The Aging Muscle Milieu and Transcription of PGC‐1α: a Role for Contractile Activity?
Authors: Carter Heather N , Shuen Michael , Gavendo Karli , Hood David A 
Published: November 2023

PGC‐1α is an established regulator of mitochondrial content and function in skeletal muscle. With advancing age it is known that expression of this transcriptional coactivator is lower than in young, healthy muscle. This deficit in PGC‐1α is a contributing factor to the defects in mitochondrial homeostasis observed in aged muscle, but the molecular mechanisms influencing this decline have not been examined. Furthermore, it has not been investigated whether the transcription of the PGC‐1α gene is altered in the aging muscle environment. Thus, we electroporated a 1.5kb PGC‐1α‐luciferase construct bilaterally into the tibialis anterior muscles of young (5 mo) and aged (35 mo) FBN344 rats. Aged muscle exhibited an ~61% decrease in transcriptional activity of the PGC‐1α promoter. This coincided with ~30% decreases in the transcription factors NFE2L2 (Nrf2) and Upstream factor‐1 (USF‐1) which have putative and known binding sites on the PGC‐1α promoter. The basal phosphorylation state of the signaling kinases p38 and AMPK, which are known activators of PGC‐1α transcription, were decreased in aged muscle. Additionally, we observed a 1.3‐fold increase in global methylation of aged DNA, an epigenetic modification associated with transcriptional silencing. Exercise is a potent stimulus that induces mitochondrial biogenesis largely through the activation of PGC‐1α. Therefore we investigated whether an acute bout of in situ contractile activity may reverse the transcriptional deficiency seen in aged muscle. The left TA muscle of young and aged electroporated animals was subjected to fatiguing contractile activity (40 mins) and 2 hours of subsequent recovery, while the right TA served as the control. In young muscle, contractile activity‐induced PGC‐1α transcription increased by ~1.5‐fold and returned to baseline with recovery. This was accompanied by a 1.2‐fold increase in PGC‐1α mRNA during the recovery period. In aged muscle, transcription increased ~1.7‐fold with contractile activity and remained elevated with the recovery period. PGC‐1α mRNA responded with a 1.6‐fold increase during recovery in the aged group, despite having a lower magnitude of transcriptional induction (Δ=0.28 transcription units) compared to the young (Δ=0.99 transcription units). Examination of p38 and AMPK also revealed attenuated phosphorylation in aged muscle in response to contractile activity. To gain insight into epigenetic regulation of the PGC‐1α promoter with aging and contractile activity, we are presently performing bisulfite sequencing and examining multiple CpG sites adjacent to the transcription start site. Our data suggest that the aged muscle milieu exhibits numerous impairments which likely contribute to the attenuation of PGC‐1α transcription in resting muscle. Despite these basal differences, contractile activity is sufficient to elicit increases in PGC‐1α gene expression, underscoring the importance of exercise to potentially correct age‐related deficits in mitochondrial homeostasis.Support or Funding InformationSupported by CIHR and NSERC.