, we observed that IG alcohol feeding also increased expression of mitochondrial glycerol phosphate dehydrogenase-2 (GPD2), transcription factor A (TFAM), and increased mitochondrial NAD+-NADH and NADP+-NADPH levels in the liver. Our findings suggest that mitochondrial dysfunction represents an incomplete picture of mitochondrial dynamics that occur in the liver following alcohol feeding. While alcohol feeding causes some mitochondrial dysfunction (i.e. succinate-driven respiration), our work suggests that the major consequence of alcohol feeding is mitochondrial remodeling in the liver as an adaptation. This mitochondrial remodeling may play an important role in the enhanced alcohol metabolism and other adaptations in the liver that develop with alcohol intake.
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Affiliation(s)
- Derick Han
- Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, USA.
| | - Heather S Johnson
- University of Southern California Research Center for Liver Diseases and Southern California Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9121, USA
| | - Madhuri P Rao
- W.M. Keck Science Department, Scripps College, Claremont, CA 91711, USA
| | - Gary Martin
- Department of Biology, Occidental College, Los Angeles, CA 90041, USA
| | - Harsh Sancheti
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Kai H Silkwood
- Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0303, USA
| | - Carl W Decker
- Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, USA
| | - Kim Tho Nguyen
- Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, USA
| | - Joseph G Casian
- Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, USA
| | - Enrique Cadenas
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Neil Kaplowitz
- University of Southern California Research Center for Liver Diseases and Southern California Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9121, USA
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15
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Croci I, Byrne NM, Chachay VS, Hills AP, Clouston AD, O’Moore-Sullivan TM, Prins JB, Macdonald GA, Hickman IJ. Independent effects of diet and exercise training on fat oxidation in non-alcoholic fatty liver disease. World J Hepatol 2016; 8:1137-1148. [PMID: 27721919 PMCID: PMC5037327 DOI: 10.4254/wjh.v8.i27.1137] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 07/13/2016] [Accepted: 08/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the independent effects of 6-mo of dietary energy restriction or exercise training on whole-body and hepatic fat oxidation of patients with non-alcoholic fatty liver disease (NAFLD).
METHODS Participants were randomised into either circuit exercise training (EX; n = 13; 3 h/wk without changes in dietary habits), or dietary energy restriction (ER) without changes in structured physical activity (ER; n = 8). Respiratory quotient (RQ) and whole-body fat oxidation rates (Fatox) were determined by indirect calorimetry under basal, insulin-stimulated and exercise conditions. Severity of disease and steatosis was determined by liver histology; hepatic Fatox was estimated from plasma β-hydroxybutyrate concentrations; cardiorespiratory fitness was expressed as VO2peak. Complete-case analysis was performed (EX: n = 10; ER: n = 6).
RESULTS Hepatic steatosis and NAFLD activity score decreased with ER but not with EX. β-hydroxybutyrate concentrations increased significantly in response to ER (0.08 ± 0.02 mmol/L vs 0.12 ± 0.04 mmol/L, P = 0.03) but remained unchanged in response to EX (0.10 ± 0.03 mmol/L vs 0.11 ± 0.07 mmol/L, P = 0.39). Basal RQ decreased (P = 0.05) in response to EX, while this change was not significant after ER (P = 0.38). VO2peak (P < 0.001) and maximal Fatox during aerobic exercise (P = 0.03) improved with EX but not with ER (P > 0.05). The increase in β-hydroxybutyrate concentrations was correlated with the reduction in hepatic steatosis (r = -0.56, P = 0.04).
CONCLUSION ER and EX lead to specific benefits on fat metabolism of patients with NAFLD. Increased hepatic Fatox in response to ER could be one mechanism through which the ER group achieved reduction in steatosis.
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16
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Scariot PPM, Manchado-Gobatto FDB, Torsoni AS, Dos Reis IGM, Beck WR, Gobatto CA. Continuous Aerobic Training in Individualized Intensity Avoids Spontaneous Physical Activity Decline and Improves MCT1 Expression in Oxidative Muscle of Swimming Rats. Front Physiol 2016; 7:132. [PMID: 27148071 PMCID: PMC4834519 DOI: 10.3389/fphys.2016.00132] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 03/28/2016] [Indexed: 11/16/2022] Open
Abstract
Although aerobic training has been shown to affect the lactate transport of skeletal muscle, there is no information concerning the effect of continuous aerobic training on spontaneous physical activity (SPA). Because every movement in daily life (i.e., SPA) is generated by skeletal muscle, we think that it is possible that an improvement of SPA could affect the physiological properties of muscle with regard to lactate transport. The aim of this study was to evaluate the effect of 12 weeks of continuous aerobic training in individualized intensity on SPA of rats and their gene expressions of monocarboxylate transporters (MCT) 1 and 4 in soleus (oxidative) and white gastrocnemius (glycolytic) muscles. We also analyzed the effect of continuous aerobic training on aerobic and anaerobic parameters using the lactate minimum test (LMT). Sixty-day-old rats were randomly divided into three groups: a baseline group in which rats were evaluated prior to initiation of the study; a control group (Co) in which rats were kept without any treatment during 12 weeks; and a chronic exercise group (Tr) in which rats swam for 40 min/day, 5 days/week at 80% of anaerobic threshold during 12 weeks. After the experimental period, SPA of rats was measured using a gravimetric method. Rats had their expression of MCTs determined by RT-PCR analysis. In essence, aerobic training is effective in maintaining SPA, but did not prevent the decline of aerobic capacity and anaerobic performance, leading us to propose that the decline of SPA is not fully attributed to a deterioration of physical properties. Changes in SPA were concomitant with changes in MCT1 expression in the soleus muscle of trained rats, suggestive of an additional adaptive response toward increased lactate clearance. This result is in line with our observation showing a better equilibrium on lactate production-remotion during the continuous exercise (LMT). We propose an approach to combat the decline of SPA of rats in their home cages. This new finding is worth for scientists who work with animal models to study the protective effects of exercise.
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Affiliation(s)
- Pedro P M Scariot
- Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas Limeira, Brazil
| | | | - Adriana S Torsoni
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas Limeira, Brazil
| | - Ivan G M Dos Reis
- Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas Limeira, Brazil
| | - Wladimir R Beck
- Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas Limeira, Brazil
| | - Claudio A Gobatto
- Laboratory of Applied Sport Physiology, School of Applied Sciences, University of Campinas Limeira, Brazil
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17
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Craig DM, Ashcroft SP, Belew MY, Stocks B, Currell K, Baar K, Philp A. Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis. Front Physiol 2015; 6:296. [PMID: 26578969 PMCID: PMC4621424 DOI: 10.3389/fphys.2015.00296] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 10/06/2015] [Indexed: 01/09/2023] Open
Abstract
Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans.
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Affiliation(s)
- Daniel M Craig
- MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham Birmingham, UK
| | - Stephen P Ashcroft
- MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham Birmingham, UK
| | - Micah Y Belew
- Molecular, Cell and Cancer Biology, University of Massachusetts Medical School Worcester, MA, USA
| | - Ben Stocks
- MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham Birmingham, UK
| | - Kevin Currell
- EIS Performance Centre, English Institute of Sport, Loughborough University Loughborough, UK
| | - Keith Baar
- Neurobiology, Physiology and Behavior, University of California Davis Davis, CA, USA
| | - Andrew Philp
- MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham Birmingham, UK
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18
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Ramos SV, Turnbull PC, MacPherson REK, LeBlanc PJ, Ward WE, Peters SJ. Changes in mitochondrial perilipin 3 and perilipin 5 protein content in rat skeletal muscle following endurance training and acute stimulated contraction. Exp Physiol 2015; 100:450-62. [PMID: 25663294 DOI: 10.1113/expphysiol.2014.084434] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 01/27/2015] [Indexed: 01/15/2023]
Abstract
NEW FINDINGS What is the central question of this study? The aim was to determine whether mitochondrial protein content of perilipin 3 (PLIN3) and perilipin 5 (PLIN5) is increased following endurance training and whether mitochondrial PLIN5 protein is increased to a greater extent in endurance-trained rats when compared with sedentary rats following acute contraction. What is the main finding and its importance? Mitochondrial PLIN3 but not PLIN5 protein was increased in endurance-trained compared with sedentary rats, suggesting a mitochondrial role for PLIN3 due to chronic exercise. Contrary to our hypothesis, acute mitochondrial PLIN5 protein was similar in both sedentary and endurance-trained rats. Endurance training results in an increased association between skeletal muscle lipid droplets and mitochondria. This association is likely to be important for the expected increase in intramuscular fatty acid oxidation that occurs with endurance training. The perilipin family of lipid droplet proteins, PLIN(2-5), are thought to play a role in skeletal muscle lipolysis. Recently, results from our laboratory demonstrated that skeletal muscle mitochondria contain PLIN3 and PLIN5 protein. Furthermore, 30 min of stimulated contraction induces an increased mitochondrial PLIN5 content. To determine whether mitochondrial content of PLIN3 and PLIN5 is altered with endurance training, Sprague-Dawley rats were randomized into sedentary or endurance-trained groups for 8 weeks of treadmill running followed by an acute (30 min) sciatic nerve stimulation to induce lipolysis. Mitochondrial PLIN3 protein was ∼1.5-fold higher in red gastrocnemius of endurance-trained rats compared with sedentary animals, with no change in mitochondrial PLIN5 protein. In addition, there was an increase in plantaris intramuscular lipid storage. Acute electrically stimulated contraction in red gastrocnemius from sedentary and endurance-trained rats resulted in a similar increase of mitochondrial PLIN5 between these two groups, with no net change in PLIN3 in either group. Plantaris intramuscular lipid content decreased to a similar extent in sedentary and endurance-trained rats. These results suggest that while total mitochondrial PLIN5 content is not altered by endurance training, PLIN5 does have an acute role in the mitochondrial fraction during muscle contraction. Conversely, mitochondrial PLIN3 does not change acutely with muscle contraction, but PLIN3 content was increased following endurance training, indicating a role in chronic adaptations of skeletal muscle.
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Affiliation(s)
- S V Ramos
- Center for Bone and Muscle Health, Brock University, St Catharines, Ontario, Canada; Department of Kinesiology, Brock University, St Catharines, Ontario, Canada
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Kim YN, Choi JY, Cho YO. Regular moderate exercise training can alter the urinary excretion of thiamin and riboflavin. Nutr Res Pract 2015; 9:43-8. [PMID: 25671067 PMCID: PMC4317479 DOI: 10.4162/nrp.2015.9.1.43] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 01/08/2015] [Accepted: 01/16/2015] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND/OBJECTIVES Physical exercise promotes energy producing pathways requiring thiamin and riboflavin as a coenzyme. Therefore, this study investigated the effects of regular exercise training on urinary excretion of thiamin and riboflavin. MATERIALS/METHODS Fifty rats were randomly assigned to one of two groups: non-exercise training (NT, n = 25) and regular exercise training (ET, n = 25) for 5 weeks. The rats performed moderate exercise on a treadmill (0.5-0.8 km/hour) for 30 min/day, 5 days/week. Twenty-four hour urine samples were collected at the end of the 0 week, 3rd week, and 5th week of training and thiamin and riboflavin were analyzed. RESULTS No significant differences in thiamin and riboflavin intakes for each week were observed between the NT and ET groups. Urinary thiamin excretion of each group was the highest at the 5th week compared to the levels at 0 and 3rd week. Urinary thiamin at the 5th week was significantly lower in the ET group than in the NT group. Urinary riboflavin excretion was increased by training duration, however, no difference was observed between NT and ET for each week. At 0 and 3rd week, no significant relationships were observed between dietary intake and urinary excretion of thiamin and riboflavin, however, at the 5th week, urinary excretion was significantly increased by dietary intake only in the NT group (P < 0.05). Thiamin excretion of both NT and ET groups was significantly increased with riboflavin excretion at the 5th week (P < 0.01). CONCLUSION Regular moderate exercise training increased urinary excretion of thiamin. Dietary intakes and urinary excretions of thiamin and riboflavin showed positive correlation in both the exercise training and non-exercise training groups as the exercise training period went by, while the correlations in the exercise training group were weaker than those in the non-exercise training group. Therefore, regular exercise training can alter the urinary excretion of thiamin and riboflavin in rats.
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Affiliation(s)
- Young-Nam Kim
- Department of Food & Nutrition, Duksung Women's University, 33, Samyangro 114 gil, Dobong-gu, Seoul, 132-714, Korea
| | - Ji Young Choi
- Department of Food & Nutrition, Duksung Women's University, 33, Samyangro 114 gil, Dobong-gu, Seoul, 132-714, Korea
| | - Youn-Ok Cho
- Department of Food & Nutrition, Duksung Women's University, 33, Samyangro 114 gil, Dobong-gu, Seoul, 132-714, Korea
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20
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Brenmoehl J, Ohde D, Walz C, Schultz J, Tuchscherer A, Rieder F, Renne U, Hoeflich A. Dynamics of Fat Mass in DUhTP Mice Selected for Running Performance - Fat Mobilization in a Walk. Obes Facts 2015; 8:373-85. [PMID: 26630291 PMCID: PMC5644887 DOI: 10.1159/000442399] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/08/2015] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE Reduction of body fat can be achieved by dietary programs and/or aerobic exercise training. More convenient methods to rid the body of excess fat are needed. However, it is unclear whether it is possible to more easily lose body weight at all. METHODS DUhTP mice bred through phenotype selection for high treadmill performance and unselected controls were voluntarily physically active in a running wheel over a period of 3 weeks. Phenotypical data were collected, and subcutaneous fat was analyzed for expression of mitochondria-relevant proteins. RESULTS Voluntary physical activity over 3 weeks exclusively in DUhTP mice severely reduced subcutaneous (-38%; p < 0.05) and epididymal (-32%; p < 0.05) fat. Following mild physical activity, subcutaneous fat derived from DUhTP mice showed increased levels of long chain acyl dehydrogenase (LCAD; +230%; p < 0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α; p < 0.01). Mitochondrial transcription factor A (Tfam) expression was similar in both sedentary genotypes but physical activity increased Tfam levels exclusively in DUhTP (p < 0.05). CONCLUSION Our findings indicate that the mitochondrial mass is highly active in DUhTP mice and responsive even to mild physical activity. While genetic predisposition could not prevent fat accretion in DUhTP mice, voluntary activity was sufficient to reduce excess body fat almost completely.
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Affiliation(s)
- Julia Brenmoehl
- Cell Signaling Unit from the Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
- Laboratory for Mouse Genetics, Institute for Genetics & Biometry, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Daniela Ohde
- Cell Signaling Unit from the Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Christina Walz
- Cell Signaling Unit from the Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
- Laboratory for Mouse Genetics, Institute for Genetics & Biometry, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Julia Schultz
- Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany
| | - Armin Tuchscherer
- Livestock Genetics and Breeding Unit, Institute for Genetics & Biometry, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Florian Rieder
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Ulla Renne
- Laboratory for Mouse Genetics, Institute for Genetics & Biometry, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Andreas Hoeflich
- Cell Signaling Unit from the Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
- Laboratory for Mouse Genetics, Institute for Genetics & Biometry, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
- *Dr. Andreas Hoeflich, Cell Signaling Unit from the Institute for Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
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Ramos SV, MacPherson REK, Turnbull PC, Bott KN, LeBlanc P, Ward WE, Peters SJ. Higher PLIN5 but not PLIN3 content in isolated skeletal muscle mitochondria following acute in vivo contraction in rat hindlimb. Physiol Rep 2014; 2:2/10/e12154. [PMID: 25318747 PMCID: PMC4254090 DOI: 10.14814/phy2.12154] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Contraction-mediated lipolysis increases the association of lipid droplets and mitochondria, indicating an important role in the passage of fatty acids from lipid droplets to mitochondria in skeletal muscle. PLIN3 and PLIN5 are of particular interest to the lipid droplet-mitochondria interaction because PLIN3 is able to move about within cells and PLIN5 associates with skeletal muscle mitochondria. This study primarily investigated: 1) if PLIN3 is detected in skeletal muscle mitochondrial fraction; and 2) if mitochondrial protein content of PLIN3 and/or PLIN5 changes following stimulated contraction. A secondary aim was to determine if PLIN3 and PLIN5 associate and whether this changes following contraction. Male Long Evans rats (n = 21; age, 52 days; weight = 317 ± 6 g) underwent 30 min of hindlimb stimulation (10 msec impulses, 100 Hz/3 sec at 10-20 V; train duration 100 msec). Contraction induced a ~50% reduction in intramuscular lipid content measured by oil red-O staining of red gastrocnemius muscle. Mitochondria were isolated from red gastrocnemius muscle by differential centrifugation and proteins were detected by western blotting. Mitochondrial PLIN5 content was ~1.6-fold higher following 30 min of contraction and PLIN3 content was detected in the mitochondrial fraction, and unchanged following contraction. An association between PLIN3 and PLIN5 was observed and remained unaltered following contraction. PLIN5 may play a role in mitochondria during lipolysis, which is consistent with a role in facilitating/regulating mitochondrial fatty acid oxidation. PLIN3 and PLIN5 may be working together on the lipid droplet and mitochondria during contraction-induced lipolysis.
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Affiliation(s)
- Sofhia V Ramos
- Department of Kinesiology, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada Center for Bone and Muscle Health, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada
| | - Rebecca E K MacPherson
- Center for Bone and Muscle Health, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada
| | - Patrick C Turnbull
- Department of Kinesiology, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada Center for Bone and Muscle Health, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada
| | - Kirsten N Bott
- Department of Kinesiology, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada Center for Bone and Muscle Health, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada
| | - Paul LeBlanc
- Center for Bone and Muscle Health, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada Department of Health Science, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada
| | - Wendy E Ward
- Department of Kinesiology, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada Center for Bone and Muscle Health, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada Department of Health Science, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada
| | - Sandra J Peters
- Department of Kinesiology, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada Center for Bone and Muscle Health, Brock University, 500 Glenridge Ave, St Catharines, L2S 3A1, Ontario, Canada
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Neels JG, Grimaldi PA. Physiological functions of peroxisome proliferator-activated receptor β. Physiol Rev 2014; 94:795-858. [PMID: 24987006 DOI: 10.1152/physrev.00027.2013] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty acids and fatty acid metabolites. PPARs regulate the transcription of a large variety of genes implicated in metabolism, inflammation, proliferation, and differentiation in different cell types. These transcriptional regulations involve both direct transactivation and interaction with other transcriptional regulatory pathways. The functions of PPARα and PPARγ have been extensively documented mainly because these isoforms are activated by molecules clinically used as hypolipidemic and antidiabetic compounds. The physiological functions of PPARβ remained for a while less investigated, but the finding that specific synthetic agonists exert beneficial actions in obese subjects uplifted the studies aimed to elucidate the roles of this PPAR isoform. Intensive work based on pharmacological and genetic approaches and on the use of both in vitro and in vivo models has considerably improved our knowledge on the physiological roles of PPARβ in various cell types. This review will summarize the accumulated evidence for the implication of PPARβ in the regulation of development, metabolism, and inflammation in several tissues, including skeletal muscle, heart, skin, and intestine. Some of these findings indicate that pharmacological activation of PPARβ could be envisioned as a therapeutic option for the correction of metabolic disorders and a variety of inflammatory conditions. However, other experimental data suggesting that activation of PPARβ could result in serious adverse effects, such as carcinogenesis and psoriasis, raise concerns about the clinical use of potent PPARβ agonists.
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Affiliation(s)
- Jaap G Neels
- Institut National de la Santé et de la Recherche Médicale U 1065, Mediterranean Center of Molecular Medicine (C3M), Team "Adaptive Responses to Immuno-metabolic Dysregulations," Nice, France; and Faculty of Medicine, University of Nice Sophia-Antipolis, Nice, France
| | - Paul A Grimaldi
- Institut National de la Santé et de la Recherche Médicale U 1065, Mediterranean Center of Molecular Medicine (C3M), Team "Adaptive Responses to Immuno-metabolic Dysregulations," Nice, France; and Faculty of Medicine, University of Nice Sophia-Antipolis, Nice, France
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Shih L, Chung Y, Sriram R, Jue T. Palmitate interaction with physiological states of myoglobin. Biochim Biophys Acta Gen Subj 2014; 1840:656-66. [PMID: 24482816 DOI: 10.1016/j.bbagen.2013.10.028] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Previous studies have shown that palmitate (PA) can bind specifically and non-specifically to Fe(III)MbCN. The present study has observed PA interaction with physiological states of Fe(II)Mb, and the observations support the hypothesis that Mb may have a potential role in facilitating intracellular fatty acid transport. METHODS 1H NMR spectra measurements of the Mb signal during PA titration show signal changes consistent with specific and non-specific binding. RESULTS Palmitate (PA) interacts differently with physiological states of Mb. Deoxy Mb does not interact specifically or non-specifically with PA, while the carbonmonoxy myoglobin (MbCO) interaction with PA decreases the intensity of selective signals and produces a 0.15ppmupfield shift of the PAmethylene peak. The selective signal change upon PA titration provides a basis to determine an apparent PA binding constant,which serves to create a model comparing the competitive PA binding and facilitated fatty acid transport of Mb and fatty acid binding protein(FABP). CONCLUSIONS Given contrasting PA interaction of ligated vs. unligated Mb, the cellular fatty acid binding protein(FABP) and Mb concentration in the cell, the reported cellular diffusion coefficients, the PA dissociation constants from ligated Mb and FABP, a fatty acid flux model suggests that Mb can compete with FABP transporting cellular fatty acid. GENERAL SIGNIFICANCE Under oxygenated conditions and continuous energy demand, Mb dependent fatty acid transport could influence the cell's preference for carbohydrate or fatty acid as a fuel source and regulate fatty acid metabolism.
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Holloszy JO. Regulation of mitochondrial biogenesis and GLUT4 expression by exercise. Compr Physiol 2013; 1:921-40. [PMID: 23737207 DOI: 10.1002/cphy.c100052] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Endurance exercise training can induce large increases mitochondria and the GLUT4 isoform of the glucose transporter in skeletal muscle. For a long time after the discovery in the 1960s that exercise results in an increase in muscle mitochondria, there was no progress in elucidation of the mechanisms involved. The reason for this lack of progress was that nothing was known regarding how expression of the genes-encoding mitochondrial proteins is coordinately regulated. This situation changed rapidly after discovery of transcription factors that control transcription of genes-encoding mitochondrial proteins and, most importantly, the discovery of peroxisome proliferator-gamma coactivator-1α (PGC-1α). This transcription coactivator binds to and activates transcription factors that regulate transcription of genes-encoding mitochondrial proteins. Thus, PGC-1α activates and coordinates mitochondrial biogenesis. It is now known that exercise rapidly activates and induces increased expression of PGC-1α. The exercise-generated signals that lead to PGC-1α activation and increased expression are the increases in cytosolic Ca(2+) and decreases in ATP and creatine phosphate (∼P). Ca(2+) mediates its effect by activating CAMKII, while the decrease in ∼P mediates its effect via activation of AMPK. Expression of the GLUT4 isoform of the glucose transporter is regulated in parallel with mitochondrial biogenesis via the same signaling pathways. This review describes what is known regarding the regulation of mitochondrial biogenesis and GLUT4 expression by exercise. A major component of this review deals with the physiological and metabolic consequences of the exercise-induced increase in mitochondria and GLUT4.
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Affiliation(s)
- John O Holloszy
- Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
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Eynon N, Hanson ED, Lucia A, Houweling PJ, Garton F, North KN, Bishop DJ. Genes for Elite Power and Sprint Performance: ACTN3 Leads the Way. Sports Med 2013; 43:803-17. [DOI: 10.1007/s40279-013-0059-4] [Citation(s) in RCA: 124] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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McCafferty WB, Horvath SM. Specificity of Exercise and Specificity of Training: A Subcellular Review. ACTA ACUST UNITED AC 2013. [DOI: 10.1080/10671315.1977.10615433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- William B. McCafferty
- a The Department of Physical Education , University of Redlands , Redlands , CA , 92373 , USA
| | - Steven M. Horvath
- b Institute of Environmental Stress , University of California at Santa Barbara , Santa Barbara , CA , 93106 , USA
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Han D, Ybanez MD, Johnson HS, McDonald JN, Mesropyan L, Sancheti H, Martin G, Martin A, Lim AM, Dara L, Cadenas E, Tsukamoto H, Kaplowitz N. Dynamic adaptation of liver mitochondria to chronic alcohol feeding in mice: biogenesis, remodeling, and functional alterations. J Biol Chem 2012; 287:42165-79. [PMID: 23086958 DOI: 10.1074/jbc.m112.377374] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Liver mitochondria undergo dynamic alterations following chronic alcohol feeding to mice. Intragastric alcohol feeding to mice resulted in 1) increased state III respiration (109% compared with control) in isolated liver mitochondria, probably due to increased levels of complexes I, IV, and V being incorporated into the respiratory chain; 2) increased mitochondrial NAD(+) and NADH levels (∼2-fold), with no change in the redox status; 3) alteration in mitochondrial morphology, with increased numbers of elongated mitochondria; and 4) enhanced mitochondrial biogenesis in the liver, which corresponded with an up-regulation of PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α). Oral alcohol feeding to mice, which is associated with less liver injury and steatosis, slightly enhanced respiration in isolated liver mitochondria (30.8% compared with control), lower than the striking increase caused by intragastric alcohol feeding. Mitochondrial respiration increased with both oral and intragastric alcohol feeding despite extensive N-acetylation of mitochondrial proteins. The alcohol-induced mitochondrial alterations are probably an adaptive response to enhance alcohol metabolism in the liver. Isolated liver mitochondria from alcohol-treated mice had a greater rate of acetaldehyde metabolism and respiration when treated with acetaldehyde than control. Aldehyde dehydrogenase-2 levels were unaltered in response to alcohol, suggesting that the greater acetaldehyde metabolism by isolated mitochondria from alcohol-treated mice was due to increased mitochondrial respiration that regenerated NAD(+), the rate-limiting substrate in alcohol/acetaldehyde metabolism. Overall, our work suggests that mitochondrial plasticity in the liver may be an important adaptive response to the metabolic stress caused by alcohol intake and could potentially play a role in many other vital functions performed by the liver.
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Affiliation(s)
- Derick Han
- University of Southern California Research Center for Liver Diseases and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9121, USA.
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Abstract
This paper reviews succinctly the evidence for a role of regular exercise in the prevention and the treatment of obesity and of its metabolic complications. Seventeen propositions relevant to an understanding of the topic are considered. The evidence suggests that regular exercise can be an important factor in the development of sustained negative energy balance conditions provided the volume of activity is high. This implies a program of low to moderate intensity exercise performed on an almost daily basis for at least one hour per session. To induce significant weight and fat losses and to treat overweight and obese patients, compliance to the program for several years becomes a necessity. Exercise increases lipid substrate oxidation and may favor carbohydrate intake for the same amount of energy intake. The acute effects of exercise on resting metabolic rate are well documented, but the long-term influences of exercise training seem to be small and are rapidly suppressed with the cessation of training. The obese benefits also from a regular exercise regimen in terms of improved insulin sensitivity, lipid and lipoprotein profile, and blood pressure, as well as reduced risk of death. Regular exercise, such as walking, is a healthy course of action for the overweight or the obese patients.
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Affiliation(s)
- C Bouchard
- Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Quebec, Canada
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29
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McFarlan JT, Yoshida Y, Jain SS, Han XX, Snook LA, Lally J, Smith BK, Glatz JFC, Luiken JJFP, Sayer RA, Tupling AR, Chabowski A, Holloway GP, Bonen A. In vivo, fatty acid translocase (CD36) critically regulates skeletal muscle fuel selection, exercise performance, and training-induced adaptation of fatty acid oxidation. J Biol Chem 2012; 287:23502-16. [PMID: 22584574 DOI: 10.1074/jbc.m111.315358] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
For ~40 years it has been widely accepted that (i) the exercise-induced increase in muscle fatty acid oxidation (FAO) is dependent on the increased delivery of circulating fatty acids, and (ii) exercise training-induced FAO up-regulation is largely attributable to muscle mitochondrial biogenesis. These long standing concepts were developed prior to the recent recognition that fatty acid entry into muscle occurs via a regulatable sarcolemmal CD36-mediated mechanism. We examined the role of CD36 in muscle fuel selection under basal conditions, during a metabolic challenge (exercise), and after exercise training. We also investigated whether CD36 overexpression, independent of mitochondrial changes, mimicked exercise training-induced FAO up-regulation. Under basal conditions CD36-KO versus WT mice displayed reduced fatty acid transport (-21%) and oxidation (-25%), intramuscular lipids (less than or equal to -31%), and hepatic glycogen (-20%); but muscle glycogen, VO(2max), and mitochondrial content and enzymes did not differ. In acutely exercised (78% VO(2max)) CD36-KO mice, fatty acid transport (-41%), oxidation (-37%), and exercise duration (-44%) were reduced, whereas muscle and hepatic glycogen depletions were accelerated by 27-55%, revealing 2-fold greater carbohydrate use. Exercise training increased mtDNA and β-hydroxyacyl-CoA dehydrogenase similarly in WT and CD36-KO muscles, but FAO was increased only in WT muscle (+90%). Comparable CD36 increases, induced by exercise training (+44%) or by CD36 overexpression (+41%), increased FAO similarly (84-90%), either when mitochondrial biogenesis and FAO enzymes were up-regulated (exercise training) or when these were unaltered (CD36 overexpression). Thus, sarcolemmal CD36 has a key role in muscle fuel selection, exercise performance, and training-induced muscle FAO adaptation, challenging long held views of mechanisms involved in acute and adaptive regulation of muscle FAO.
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Affiliation(s)
- Jay T McFarlan
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada
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Broderick TL, El Midaoui A, Chiasson JL, Wang D, Jankowski M, Gutkowska J. The effects of exercise training on γ-butyrobetaine hydroxylase and novel organic cation transporter-2 gene expression in the rat. Appl Physiol Nutr Metab 2011; 36:781-9. [DOI: 10.1139/h11-094] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The concentration of carnitine in plasma is generally increased with exercise training, suggesting that either carnitine biosynthesis is stimulated or renal reabsorption of carnitine is enhanced, or both. Carnitine, an essential cofactor in the oxidation of fatty acids, is released into the plasma following hydroxylation by γ-butyrobetaine hydroxylase (BBH), the final enzyme in the biosynthetic pathway found primarily in the liver. The organic cation transporter (OCTN2), the carnitine transporter found in kidney, is important in the distribution of carnitine by facilitating its renal reabsorption from urine. In this study, we tested the hypothesis that exercise training increases gene and protein expression of BBH and OCTN2, resulting in enhanced plasma carnitine levels. Male Wistar rats were subjected to 2 daily exercise sessions of treadmill running, 5 days per week, for a 10-week period. The concentration of total carnitine in plasma was significantly increased in trained rats compared with sedentary rats. In trained rats, mRNA and protein expression of BBH were increased in liver, whereas only BBH mRNA expression was increased in kidney. Liver of trained rats demonstrated increased mRNA and protein expression of OCTN2 compared with sedentary rats. In kidney of trained rats, however, only an increase in mRNA expression of OCTN2 was observed. Our results suggest that the improved plasma carnitine status in the trained rat is associated with increased carnitine biosynthesis in liver and kidney. The observation that OCTN2 expression was increased in kidney suggests a potential role of the kidney in the reabsorption of carnitine from the urine.
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Affiliation(s)
- Tom L. Broderick
- Laboratory of Diabetes and Exercise Metabolism, Department of Physiology, Midwestern University, 19555 North 59th Avenue, Glendale, AZ 85308, USA
| | - Adil El Midaoui
- Research Centre, Centre Hospitalier de l’Université de Montréal-Hôtel-Dieu, Montréal, QC H2W 1T7, Canada
| | - Jean-Louis Chiasson
- Research Centre, Centre Hospitalier de l’Université de Montréal-Hôtel-Dieu, Montréal, QC H2W 1T7, Canada
| | - Donghao Wang
- Laboratory of Cardiovascular Biochemistry, Research Centre, Centre Hospitalier de L’Université de Montréal-Hôtel-Dieu, Montréal, QC H2W 1T7, Canada
| | - Marek Jankowski
- Laboratory of Cardiovascular Biochemistry, Research Centre, Centre Hospitalier de L’Université de Montréal-Hôtel-Dieu, Montréal, QC H2W 1T7, Canada
| | - Jolanta Gutkowska
- Laboratory of Cardiovascular Biochemistry, Research Centre, Centre Hospitalier de L’Université de Montréal-Hôtel-Dieu, Montréal, QC H2W 1T7, Canada
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Fiddler RE, Smith DB, Jacobson BH, Klein CD, Warren AJ, O'Brien MS, Thompson BJ, Everett KL. The Effect of Energy Patches on Substrate Utilization in Collegiate Cross-Country Runners. INTERNATIONAL JOURNAL OF EXERCISE SCIENCE 2011; 4:113-121. [PMID: 27182358 PMCID: PMC4738995 DOI: 10.70252/ozwd7744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/15/2025]
Abstract
It is well established that an increased capacity of skeletal muscle to oxidize fatty acids can spare glycogen and delay the onset of fatigue in mild- to moderate-intensity exercise. The purpose of the following study was to examine the effect of LifeWave® energy patches on non-protein substrate utilization in Division-1 cross-country runners. To determine the effect of the patches subjects were pretested to establish baselines and randomly assigned to an experimental (EX) or placebo (PL) group. Twenty-two trained male (n = 11; mean ± SD, age = 21.1 ± 2.6years, height = 179.6 ± 4.2cm, body mass = 71.4 ± 7.4kg, VO2max = 72.6 ± 7.1mL·kg-1·min-1) and female (n = 11; mean ± SD, age = 21.5 ± 2.4years, height = 166.7 ± 5.7cm, body mass = 53.7 ± 3.2kg, VO2max = 63.6 ± 6.9mL·kg-1·min-1) cross-country runners volunteered to participate in the study. Dependent variables included maximal oxygen consumption (VO2max), rating of perceived exertion (RPE), respiratory exchange ratio (RER), maximum heart rate (HRmax), and time to exhaustion (TTE). Results indicated there were no significant differences between the EX and PL groups at posttesting for RPE, TTE, HRmax, or VO2max. RER was found to be significantly higher for the EX group compared to the PL group during stage 1 of the Bruce-protocol graded exercise test (p = 0.02). Based on the limited available research regarding LifeWave® energy patches effect on non-protein substrate utilization during aerobic exercise there appears to be no performance enhancing benefits.
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Affiliation(s)
- Ryan E Fiddler
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
| | - Douglas B Smith
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
| | - Bert H Jacobson
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
| | - Crishel D Klein
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
| | - Aric J Warren
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
| | - Matthew S O'Brien
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
| | - Brennan J Thompson
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
| | - K Lee Everett
- Applied Musculoskeletal and Human Physiology Laboratory, Department of Health and Human Performance, Oklahoma State University, Stillwater, OK, USA
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Kawasaki E, Hokari F, Sasaki M, Sakai A, Koshinaka K, Kawanaka K. The effects of β-adrenergic stimulation and exercise on NR4A3 protein expression in rat skeletal muscle. J Physiol Sci 2011; 61:1-11. [PMID: 20936441 PMCID: PMC10717076 DOI: 10.1007/s12576-010-0114-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Accepted: 09/08/2010] [Indexed: 12/01/2022]
Abstract
β-Adrenergic stimulation and exercise up-regulate the mRNA expression of nuclear receptor NR4A3, which is involved in the regulation of glucose and fatty acid utilization genes in skeletal muscle. The objective of our study was to examine the effects of β-adrenergic stimulation and exercise on the expression of NR4A3 protein in rat skeletal muscle. A single subcutaneous injection of clenbuterol, which is a β2-adrenergic receptor (β2-AR) agonist, increased NR4A3 mRNA and protein expression in the fast-twitch glycolytic triceps muscle. On the other hand, an acute 3-h session of either treadmill running or swimming did not increase the NR4A3 protein level in the exercised muscle, although both treadmill running and swimming increased NR4A3 mRNA. Finally, loss of postural contractile activity because of hindlimb immobilization reduced NR4A3 mRNA and protein in the slow-twitch oxidative soleus muscle. These results suggest that: β-adrenergic stimulation up-regulates not only NR4A3 mRNA but also NR4A3 protein in fast-twitch glycolytic muscle; exercise may increase NR4A3 mRNA but not NR4A3 protein in skeletal muscle; and local postural contractile activity plays a crucial role in maintaining NR4A3 protein expression level in postural muscle.
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Affiliation(s)
- Emi Kawasaki
- Department of Health and Nutrition, Niigata University of Health and Welfare, 1398 Shimami-cho, Niigata, Niigata 950-3198, Japan.
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Rumsey WL, Wilson DF. Tissue Capacity for Mitochondrial Oxidative Phosphorylation and its Adaptation to Stress. Compr Physiol 2011. [DOI: 10.1002/cphy.cp040247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Saltin B, Gollnick PD. Skeletal Muscle Adaptability: Significance for Metabolism and Performance. Compr Physiol 2011. [DOI: 10.1002/cphy.cp100119] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Kelly KR, Abbott MJ, Turcotte LP. Short-term AMP-regulated protein kinase activation enhances insulin-sensitive fatty acid uptake and increases the effects of insulin on fatty acid oxidation in L6 muscle cells. Exp Biol Med (Maywood) 2010; 235:514-21. [PMID: 20407084 DOI: 10.1258/ebm.2009.009228] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Evidence shows that exercise increases insulin-sensitive glucose uptake and that exercise-induced AMP-regulated protein kinase (AMPK) activation is a likely candidate to mediate this metabolic adaptation. The purpose of this study was to determine whether repeated AMPK activation can similarly enhance insulin-sensitive fatty acid (FA) metabolism. L6 myotubes were incubated under the following conditions: repeated plus acute 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) treatment (RAA; 1 mmol/L AICAR for 5 h/d for 5 days plus 1 mmol/L AICAR for 60 min on day 6), repeated AICAR (RA; 1 mmol/L AICAR for 5 h/d for five days) or acute AICAR (AA; 1 mmol/L AICAR for 60 min) and were compared with control cells that were not treated with AICAR. On day six, cells from each group were incubated with or without 100 nmol/L insulin. AICAR treatment and insulin stimulation independently increased (P < 0.05) palmitate uptake in all groups. RAA potentiated the insulin-induced increase in palmitate uptake by 97% (P < 0.05) as compared with control cells. RA and AA treatments prevented the insulin-induced decrease in palmitate oxidation, while RAA treatment restored the sensitivity of the cells to insulin action on palmitate oxidation. Total peroxisome proliferator-activated receptor-gamma co-activator-1 alpha, atypical protein kinase C-zeta, cytochrome C and CD36 protein content was increased (P < 0.05) by RA treatment, but unaffected by insulin. These results indicate that repeated AMPK activation induces improvements in insulin-sensitive FA uptake and oxidation and that this occurs partly via changes in the expression of proteins linked to insulin signaling and FA uptake and oxidation capacity.
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Affiliation(s)
- Karen R Kelly
- Department of Kinesiology, College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089-0652, USA
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Zarins ZA, Wallis GA, Faghihnia N, Johnson ML, Fattor JA, Horning MA, Brooks GA. Effects of endurance training on cardiorespiratory fitness and substrate partitioning in postmenopausal women. Metabolism 2009; 58:1338-46. [PMID: 19573883 PMCID: PMC2728793 DOI: 10.1016/j.metabol.2009.04.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Revised: 04/06/2009] [Accepted: 04/27/2009] [Indexed: 10/20/2022]
Abstract
We examined the effect of endurance training on energy substrate partitioning during rest and exercise in postmenopausal women. Ten healthy sedentary (55 +/- 1 years old) subjects completed 12 weeks of endurance exercise training on a cycle ergometer (5 d/wk, 1 h/d, 65% peak oxygen consumption [Vo(2)peak]). Whole-body energy substrate oxidation was determined by indirect calorimetry during 90 minutes of rest and 60 minutes of cycle ergometer exercise. Subjects were studied at 65% Vo(2)peak before training and after training at the same absolute exercise intensity (same absolute workload as 65% of pretraining Vo(2)peak) and same relative exercise intensity (65% of posttraining Vo(2)peak). After training, Vo(2)peak increased by 16.3% +/- 3.9% and resting heart rate decreased by 4 beats per minute (P < .05). During exercise at same absolute intensity, mean arterial pressure decreased by 8 mm Hg (P < .05), heart rate decreased by 19 beats per minute (P < .05), energy derived from carbohydrate decreased by 9.6%, and the energy derived from lipid increased by 9.2% (P < .05). Lactate concentration was lower at the same absolute and relative exercise intensities (P < .05). Changes in substrate partitioning during exercise were accomplished without changes in dietary composition, body weight, or body composition. We conclude that endurance training in healthy postmenopausal women who remain in energy balance results in many of the classic cardiopulmonary training effects, decreases the reliance on carbohydrate, and increases lipid oxidation during a given submaximal exercise task without a reduction in body weight.
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Affiliation(s)
- Zinta A Zarins
- Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, CA 94720, USA
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41
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Eynon N, Sagiv M, Meckel Y, Duarte JA, Alves AJ, Yamin C, Sagiv M, Goldhammer E, Oliveira J. NRF2 intron 3 A/G polymorphism is associated with endurance athletes' status. J Appl Physiol (1985) 2009; 107:76-9. [PMID: 19478192 DOI: 10.1152/japplphysiol.00310.2009] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The aim of this study was to determine the frequency distribution of nuclear respiratory factor 2 (NRF2) intron 3 A/G polymorphism (rs7181866) among 155 Israeli athletes (endurance athletes and sprinters) and 240 healthy controls. Results showed that there was a significantly higher proportion of the AG genotype, rather than the AA genotype, in the group of endurance athletes compared with the sprinters (P = 0.014) and controls (P = 0.0008). However, the sprinters' genotype and allele frequencies were similar to those of the control group (P = 0.62 for genotype distribution percentage). These results were even more pronounced when we compared between the subgroups of 20 elite endurance athletes (those who had represented Israel in a world track-and-field championship or in the Olympic Games) and 54 national-level endurance athletes. In the group of elite endurance athletes the G allele was more frequent than in the national-level endurance athletes (P = 0.047). We conclude that 1) in Israeli athletes the NRF2 AG genotype is more frequent in elite endurance athletes than in sprinters, and 2) within the endurance group the NRF2 AG genotype and the G allele are more frequent in elite athletes, suggesting a positive association between the AG genotype, and possibly the G allele, and the likelihood of being an elite endurance athlete.
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Affiliation(s)
- Nir Eynon
- Genetics and Molecular Biology Laboratory, Life Sciences Division, The Zinman College of Physical Education and Sport Sciences at the Wingate Institute, 42902 Netanya, Israel.
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42
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Kawasaki E, Hokari F, Sasaki M, Sakai A, Koshinaka K, Kawanaka K. Role of local muscle contractile activity in the exercise-induced increase in NR4A receptor mRNA expression. J Appl Physiol (1985) 2009; 106:1826-31. [PMID: 19359610 DOI: 10.1152/japplphysiol.90923.2008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Exercise upregulates the expression of NR4A receptors, which are involved in regulation of glucose and fatty acid utilization genes in skeletal muscle. The aims of our study were 1) to determine the role of local contractile activity on NR4A mRNA expression in skeletal muscle during exercise; and 2) to elucidate the mechanisms underlying the induction of NR4A mRNA expression in response to muscle contractile activity. Rats were subjected to an acute 3-h low-intensity swimming or a 3-h low-intensity treadmill running as a model of endurance exercise. Low-intensity swimming increased NR4A1 and NR4A3 mRNA in triceps but not in soleus muscle. Conversely, low-intensity treadmill running increased NR4A1 and NR4A3 mRNA in soleus but not in triceps muscle. NR4A mRNA increased concomitantly with reduced postexercise muscle glycogen, suggesting that gene expression of NR4A receptors occurs in muscles recruited during exercise. Furthermore, in resting rats, an acute 1-h local electrical stimulation of a motor nerve to the tibialis anterior muscle caused increases in NR4A1 and NR4A3 mRNA relative to the contralateral control muscle of the same animals. On the other hand, after 6 h of hindlimb immobilization, NR4A1 and NR4A3 mRNA were reduced in immobilized soleus muscle relative to contralateral control muscle. In addition, both NR4A1 and NR4A3 mRNA in epitrochlearis muscle were increased after 6-h incubation with 0.5 mM 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, which activates AMP-activated protein kinase. These results suggest that 1) local muscle contractile activity is required for increased expressions of NR4A1 and NR4A3 mRNA during exercise; and 2) muscle contractile activity-induced increases in NR4A1 and NR4A3 mRNA may be mediated by AMPK activation, at least in part.
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Affiliation(s)
- Emi Kawasaki
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata City, Niigata 950-3198, Japan
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Mittendorfer B, Klein S. Physiological factors that regulate the use of endogenous fat and carbohydrate fuels during endurance exercise. Nutr Res Rev 2009; 16:97-108. [DOI: 10.1079/nrr200357] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Benton CR, Wright DC, Bonen A. PGC-1alpha-mediated regulation of gene expression and metabolism: implications for nutrition and exercise prescriptions. Appl Physiol Nutr Metab 2008; 33:843-62. [PMID: 18923559 DOI: 10.1139/h08-074] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The discovery 10 years ago of PGC-1alpha represented a major milestone towards understanding of the molecular processes regulating energy metabolism in many tissues, including skeletal muscle. PGC-1alpha 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-1alpha regulation of substrate metabolism and mitochondrial biogenesis in skeletal muscle. Surprisingly, studies with PGC-1alpha null and transgenic mice have revealed unexpected pathologies when PGC-1alpha is completely repressed (KO animals) or is massively overexpressed. In contrast, PGC-1alpha 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-1alpha expression. We speculate that optimal targeting of PGC-1alpha 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.
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Affiliation(s)
- Carley R Benton
- Louvain Medical School, Universite catholique de Louvain, 1200 Brussels, Belgium
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45
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Increased substrate oxidation and mitochondrial uncoupling in skeletal muscle of endurance-trained individuals. Proc Natl Acad Sci U S A 2008; 105:16701-6. [PMID: 18936488 DOI: 10.1073/pnas.0808889105] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Endurance exercise training is accompanied by physiological changes that improve muscle function and performance. Several studies have demonstrated that markers of mitochondrial capacity are elevated, however, these studies tend to be performed ex vivo under conditions that yield maximal enzyme activities or in vivo but monitoring the response to exercise. Therefore, it is unclear whether basal mitochondrial metabolism is affected by exercise training. To explore whether resting muscle metabolism was altered in trained individuals in vivo, two independent parameters of metabolic function-tricarboxylic acid (TCA) cycle flux (V(TCA)), and ATP synthesis (V(ATP))-were assessed noninvasively by using magnetic resonance spectroscopy in a cohort of young endurance trained subjects (n = 7) and a group of matched sedentary subjects (n = 8). V(TCA) was 54% higher in the muscle of endurance trained compared with sedentary subjects (91.7 +/- 7.6 vs. 59.6 +/- 4.9 nmol/g/min, P < 0.01); however, V(ATP) was not different between the trained and sedentary subjects (5.98 +/- 0.43 vs. 6.35 +/- 0.70 mumol/g/min, P = 0.67). The ratio V(ATP)/V(TCA) (an estimate of mitochondrial coupling) was also significantly reduced in trained subjects (P < 0.04). These data demonstrate that basal mitochondrial substrate oxidation is increased in the muscle of endurance trained individuals yet energy production is unaltered, leading to an uncoupling of oxidative phosphorylation at rest. Increased mitochondrial uncoupling may represent another mechanism by which exercise training enhances muscle insulin sensitivity via increased fatty acid oxidation in the resting state.
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Bye A, Høydal MA, Catalucci D, Langaas M, Kemi OJ, Beisvag V, Koch LG, Britton SL, Ellingsen Ø, Wisløff U. Gene expression profiling of skeletal muscle in exercise-trained and sedentary rats with inborn high and low VO2max. Physiol Genomics 2008; 35:213-21. [PMID: 18780757 DOI: 10.1152/physiolgenomics.90282.2008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The relationship between inborn maximal oxygen uptake (VO(2max)) and skeletal muscle gene expression is unknown. Since low VO(2max) is a strong predictor of cardiovascular mortality, genes related to low VO(2max) might also be involved in cardiovascular disease. To establish the relationship between inborn VO(2max) and gene expression, we performed microarray analysis of the soleus muscle of rats artificially selected for high- and low running capacity (HCR and LCR, respectively). In LCR, a low VO(2max) was accompanied by aggregation of cardiovascular risk factors similar to the metabolic syndrome. Although sedentary HCR were able to maintain a 120% higher running speed at VO(2max) than sedentary LCR, only three transcripts were differentially expressed (FDR <or=0.05) between the groups. Sedentary LCR expressed high levels of a transcript with strong homology to human leucyl-transfer RNA synthetase, of whose overexpression has been associated with a mutation linked to mitochondrial dysfunction. Moreover, we studied exercise-induced alterations in soleus gene expression, since accumulating evidence indicates that long-term endurance training has beneficial effects on the metabolic syndrome. In terms of gene expression, the response to exercise training was more pronounced in HCR than LCR. HCR upregulated several genes associated with lipid metabolism and fatty acid elongation, whereas LCR upregulated only one transcript after exercise training. The results indicate only minor differences in soleus muscle gene expression between sedentary HCR and LCR. However, the inborn level of fitness seems to influence the transcriptional adaption to exercise, as more genes were upregulated after exercise training in HCR than LCR.
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Affiliation(s)
- Anja Bye
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology NTNU, Trondheim, Norway
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Hancock CR, Han DH, Chen M, Terada S, Yasuda T, Wright DC, Holloszy JO. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci U S A 2008; 105:7815-20. [PMID: 18509063 PMCID: PMC2409421 DOI: 10.1073/pnas.0802057105] [Citation(s) in RCA: 398] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2008] [Indexed: 11/18/2022] Open
Abstract
It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-activated receptor (PPAR)delta by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR gamma coactivator 1alpha (PGC-1alpha) protein expression. Similarly, overexpression of PPARdelta results in a large increase in PGC-1alpha protein in the absence of any increase in PGC-1alpha mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPARdelta, which mediates a posttranscriptional increase in PGC-1alpha. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria.
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Affiliation(s)
- Chad R. Hancock
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Dong-Ho Han
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - May Chen
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Shin Terada
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Toshihiro Yasuda
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - David C. Wright
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - John O. Holloszy
- Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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Newsholme EA. The glucose/fatty acid cycle and physical exhaustion. CIBA FOUNDATION SYMPOSIUM 2008; 82:89-101. [PMID: 6913480 DOI: 10.1002/9780470715420.ch6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The energy required for sustained exercise is provided by the oxidation of two fuels, glucose and long-chain fatty acids, which are stored as liver and muscle glycogen and adipose tissue triglyceride. The latter provides the largest energy reserve in the body; there is sufficient energy for about five days of continuous marathon running. Glycogen reserves, in contrast, are very limited and, at most, could provide energy for 100 minutes. Evidence is presented of a metabolic limit in the rate of fatty acid utilization, so that sustained exercise at a high power output requires the utilization of both fat and carbohydrate simultaneously. There is a regulatory mechanism by which fatty acid oxidation reduces carbohydrate utilization in muscle--the glucose/fatty acid cycle. This plays an important part in ensuring that marathon runners can continue beyond the theoretical limit of 100 minutes. Triglyceride is mobilized from adipose tissue as long-chain fatty acids and the oxidation of these by muscle reduces the rate of glucose utilization. The availability of fatty acids for oxidation as early as possible in exercise will allow the use of both fuels (fatty acids and glucose) for a longer period of time. Since it appears that fatigue occurs when carbohydrate reserves are depleted, reduction in the rate of glucose utilization by the oxidation of fatty acids is obviously beneficial. The ability of ultra-distance runners to exceed these limits poses interesting metabolic questions relating to exhaustion.
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49
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Zhang SJ, Sandström ME, Aydin J, Westerblad H, Wieringa B, Katz A. Activation of glucose transport and AMP-activated protein kinase during muscle contraction in adenylate kinase-1 knockout mice. Acta Physiol (Oxf) 2008; 192:413-20. [PMID: 17973952 DOI: 10.1111/j.1748-1716.2007.01767.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
AIM Recently it was reported that adenylate kinase-1 knockout mice (AK(-/-)) exhibit elevated rates of glucose uptake following repeated contractions and hypoxia, but the mechanism was not investigated. The purpose of the present study was to measure the changes in glucose transport and AMP-activated protein kinase (AMPK) phosphorylation/activity following repeated contractions in isolated muscles from AK(-/-) mice. METHODS Extensor digitorum longus muscles underwent an intense stimulation protocol that decreased force to less than 10% of initial by the end of 10 min. Glucose uptake was measured with 2-deoxy-D-[1,2-(3)H]glucose. RESULTS Muscle glucose uptake in the basal state was identical between control and AK(-/-) mice and increased twofold in both groups during contraction. The general antioxidant: N-acetylcysteine, decreased contraction-mediated glucose uptake by 30% in both groups. AMPK activity and phosphorylation were similar in the two groups in the basal state and, surprisingly, after contraction as well (approximately threefold increase). Both groups exhibited marked decreases in adenosine triphosphate following contraction (60-70% depletion), which coincided with stoichiometric increases in the content of inosine monophosphate, an indirect marker of AMP production. Adenylate kinase activity averaged 2081 +/- 106 micromol min(-1) (g dry wt)(-1) for control and 37 +/- 10 for AK(-/-) muscles; the activity in the AK(-/-) muscle is likely accounted for by isoforms other than AK1. CONCLUSION In conclusion, AK(-/-) mice have a normal capacity for contraction-mediated glucose uptake. This appears to occur via increases in AMP and reactive oxygen species that result in the activation of AMPK.
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Affiliation(s)
- S-J Zhang
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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50
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Garcia-Roves P, Huss JM, Han DH, Hancock CR, Iglesias-Gutierrez E, Chen M, Holloszy JO. Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci U S A 2007; 104:10709-13. [PMID: 17548828 PMCID: PMC1965577 DOI: 10.1073/pnas.0704024104] [Citation(s) in RCA: 187] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2007] [Indexed: 12/29/2022] Open
Abstract
A number of studies have reported that a high-fat diet induces increases in mitochondrial fatty acid oxidation enzymes in muscle. In contrast, in two recent studies raising plasma free fatty acids (FFA) resulted in a decrease in mitochondria. In this work, we reevaluated the effects of raising FFA on muscle mitochondrial biogenesis and capacity for fat oxidation. Rats were fed a high-fat diet and given daily injections of heparin to raise FFA. This treatment induced an increase in mitochondrial biogenesis in muscle, as evidenced by increases in mitochondrial enzymes of the fatty acid oxidation pathway, citrate cycle, and respiratory chain, with an increase in the capacity to oxidize fat, as well as an increase in mitochondrial DNA copy number. Raising FFA also resulted in an increase in binding of peroxisome proliferator-activated receptor (PPAR) delta to the PPAR response element on the carnitine palmitoyltransferase 1 promoter. We interpret our results as evidence that raising FFA induces an increase in mitochondrial biogenesis in muscle by activating PPARdelta.
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Affiliation(s)
- Pablo Garcia-Roves
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Janice M. Huss
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Dong-Ho Han
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Chad R. Hancock
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Eduardo Iglesias-Gutierrez
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - May Chen
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - John O. Holloszy
- Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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