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

Miki Tadaishi,Yuichi Oishi,Yutaka Kano,Shinji Miura,Yuko Kai,Osamu Ezaki,Alejandro Lucia

doi:10.1371/journal.pone.0028290

Abstract

BackgroundMaximal 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 γ coactivator 1α (PGC-1α), a nuclear receptor coactivator, promotes mitochondrial biogenesis, a fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training increases PGC-1α in skeletal muscle, PGC-1α-mediated changes may contribute to the improvement of exercise capacity and VO2max. There are three isoforms of PGC-1α mRNA. PGC-1α-b protein, whose amino terminus is different from PGC-1α-a protein, is a predominant PGC-1α isoform in response to exercise. We investigated whether alterations of skeletal muscle metabolism by overexpression of PGC-1α-b in skeletal muscle, but not heart, would increase VO2max and exercise capacity.Methodology/Principal FindingsTransgenic mice showed overexpression of PGC-1α-b protein in skeletal muscle but not in heart. Overexpression of PGC-1α-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/SignificanceIncreased 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-1α-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.

Highlights

Cardiorespiratory fitness (CRF) is a strong and independent predictor of all-cause and cardiovascular disease mortality [1,2]
PGC-1a protein was identified by Western blot analysis with an antibody against the carboxyl terminus of the PGC-1a-a protein, because the carboxyl terminus is the same in all PGC-1a isoforms [13]
No significant change was observed between the genotypes, which confirmed that PGC-1a-b protein was not over-expressed in these transgenic mice

Summary

Introduction

Cardiorespiratory fitness (CRF) is a strong and independent predictor of all-cause and cardiovascular disease mortality [1,2]. Aerobic interval training was shown to improve maximal stroke volume (measured as peak O2 pulse) and Ca2+ cycling and mitochondrial capacity in skeletal muscle (assessed by improved sarcoplasmic reticulum ATPase capacity and peroxisome proliferator-activated receptor c coactivator 1a (PGC-1a) levels in skeletal muscle) to a larger extent than continuous moderate exercise in heart failure and metabolic syndrome patients [9,10]. It is not clear whether increased mitochondrial capacity, fatty acid oxidation and blood flow in skeletal muscle in response to exercise training contribute to an increase in VO2max. We investigated whether alterations of skeletal muscle metabolism by overexpression of PGC-1a-b in skeletal muscle, but not heart, would increase VO2max and exercise capacity

Methods

Results

Conclusion