PGC-1α transcription, exercise and aging muscle.
Heather N. Carter, Michael Shuen, Rosette P. Joseph and David A. Hood
York University, Muscle Health Research Centre, Toronto, ON M3J 1P3.
The transcriptional coactivator PGC-1α is responsible for the expression of many nuclear genes
encoding mitochondrial proteins in skeletal muscle. With aging, PGC-1α expression declines,
correlating with the reduction of mitochondria in skeletal muscles. Acute exercise is a potent
stimulus for PGC-1α transcriptional activation in young muscle. With successive exercise bouts,
this culminates in mitochondrial biogenesis. Previous work comparing adaptations between
young and aged muscle has documented that mitochondrial adaptations are blunted in aged
muscle after exercise. This tempered response may be due to transcriptional insufficiency, as
signaling kinases important for transcriptional activation are less responsive. Furthermore, aged
muscle contains hypermethylated DNA, which can prevent access of transcription factors to the
gene promoters. Whether contractile activity stimulates PGC-1α transcription in aged animals to
the same degree as in their younger counterparts has not been determined. Thus, we investigated
PGC-1α transcription following acute contractile activity in young and aged muscle. The tibialis
anterior (TA) muscles of 6 and 35 month old Fischer 344 BN rats were electrotransfected with a
1.5kb rat PGC-1α promoter construct upstream of a luciferase reporter. One week later, the left
TA was subjected to 15 mins of contractions (5 mins, 1Hz; 10 mins, 10Hz) followed by 1 hour of
recovery. In the aged animals, mitochondrial content and muscle mass were reduced by 28% and
40%, respectively. This reduction in mitochondria likely contributed the greater rate of muscle
fatigue in aged animals during 1 and 10Hz contractions. PGC-1α transcription in resting muscle
of aged animals was 64% of that found in young animals. In response to contractile activity,
PGC-1α transcription was increased by 2.3-fold in young animals. Interestingly, the transcription
of PGC-1α was suppressed by 6.7-fold following contractions in aged animals. Assessment of
transcript levels for the DNA methyltransferases, DNMT3a and DNMT3b, revealed less
expression after acute exercise in young animals. However, transcript levels were also reduced in
aged animals with or without acute exercise and recovery. These data suggest that the lower
levels of PGC-1α in aged muscle may be mediated by transcriptional deficits, and that these are
exacerbated in response to contractile activity. This may be a result of altered signaling directed
toward the PGC-1α promoter, or a markedly divergent time course of transcriptional activation
in response to exercise, compared to younger counterparts.