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


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 PGC1. Electotransfection of PGC1 cDNA into lean animals tested the notion that increased nuclear PGC1 preferentially targeted subsarcolemmal mitochondria.


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. PGC1 mRNA and total protein were not altered in ZDF animals; however, a greater (~70%; P < 0.05) amount of PGC1 was located in nuclei. Overexpression of PGC1 only increased subsarcolemmal mitochondrial oxidation rates.


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 PGC1, as under basal conditions, overexpression of PGC1 appears to target subsarcolemmal mitochondria.


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