Skeletal Muscle-Specific Expression of PGC-1α-b, an Exercise-Responsive Isoform, Increases Exercise Capacity and Peak Oxygen Uptake

Background: Maximal oxygen uptake (VO2max) predicts mortality and is associated with endurance performance. Trained subjects have a high VO2max due to a high cardiac output and high metabolic capacity of skeletal muscles. Peroxisome proliferator-activated receptor c coactivator 1 alpha (PGC-1 alpha), a nuclear receptor coactivator, promotes mitochondrial biogenesis, a fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training increases PGC-1 alpha in skeletal muscle, PGC-1 alpha-mediated changes may contribute to the improvement of exercise capacity and VO2max. There are three isoforms of PGC-1 alpha mRNA. PGC-1 alpha-b protein, whose amino terminus is different from PGC-1 alpha-a protein, is a predominant PGC-1a isoform in response to exercise. We investigated whether alterations of skeletal muscle metabolism by overexpression of PGC-1 alpha-b in skeletal muscle, but not heart, would increase VO(2ma)x and exercise capacity. Methodology/Principal Findings: Transgenic mice showed overexpression of PGC-1 alpha-b protein in skeletal muscle but not in heart. Overexpression of PGC-1 alpha-b promoted mitochondrial biogenesis 4-fold, increased the expression of fatty acid transporters, enhanced angiogenesis in skeletal muscle 1.4 to 2.7-fold, and promoted exercise capacity (expressed by maximum speed) by 35% and peak oxygen uptake by 20%. Across a broad range of either the absolute exercise intensity, or the same relative exercise intensities, lipid oxidation was always higher in the transgenic mice than wild-type littermates, suggesting that lipid is the predominant fuel source for exercise in the transgenic mice. However, muscle glycogen usage during exercise was absent in the transgenic mice. Conclusions/Significance: Increased mitochondrial biogenesis, capillaries, and fatty acid transporters in skeletal muscles may contribute to improved exercise capacity via an increase in fatty acid utilization. Increases in PGC-1 alpha-b protein or function might be a useful strategy for sedentary subjects to perform exercise efficiently, which would lead to prevention of life-style related diseases and increased lifespan.