title: Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction.
abstract: Common inbred strains of the laboratory rat can be divided into four major mitochondrial DNA (mtDNA) haplotype groups represented by the BN, F344, LEW, and SHR strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. F344 mtDNA by comparing the SHR vs. SHR-mt(F344) conplastic strains that are genetically identical except for their mitochondrial genomes. Altogether 13 amino acid substitutions in protein coding genes, seven single nucleotide polymorphisms in tRNA genes, and 12 single nucleotide changes in rRNA genes were detected in F344 mtDNA compared with SHR mtDNA. Analysis of oxidative phosphorylation system (OXPHOS) in heart left ventricles (LV), muscle, and liver revealed reduced activity and content of several respiratory chain complexes in SHR-mt(F344) conplastic rats compared with the SHR strain. Lower function of OXPHOS in LV of conplastic rats was associated with significantly increased relative ventricular mass and reduced fractional shortening that was independent of blood pressure. In addition, conplastic rats exhibited reduced sensitivity of skeletal muscles to insulin action and impaired glucose tolerance. These results provide evidence that inherited alterations in mitochondrial genome, in the absence of variation in the nuclear genome and other confounding factors, predispose to insulin resistance, cardiac hypertrophy and systolic dysfunction.
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Josef
authors: J
authors: Houštěk
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Marek
authors: M
authors: Vrbacký
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Kateřina
authors: K
authors: Hejzlarová
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Václav
authors: V
authors: Zídek
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Vladimír
authors: V
authors: Landa
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Jan
authors: J
authors: Šilhavý
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Miroslava
authors: M
authors: Šimáková
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Petr
authors: P
authors: Mlejnek
authors: Institute for Clinical and Experimental Medicine, Prague, Czech Republic; and.
authors: Ludmila
authors: L
authors: Kazdová
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Ivan
authors: I
authors: Mikšík
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: Jan
authors: J
authors: Neckář
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: František
authors: F
authors: Papoušek
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic;
authors: František
authors: F
authors: Kolář
authors: Department of Laboratory Medicine, University of California, San Francisco, California.
authors: Theodore W
authors: TW
authors: Kurtz
authors: Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic; pravenec@biomed.cas.cz.
authors: Michal
authors: M
authors: Pravenec
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology*; D004272:DNA, Mitochondrial / Q000235:genetics*; D004562:Electrocardiography; D004579:Electron Transport / Q000187:drug effects; D018628:Gene Dosage; D050259:Genes, Mitochondrial; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006239:Haplotypes / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009929:Organ Size / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010641:Phenotype; D012343:RNA, Transfer / Q000235:genetics; D011916:Rats, Inbred F344; D011918:Rats, Inbred SHR; D017422:Sequence Analysis, DNA; D013599:Systole / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000227:Adenine Nucleotides; D004272:DNA, Mitochondrial; D007328:Insulin; D012343:RNA, Transfer; D005947:Glucose
keywords: conplastic; diabetes; heart mass; mitochondria; spontaneously hypertensive rat