A role for the transcriptional coactivator PGC-1alpha in muscle refueling.
The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been identified as an inducible regulator of mitochondrial function. Skeletal muscle PGC-1alpha expression is induced post-exercise. Therefore, we sought to determine its role in the regulation of muscle fuel metabolism. Studies were performed using conditional, muscle-specific, PGC-1alpha gain-of-function and constitutive, generalized, loss-of-function mice. Forced expression of PGC-1alpha increased muscle glucose uptake concomitant with augmentation of glycogen stores, a metabolic response similar to post-exercise recovery. Induction of muscle PGC-1alpha expression prevented muscle glycogen depletion during exercise. Conversely, PGC-1alpha-deficient animals exhibited reduced rates of muscle glycogen repletion post-exercise. PGC-1alpha was shown to increase muscle glycogen stores via several mechanisms including stimulation of glucose import, suppression of glycolytic flux, and by down-regulation of the expression of glycogen phosphorylase and its activating kinase, phosphorylase kinase alpha. These findings identify PGC-1alpha as a critical regulator of skeletal muscle fuel stores.
Wende
Adam R
AR
Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Schaeffer
Paul J
PJ
Parker
Glendon J
GJ
Zechner
Christoph
C
Han
Dong-Ho
DH
Chen
May M
MM
Hancock
Chad R
CR
Lehman
John J
JJ
Huss
Janice M
JM
McClain
Donald A
DA
Holloszy
John O
JO
Kelly
Daniel P
DP
D000818:Animals; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000235:genetics / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010764:Phosphorylase Kinase / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors
D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D006003:Glycogen; D024981:Glycogen Phosphorylase; D010764:Phosphorylase Kinase; D005947:Glucose