Compensatory Increases in Nuclear PGC1α Protein Are Primarily Associated With Subsarcolemmal Mitochondrial Adaptations in ZDF Rats

  1. Arend Bonen1
  1. 1Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada;
  2. 2School of Kinesiology, Queen's University, Kingston, Ontario, Canada.
  1. Corresponding author: Graham Holloway, ghollowa{at}uoguelph.ca.
  1. G.P.H. and B.J.G. contributed equally to this manuscript.

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) γ coactivator (PGC) 1α and the adaptations of specific mitochondrial subpopulations.

RESEARCH DESIGN AND 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 PGC1α. Electotransfection of PGC1α cDNA into lean animals tested the notion that increased nuclear PGC1α 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 ∼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. PGC1α mRNA and total protein were not altered in ZDF animals; however, a greater (∼70%; P < 0.05) amount of PGC1α was located in nuclei. Overexpression of PGC1α 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 PGC1α, as under basal conditions, overexpression of PGC1α appears to target subsarcolemmal mitochondria.

Footnotes

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    • Received October 13, 2009.
    • Accepted January 17, 2010.

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  1. Diabetes vol. 59 no. 4 819-828
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