PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis
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{"title"=>"PGC-1α deficiency causes multi-system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis", "type"=>"journal", "authors"=>[{"first_name"=>"Teresa C.", "last_name"=>"Leone", "scopus_author_id"=>"6701375491"}, {"first_name"=>"John J.", "last_name"=>"Lehman", "scopus_author_id"=>"7101828072"}, {"first_name"=>"Brian N.", "last_name"=>"Finck", "scopus_author_id"=>"6701396062"}, {"first_name"=>"Paul J.", "last_name"=>"Schaeffer", "scopus_author_id"=>"7006088606"}, {"first_name"=>"Adam R.", "last_name"=>"Wende", "scopus_author_id"=>"6602484414"}, {"first_name"=>"Sihem", "last_name"=>"Boudina", "scopus_author_id"=>"6508283819"}, {"first_name"=>"Michael", "last_name"=>"Courtois", "scopus_author_id"=>"7006373791"}, {"first_name"=>"David F.", "last_name"=>"Wozniak", "scopus_author_id"=>"7005575228"}, {"first_name"=>"Nandakumar", "last_name"=>"Sambandam", "scopus_author_id"=>"6603234077"}, {"first_name"=>"Carlos", "last_name"=>"Bernal-Mizrachi", "scopus_author_id"=>"6506418013"}, {"first_name"=>"Zhouji", "last_name"=>"Chen", "scopus_author_id"=>"7409486365"}, {"first_name"=>"John O.", "last_name"=>"Holloszy", "scopus_author_id"=>"7102059048"}, {"first_name"=>"Denis M.", "last_name"=>"Medeiros", "scopus_author_id"=>"7103048420"}, {"first_name"=>"Robert E.", "last_name"=>"Schmidt", "scopus_author_id"=>"7404918158"}, {"first_name"=>"Jeffrey E.", "last_name"=>"Saffitz", "scopus_author_id"=>"7102758017"}, {"first_name"=>"E. Dale", "last_name"=>"Abel", "scopus_author_id"=>"7202417444"}, {"first_name"=>"Clay F.", "last_name"=>"Semenkovich", "scopus_author_id"=>"7006372841"}, {"first_name"=>"Daniel P.", "last_name"=>"Kelly", "scopus_author_id"=>"7403137640"}], "year"=>2005, "source"=>"PLoS Biology", "identifiers"=>{"issn"=>"15449173", "scopus"=>"2-s2.0-21144446106", "pui"=>"40721160", "doi"=>"10.1371/journal.pbio.0030101", "isbn"=>"1545-7885 (Electronic)\\r1544-9173 (Linking)", "sgr"=>"21144446106", "pmid"=>"15760270"}, "id"=>"c3cd5fb5-6ca0-32e8-bf39-718954b341fe", "abstract"=>"The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (PGC-1alpha(-/-)) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha(-/-) mice. With age, the PGC-1alpha(-/-) mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha(-/-) mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha(-/-) mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha(-/-) mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha(-/-) mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha(-/-) mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.", "link"=>"http://www.mendeley.com/research/pgc1%CE%B1-deficiency-causes-multisystem-energy-metabolic-derangements-muscle-dysfunction-abnormal-weight", "reader_count"=>250, "reader_count_by_academic_status"=>{"Unspecified"=>9, "Professor > Associate Professor"=>16, "Student > Doctoral Student"=>12, "Researcher"=>49, "Student > Ph. D. 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Student"=>72, "Student > Postgraduate"=>8, "Student > Master"=>38, "Other"=>3, "Student > Bachelor"=>28, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>2, "Professor"=>12}, "reader_count_by_subject_area"=>{"Unspecified"=>17, "Agricultural and Biological Sciences"=>128, "Veterinary Science and Veterinary Medicine"=>1, "Chemistry"=>1, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>40, "Nursing and Health Professions"=>2, "Medicine and Dentistry"=>40, "Neuroscience"=>5, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Sports and Recreations"=>9, "Physics and Astronomy"=>2, "Psychology"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>40}, "Sports and Recreations"=>{"Sports and Recreations"=>9}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Psychology"=>{"Psychology"=>1}, "Unspecified"=>{"Unspecified"=>17}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Neuroscience"=>{"Neuroscience"=>5}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>128}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>40}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Republic of Singapore"=>1, "Canada"=>1, "United States"=>5, "Japan"=>1, "Finland"=>1, "Brazil"=>1, "United Kingdom"=>2, "Iraq"=>1, "Chile"=>1, "Portugal"=>1, "Spain"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/963019"], "description"=>"<div><p>(A) PGC-1α<sup>+/+</sup> (<i>n</i> = 15) and PGC-1α<sup>−/−</sup> (<i>n</i> = 21) mice aged 28–37 d were subjected to cold (4 °C). Core rectal temperature was monitored over a 5-h period. The change in core temperature ± SEM is shown in the graph (left) as a function of time. * <i>p</i> < 0.05.</p>\n <p>(B) Representative Northern blot analysis (blot and gel at top) performed with RNA isolated from BAT to detect UCP-1 transcript at baseline (RT) and after 5 h of exposure to cold (4 °C) (UCP1). Ethidium bromide (Eth Br) staining of ribosomal RNA is shown as a control. Quantitative real-time RT-PCR for UCP-1 transcript is shown on the graph at the bottom. The values represent mean arbitrary units normalized to a 36B4 transcript (control).</p>\n <p>(C) Altered response to β<sub>3</sub>-adrenergic agonist. To evaluate the oxygen consumption (VO<sub>2</sub>) in response to the stimulation of BAT uncoupled respiration, the β<sub>3</sub>-adrenergic agonist BRL 37344 was administered to littermate PGC-1α<sup>+/+</sup> (<i>n</i> = 5) and PGC-1α<sup>−/−</sup> (<i>n</i> = 5) female mice followed by measurement of VO<sub>2</sub> by indirect calorimetry. Mean ± SEM VO<sub>2</sub> is shown. * <i>p</i> < 0.05.</p></div>", "links"=>[], "tags"=>["mice", "abnormal", "thermogenic"], "article_id"=>632960, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PGC_1_8722_8722_Mice_Exhibit_an_Abnormal_Thermogenic_Response_/632960", "title"=>"PGC-1α<sup>−/−</sup> Mice Exhibit an Abnormal Thermogenic Response", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:08:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/962445"], "description"=>"<div><p>(A) Schematic of the gene targeting strategy. A region of the murine <i>PGC-1α</i> gene containing exons 3–6 is shown schematically at the top. Relevant restriction endonuclease sites are also shown. The targeting construct containing a neomycin (Neo) cassette is shown below the <i>PGC-1α</i> gene with dashed lines indicating the regions targeted for homologous recombination. Homologous recombination between the 3′ end of the targeting vector and the <i>PGC-1α</i> gene is indicated by the solid lines. The targeting construct inserted into the <i>PGC-1α</i> gene resulting in a duplication of exon 3 and incorporation of the targeting construct DNA into the final recombinant as shown. Probes used for the Southern blot studies and relevant restriction fragments predicted by digestion of the recombinant are also shown.</p>\n <p>(B) Southern blot analysis of embryonic stem cells (ESC) (digested with Xba1) and tail DNA (digested with Pst1) is shown. The blots were hybridized with the probes shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#pbio-0030101-g001\" target=\"_blank\">Figure 1</a>A. Results for PGC-1α<sup>+/+</sup> (+/+), PGC-1α<sup>+/−</sup> (+/−), and PGC-1α<sup>−/−</sup> (−/−) genotypes are shown as denoted at the bottom.</p>\n <p>(C) Northern blot analysis using RNA isolated from the hearts of the three relevant PGC-1α genotypes (as in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#pbio-0030101-g001\" target=\"_blank\">Figure 1</a>B) is shown using PGC-1α cDNA as a probe. In addition, PGC-1β and PRC cDNA probes were used as shown. Ethidium bromide staining of 18S ribosomal RNA is shown at the bottom.</p>\n <p>(D) Quantitative real time RT-PCR (Sybr green) was used to detect PGC-1α transcripts using primer sets crossing different exon borders as denoted. The exon 5–3 primer set detects only the mutant transcript (−/−), whereas the exon 5–6 primer set detects only the WT transcript. The values represent arbitrary units for RNA isolated from the tissues shown for the three amplicons comparing PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup>. N.D. = not detectable. The exon 10–11 amplicon was evaluated to assess levels of mutant versus WT transcripts. The values represent arbitrary units normalized to actin control.</p>\n <p>(E) Western blot analysis using whole-cell protein extracts prepared from BAT under basal conditions and following exposure to 4 °C for 8 h. The signal shown was obtained with polyclonal anti-PGC-1α antibody [<a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#pbio-0030101-b10\" target=\"_blank\">10</a>]. An epitope-tagged PGC-1α, overexpressed in neonatal cardiac myocytes using an adenoviral vector (Ad-PGC-1α), is shown as a positive control. The Ponceau S stain of the protein gel is shown at the bottom.</p></div>", "links"=>[], "tags"=>["genetics and genomics", "physiology"], "article_id"=>632417, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Deletion_of_the_PGC_1_945_Gene_/632417", "title"=>"Deletion of the PGC-1α Gene", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:04:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/963422"], "description"=>"<div><p>(A) At 4.5 mo of age, glucose tolerance testing (GTT) was performed on female PGC-1α<sup>+/+</sup> (<i>n</i> = 6) and PGC-1α<sup>−/−</sup> (<i>n</i> = 6) mice maintained on standard chow.</p>\n <p>(B) At 8 wk of age, PGC-1α<sup>+/+</sup> (<i>n</i> = 8) and PGC-1α<sup>−/−</sup> (<i>n</i> = 11) mice were provided a diet containing 43% of its calories from fat (HF chow). The graphs depict blood glucose levels ± SEM in PGC-1α<sup>−/−</sup> mice during GTT (left graph) and ITT (right graph) studies. Studies were performed 5 wk (GTT) and 6 wk (ITT) after the initiation of the high-fat diet. * <i>p</i> < 0.05 compared to PGC-1α<sup>+/+</sup> mice at the same time point.</p></div>", "links"=>[], "tags"=>["mice", "glucose", "tolerant", "insulin", "compared", "high-fat"], "article_id"=>633346, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g009", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Female_PGC_1_8722_8722_Mice_Are_More_Glucose_Tolerant_and_Insulin_Sensitive_Compared_to_PGC_1_945_on_High_Fat_Diet_/633346", "title"=>"Female PGC-1α<sup>−/−</sup> Mice Are More Glucose Tolerant and Insulin Sensitive Compared to PGC-1α<sup>+/+</sup> on High-Fat Diet", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:10:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/963191"], "description"=>"<div><p>(A) The photograph depicts the development of a pale liver in PGC-1α<sup>−/−</sup> mice subjected to a 24-h fast.</p>\n <p>(B) Oil red O staining of histologic sections of liver taken from PGC-1α<sup>−/−</sup> mice under fed and 24 h fasted conditions. The red staining indicates neutral lipid.</p>\n <p>(C) Representative electron micrographs of the liver from PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup> mice following a 24-h fast. The droplets are indicative of neutral lipid accumulation.</p>\n <p>(D) Mean liver TAG levels in PGC-1α<sup>+/+</sup> (<i>n</i> = 5) and PGC-1α<sup>−/−</sup> (<i>n</i> = 5) mice under fed and 24-h fasted conditions. * <i>p</i> < 0.05.</p></div>", "links"=>[], "tags"=>["hepatic", "steatosis", "develops"], "article_id"=>633125, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g007", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fasting_Induced_Hepatic_Steatosis_Develops_in_PGC_1_8722_8722_Mice_/633125", "title"=>"Fasting-Induced Hepatic Steatosis Develops in PGC-1α<sup>−/−</sup> Mice", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:09:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/963323"], "description"=>"<div><p>(A) Oil red O staining of isolated hepatocytes exposed to BSA alone (BSA) or 50 μM oleate complexed to BSA (oleate).</p>\n <p>(B) <sup>3</sup>H-palmitate oxidation rates. <sup>3</sup>H-palmitate oxidation rates determined in hepatocytes isolated from PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup> mice under cell culture conditions containing BSA or BSA + 50 μM oleate (2:1 oleate/BSA ratio). Values were derived from ten sets of triplicates for each group using hepatocytes from 5 mice of each genotype. The bars represent mean oxidation rates (<i>n</i> = 100) normalized to the condition of PGC-1α<sup>+/+</sup> in BSA alone. * <i>p</i> < 0.05 compared to the corresponding PGC-1α<sup>+/+</sup> mice. † <i>p</i> < 0.05 compared to PGC-1α<sup>+/+</sup> with BSA treatment.</p>\n <p>(C) State 2 and 3 respiration rates determined for hepatocytes isolated from PGC-1α<sup>+/+</sup> (<i>n</i> = 3) and PGC-1α<sup>−/−</sup> (<i>n</i> = 3) mice using succinate/rotenone as a substrate. * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup>.</p>\n <p>(D) TAG synthesis rates in isolated hepatocytes. The bars represent mean TAG synthesis rates (glycerol incorporation, see <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#s4\" target=\"_blank\">Materials and Methods</a>) for hepatocytes isolated from PGC-1α<sup>+/+</sup> (<i>n</i> = 6) and PGC-1α<sup>−/−</sup> (<i>n</i> = 6) mice. * <i>p</i> < 0.05 compared to the corresponding PGC-1α<sup>+/+</sup> condition.</p></div>", "links"=>[], "tags"=>["mice", "reduced", "oxidative"], "article_id"=>633253, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g008", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hepatocytes_Isolated_from_PGC_1_8722_8722_Mice_Exhibit_Reduced_Oxidative_Capacity_/633253", "title"=>"Hepatocytes Isolated from PGC-1α<sup>−/−</sup> Mice Exhibit Reduced Oxidative Capacity", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:10:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/963587"], "description"=>"<div><p>(A) Light microscopic appearance of representative cerebral cortex of 2-mo-old PGC-1α<sup>−/−</sup> mice demonstrates marked vacuolation of the neuropil (arrows) and scattered neuronal perikarya, which are absent in PGC-1α<sup>+/+</sup> mice (hematoxylin and eosin). The scale bar shown is applicable to all sections.</p>\n <p>(B) Ultrastructural appearance of typical vacuoles containing membranous debris, denoted by the arrow, in the cerebral cortex of a representative PGC-1α<sup>−/−</sup> mouse in comparison to PGC-1α<sup>+/+</sup> (magnification 4000×).</p></div>", "links"=>[], "tags"=>["genetics and genomics", "physiology"], "article_id"=>633514, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g010", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Neuropathology_of_the_Central_Nervous_System_of_PGC_1_8722_8722_Mice_/633514", "title"=>"Neuropathology of the Central Nervous System of PGC-1α<sup>−/−</sup> Mice", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:12:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/962657"], "description"=>"<div><p>(A) Representative electron micrograph of soleus muscle from 1-mo-old female PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup> mice.</p>\n <p>(B) Quantitative morphometric measurements of the cellular volume density for the mitochondrial (Mito) and myofibrillar (Myo) fractions based on analysis of electron micrographs (three sections from three animals per group). The bars represent mean ± SEM. * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup> values.</p>\n <p>(C) Gene expression data. The results of real-time PCR analysis of nuclear and mitochondrial genes involved in various components of mitochondrial metabolism and mitochondrial biogenesis: cytochrome C (Cyto c), ATP synthase β, Tfam, and cytochrome oxidase IV (COX IV). Eight littermate pairs were used for analysis at 1–2 mo of age and normalized to the WT value, which was assigned a value of 100, in each case. * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup> values.</p>\n <p>(D) Mitochondrial respiration rates as determined by oxygen consumption (VO<sub>2</sub>) performed on saponin-permeabilized muscle strips prepared from soleus of PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup> mice (as described in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#s4\" target=\"_blank\">Materials and Methods</a>). The results are based on six female animals in each group, using succinate as a substrate in the presence of rotenone. Mean values (± SEM) are shown for state 2 (basal), state 3 (ADP-stimulated), and state 4 respiration (presence of oligomycin).</p></div>", "links"=>[], "tags"=>["mitochondrial", "phenotype", "slow-twitch", "skeletal"], "article_id"=>632620, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g003", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Abnormal_Mitochondrial_Phenotype_in_Slow_Twitch_Skeletal_Muscle_of_PGC_1_8722_8722_Mice_/632620", "title"=>"Abnormal Mitochondrial Phenotype in Slow-Twitch Skeletal Muscle of PGC-1α<sup>−/−</sup> Mice", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:05:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/473324", "https://ndownloader.figshare.com/files/473368", "https://ndownloader.figshare.com/files/473409", "https://ndownloader.figshare.com/files/473434", "https://ndownloader.figshare.com/files/473483"], "description"=>"<div><p>The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α<sup>−/−</sup>) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α<sup>−/−</sup> mice. With age, the PGC-1α<sup>−/−</sup> mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α<sup>−/−</sup> mice, leading to reduced muscle performance and exercise capacity. PGC-1α<sup>−/−</sup> mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α<sup>−/−</sup> mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α<sup>−/−</sup> mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α<sup>−/−</sup> mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α<sup>−/−</sup> mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.</p> </div>", "links"=>[], "tags"=>["deficiency", "causes", "multi-system", "metabolic", "abnormal", "hepatic", "steatosis"], "article_id"=>153253, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.0030101.sg001", "https://dx.doi.org/10.1371/journal.pbio.0030101.sg002", "https://dx.doi.org/10.1371/journal.pbio.0030101.sg003", "https://dx.doi.org/10.1371/journal.pbio.0030101.sg004", "https://dx.doi.org/10.1371/journal.pbio.0030101.st001"], "stats"=>{"downloads"=>18, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/PGC_1_Deficiency_Causes_Multi_System_Energy_Metabolic_Derangements_Muscle_Dysfunction_Abnormal_Weight_Control_and_Hepatic_Steatosis/153253", "title"=>"PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-01-20 11:33:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/962549"], "description"=>"<div><p>(A) The bars represent total body weight for the ages indicated for male (left graph) and female (center graph) PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup> mice. The body weight (BW) of the 1-wk-old PGC-1α<sup>−/−</sup> mice was normalized to that of PGC-1α<sup>+/+</sup> littermates, which was assigned a value of 100 (left axis). For the 3-, 18-, and 24-wk time points, absolute weights of PGC-1α<sup>−/−</sup> mice were compared to age-matched controls (right axis). Percent fat as determined by DEXA scanning for PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup> mice (right graph). The results represent <i>n</i> = 4 (males) and <i>n</i> ≥ 11 (females) for each genotype at 24 wk. * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup> mice.</p>\n <p>(B) The bars represent organ weights corrected to body weight for 3-wk-old male and female PGC-1α<sup>+/+</sup> and PGC-1α<sup>−/−</sup> mice. The error bars represent ± SEM. Results represent <i>n</i> ≥ 14 for each group. * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup> mice.</p></div>", "links"=>[], "tags"=>["tissue-specific", "abnormalities", "age-dependent", "obesity"], "article_id"=>632509, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g002", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Evidence_for_Tissue_Specific_Growth_Abnormalities_and_Mild_Sex_Limited_Age_Dependent_Obesity_in_PGC_1_8722_8722_Mice_/632509", "title"=>"Evidence for Tissue-Specific Growth Abnormalities and Mild Sex-Limited, Age-Dependent Obesity in PGC-1α<sup>−/−</sup> Mice", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:04:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/962747"], "description"=>"<div><p>(A) Measures of general activity and muscle strength. General activity levels were measured in 3.5-mo-old male PGC-1α<sup>+/+</sup> (<i>n</i> = 8) and PGC-1α<sup>−/−</sup> (<i>n</i> = 11) mice using a photobeam system as described in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#s4\" target=\"_blank\">Materials and Methods</a>. Total ambulations (left graph), and rearings (center graph) provide a general measure of locomotor activity. Time spent on an inverted screen (right graph) represents a general measure of extremity muscle strength. The results from two trials are shown. * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup>.</p>\n <p>(B) Exercise studies. Male 6–8-mo-old PGC-1α<sup>−/−</sup> and PGC-1α<sup>+/+</sup> mice were subjected to a run-to-exhaustion protocol on a motorized treadmill (left graph) as described in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#s4\" target=\"_blank\">Materials and Methods</a>. * <i>p</i> < 0.001 compared to corresponding PGC-1α<sup>+/+</sup> values. VO<sub>2max</sub> measurements were determined for 2-mo-old male mice for each genotype using a motorized treadmill at an elevation of 150 m and indirect calorimetry set-up (right graph) as described in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#s4\" target=\"_blank\">Materials and Methods</a>. * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup> values.</p>\n <p>(C) Time course of fatigue following repeated stimulation of soleus muscle is shown for 4-mo-old male PGC-1α<sup>−/−</sup> (<i>n</i> = 5) and PGC-1α<sup>+/+</sup> (<i>n</i> = 5) mice (left graph). The mean percent force remaining at 2 min (Fatigue Resistance Index) is shown (right graph). * <i>p</i> < 0.05 compared to corresponding PGC-1α<sup>+/+</sup> values.</p></div>", "links"=>[], "tags"=>["mice", "abnormal", "skeletal"], "article_id"=>632702, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g004", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PGC_1_8722_8722_Mice_Exhibit_an_Abnormal_Skeletal_Muscle_Functional_Phenotype_/632702", "title"=>"PGC-1α<sup>−/−</sup> Mice Exhibit an Abnormal Skeletal Muscle Functional Phenotype", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:06:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/962853"], "description"=>"<div><p>(A) Exercise echocardiographic studies. PGC-1α<sup>+/+</sup> (<i>n</i> = 4) and PGC-1α<sup>−/−</sup> (<i>n</i> = 8) female mice aged 6–8 mo were subjected to an exercise protocol on a motorized treadmill. This protocol was designed such that the PGC-1α<sup>−/−</sup> mice ran to exhaustion based on the results of the exercise studies shown in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#pbio-0030101-g004\" target=\"_blank\">Figure 4</a>. Accordingly, an exercise regimen of 60 s was used for both groups. The graphs depict the heart rate (left graph) and echocardiographically-determined ventricular fractional shortening (FS) as a percent (right graph). Responses were monitored for 10 min immediately post exercise.</p>\n <p>(B) In vivo hemodynamic response to the β<sub>1</sub>,α<sub>1</sub>-adrenergic agonist dobutamine. Male and female PGC-1α<sup>+/+</sup> (<i>n</i> = 6) and PGC-1α<sup>−/−</sup> (<i>n</i> = 6) mice at 10–12 wk of age were anesthetized and a 1.4-French Millar catheter was placed through the carotid artery into the left ventricle as described in <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030101#s4\" target=\"_blank\">Materials and Methods</a>. Heart rate (left graph) and a measurement of ventricular systolic performance, dP/dt (right graph), were measured following infusion of dobutamine. * <i>p</i> < 0.05.</p></div>", "links"=>[], "tags"=>["cardiac", "physiologic"], "article_id"=>632805, "categories"=>["Physiology", "Genetics"], "users"=>["Teresa C Leone", "John J Lehman", "Brian N Finck", "Paul J Schaeffer", "Adam R Wende", "Sihem Boudina", "Michael Courtois", "David F Wozniak", "Nandakumar Sambandam", "Carlos Bernal-Mizrachi", "Zhouji Chen", "John O. Holloszy", "Denis M Medeiros", "Robert E Schmidt", "Jeffrey E Saffitz", "E. Dale Abel", "Clay F Semenkovich", "Daniel P Kelly"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.0030101.g005", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Abnormal_Cardiac_Response_to_Physiologic_Stress_in_PGC_1_8722_8722_Mice_/632805", "title"=>"Abnormal Cardiac Response to Physiologic Stress in PGC-1α<sup>−/−</sup> Mice", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:07:05"}

PMC Usage Stats | Further Information

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