Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria

PGC-1 alpha overexpression in skeletal muscle, in vivo, has yielded disappointing and unexpected effects, including disrupted cellular integrity and insulin resistance. These unanticipated results may stem from an excessive PGC-1 alpha overexpression in transgenic animals. Therefore, we examined the effects of a modest PGC-1 alpha overexpression in a single rat muscle, in vivo, on fuel-handling proteins and insulin sensitivity. We also examined whether modest PGC-1 alpha overexpression selectively targeted subsarcolemmal (SS) mitochondrial proteins and fatty acid oxidation, because SS mitochondria are metabolically more plastic than intermyofibrillar (IMF) mitochondria. Among metabolically heterogeneous rat hindlimb muscles, PGC-1 alpha was highly correlated with their oxidative fiber content and with substrate transport proteins (GLUT4, FABPpm, and FAT/ CD36) and mitochondrial proteins (COXIV and mTFA) but not with insulin-signaling proteins (phosphatidylinositol 3-kinase, IRS-1, and Akt2), nor with 5'-AMP-activated protein kinase, alpha 2 subunit, and HSL. Transfection of PGC-1 alpha into the red (RTA) and white tibialis anterior (WTA) compartments of the tibialis anterior muscle increased PGC-1 alpha protein by 23-25%. This also induced the up-regulation of transport proteins (FAT/ CD36, 35-195%; GLUT4, 20-32%) and 5'-AMP-activated protein kinase, alpha 2 subunit (37-48%), but not other proteins (FABPpm, IRS-1, phosphatidylinositol 3-kinase, Akt2, and HSL). SS and IMF mitochondrial proteins were also up-regulated, including COXIV (15-75%), FAT/ CD36 (17-30%), and mTFA (15-85%). PGC-1 alpha overexpression also increased palmitate oxidation in SS (RTA, + 116%; WTA, + 40%) but not in IMF mitochondria, and increased insulin-stimulated phosphorylation of AKT2 (28 - 43%) and rates of glucose transport (RTA, + 20%; WTA, + 38%). Thus, in skeletal muscle in vivo, a modest PGC-1 alpha overexpression up-regulated selected plasmalemmal and mitochondrial fuel-handling proteins, increased SS (not IMF) mitochondrial fatty acid oxidation, and improved insulin sensitivity.