Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria

Abstract

PGC-1␣ 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␣ overexpression in transgenic animals. Therefore, we examined the effects of a modest PGC-1␣ overexpression in a single rat muscle, in vivo, on fuel-handling proteins and insulin sensitivity. We also examined whether modest PGC-1␣ 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␣ 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, ␣2 subunit, and HSL. Transfection of PGC-1␣ into the red (RTA) and white tibialis anterior (WTA) compartments of the tibialis anterior muscle increased PGC-1␣ 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, ␣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␣ 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␣ overexpression up-regulated selected plasmalemmal and mitochondrial fuel-handling proteins, increased SS (not IMF) mitochondrial fatty acid oxidation, and improved insulin sensitivity.

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

“…Viewed in this light, PGC-1α-induced insulin resistance in transgenic mice is less of a paradox than has been suggested [11]. Recently, we showed that inducing a modest increase in PGC-1α protein, based on physiological and metabolic considerations, has an insulin-sensitising effect in healthy muscle [3]. Nevertheless, some very critical questions remain unanswered, e.g.…”

“…Muscle fibre composition of muscles in lean and obese animals was determined as described by us recently [3], by staining serial cross sections (10 µm) for myofibrillar ATPase and succinate dehydrogenase, from which we determined their physiological and metabolic characteristics [3].…”

“…Excessive PGC-1α production induces many undesirable consequences, including abnormal mitochondrial proliferation, disruption of myofibrillar architecture, displacement of nuclei [12], obesity, intramuscular lipid accumulation and insulin resistance [10,11]. We [3,13] have suggested that insulin resistance in PGC-1α transgenic mice [10,11] may stem from a large, PGC-1α-induced increase in the fatty acid transporter, fatty acid translocase (FAT), which has been associated with increases in intramuscular lipids and insulin resistance in humans and in animals [14,15]. Viewed in this light, PGC-1α-induced insulin resistance in transgenic mice is less of a paradox than has been suggested [11].…”

“…The accumulation of lipids within skeletal muscle has been associated with the development of insulin resistance, as excess intramuscular lipid metabolites interfere with insulin signalling, leading to impaired removal of glucose from the circulation [1]. Increasing fatty acid oxidation while reducing intramuscular lipids is thought to be an effective means to improve insulin sensitivity, as has been shown with genetic studies and with exercise [2][3][4].…”

Nifedipine increases energy expenditure by increasing PGC-1α expression in skeletal muscle

“…Previous studies have reported that expression of PGC-1a is upregulated by prolonged exercise in rats 31 and that moderate PGC-1a overexpression in rat skeletal muscle in vivo improves insulin sensitivity. 32 Future investigations could address whether prolonged exercise combined with nifedipine treatment could synergistically elevate PGC-1a mRNA levels and improve insulin sensitivity in patients with obesity and/or type 2 diabetes.…”