PGC-1α increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4

Abstract

We examined the relationship between PGC-1alpha protein; the monocarboxylate transporters MCT1, 2, and 4; and CD147 1) among six metabolically heterogeneous rat muscles, 2) in chronically stimulated red (RTA) and white tibialis (WTA) muscles (7 days), and 3) in RTA and WTA muscles transfected with PGC-1alpha-pcDNA plasmid in vivo. Among rat hindlimb muscles, there was a strong positive association between PGC-1alpha and MCT1 and CD147, and between MCT1 and CD147. A negative association was found between PGC-1alpha and MCT4, and CD147 and MCT4, while there was no relationship between PGC-1alpha or CD147 and MCT2. Transfecting PGC-1alpha-pcDNA plasmid into muscle increased PGC-1alpha protein (RTA +23%; WTA +25%) and induced the expression of MCT1 (RTA +16%; WTA +28%), but not MCT2 and MCT4. As a result of the PGC-1alpha-induced upregulation of MCT1 and its chaperone CD147 (+29%), there was a concomitant increase in the rate of lactate uptake (+20%). In chronically stimulated muscles, the following proteins were upregulated, PGC-1alpha in RTA (+26%) and WTA (+86%), MCT1 in RTA (+61%) and WTA (+180%), and CD147 in WTA (+106%). In contrast, MCT4 protein expression was not altered in either RTA or WTA muscles, while MCT2 protein expression was reduced in both RTA (-14%) and WTA (-10%). In these studies, whether comparing oxidative capacities among muscles or increasing their oxidative capacities by PGC-1alpha transfection and chronic muscle stimulation, there was a strong relationship between the expression of PGC-1alpha and MCT1, and PGC-1alpha and CD147 proteins. Thus, MCT1 and CD147 belong to the family of metabolic genes whose expression is regulated by PGC-1alpha in skeletal muscle.

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

“…Based on our transfection efficiency, we estimate that PGC-1α is upregulated by 60 to 75% in the transfected muscle fibres, an effect that is within a physiologically meaningful range [30,38]. Importantly, this yields metabolically meaningful changes in whole-muscle mitochondrial biogenesis, protein levels, insulin sensitivity and lipid metabolism, as seen in the present study and others [3,16].…”

“…Muscle transfection efficiencies are typically maintained within a 30% to 40% range, as was done in the present study and others [3,4,16,17,20,34,35]. A greater transfection efficiency requires higher electroporation voltages, which induce muscle damage (C. R. Benton and A. Bonen, unpublished data) [20].…”

“…The correlations between PGC-1α and rodent muscle oxidative capacity, and between PGC-1α and both GLUT4 and FAT support the idea that in lean and obese muscles PGC-1α is central to a coordinated metabolic programme that upregulates a number of genes simultaneously to produce an oxidative muscle phenotype that relies extensively on blood-borne substrates for energy provision [3,5,31]. The small range of PGC-1α protein abundance across a range of heterogeneous muscles implies that small, physiologically induced changes in PGC-1α protein [6,30,32,33] can have pronounced effects on muscle metabolism, as shown by the present study and others [3,16].…”

“…Electrotransfection of tibialis anterior muscle was performed as previously described in detail [3,16,17]. Briefly, animals were anaesthetised with isoflurane and the lower hindlimbs were shaved and sterilised (iodine and 70% ethanol [vol./vol.]).…”

“…Overexpression of Pgc-1α in skeletal muscle of lean and obese Zucker rats To upregulate PGC-1α protein in muscle, we used an electrotransfection procedure, as we [3,16,17,21,34] and others [4,20,35] have done previously for different genes. Muscle transfection efficiencies are typically maintained within a 30% to 40% range, as was done in the present study and others [3,4,16,17,20,34,35].…”