title: Compensatory increases in nuclear PGC1alpha protein are primarily associated with subsarcolemmal mitochondrial adaptations in ZDF rats.
abstract: OBJECTIVE
  We examined in insulin-resistant muscle if, in contrast to long-standing dogma, mitochondrial fatty acid oxidation is increased and whether this is attributed to an increased nuclear content of peroxisome proliferator-activated receptor (PPAR) gamma coactivator (PGC) 1alpha and the adaptations of specific mitochondrial subpopulations.
  
  
  METHODS
  Skeletal muscles from male control and Zucker diabetic fatty (ZDF) rats were used to determine 1) intramuscular lipid distribution, 2) subsarcolemmal and intermyofibrillar mitochondrial morphology, 3) rates of palmitate oxidation in subsarcolemmal and intermyofibrillar mitochondria, and 4) the subcellular localization of PGC1alpha. Electotransfection of PGC1alpha cDNA into lean animals tested the notion that increased nuclear PGC1alpha preferentially targeted subsarcolemmal mitochondria.
  
  
  RESULTS
  Transmission electron microscope analysis revealed that in ZDF animals the number (+50%), width (+69%), and density (+57%) of subsarcolemmal mitochondria were increased (P < 0.05). In contrast, intermyofibrillar mitochondria remained largely unchanged. Rates of palmitate oxidation were approximately 40% higher (P < 0.05) in ZDF subsarcolemmal and intermyofibrillar mitochondria, potentially as a result of the increased PPAR-targeted proteins, carnitine palmitoyltransferase-I, and fatty acid translocase (FAT)/CD36. PGC1alpha mRNA and total protein were not altered in ZDF animals; however, a greater (approximately 70%; P < 0.05) amount of PGC1alpha was located in nuclei. Overexpression of PGC1alpha only increased subsarcolemmal mitochondrial oxidation rates.
  
  
  CONCLUSIONS
  In ZDF animals, intramuscular lipids accumulate in the intermyofibrillar region (increased size and number), and this is primarily associated with increased oxidative capacity in subsarcolemmal mitochondria (number, size, density, and oxidation rates). These changes may result from an increased nuclear content of PGC1alpha, as under basal conditions, overexpression of PGC1alpha appears to target subsarcolemmal mitochondria.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada. ghollowa@uoguelph.ca
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Gurd
authors.forename: Laelie A
authors.initials: LA
authors.lastname: Snook
authors.forename: Jamie
authors.initials: J
authors.lastname: Lally
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
mesh_terms: D000064:Acclimatization; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation; D007328:Insulin / Q000097:blood; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000502:physiology; D009210:Myofibrils / Q000502:physiology; D009245:NADH Dehydrogenase / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics*; D051381:Rats; D011924:Rats, Zucker; D012016:Reference Values; D012508:Sarcolemma / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D017931:DNA Primers; D018076:DNA, Complementary; D004272:DNA, Mitochondrial; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides; D009245:NADH Dehydrogenase; D002334:Carnitine O-Palmitoyltransferase