Upstream activators of PGC‐1α transcription with acute contractile activity (1164.4)

Abstract

PGC‐1α is a potent transcriptional coactivator of numerous genes involved in contractile activity‐induced mitochondrial biogenesis. We sought to describe the role of transcription factors that regulate the PGC‐1α promoter in the context of acute contractile activity along with established downstream targets. A 1.5kb upstream region of the PGC‐1α promoter fused to a luciferase reporter was injected and electroporated into the rat tibialis anterior (TA) muscle bilaterally. Five days after injection the left TA was subjected to in situ contractile activity for 15 mins (5 mins at 1 Hz, 10 mins at 10Hz) while the right TA served as a resting control. Animals were allowed to recover for 2 hours, and then tissues were extracted. During stimulation, muscle force declined to 40% of initial tension. Transcriptional activity of the PGC‐1α promoter was elevated 3.6‐fold in the stimulated TA, while PGC‐1α mRNA was increased by 1.4‐fold. COX IV and NRF‐1, transcriptional targets of PGC‐1α, were each elevated by 1.2‐fold. NF‐E2 related factor 2 (Nrf2), a transcription factor with a putative binding site on the PGC‐1α promoter was increased by 1.4‐fold at the mRNA level, while GATA4, previously identified as a transcriptional regulator of PGC‐1α, remained unchanged. Thus, contractile activity signals lead to large increases in PGC‐1α transcription along with smaller increments in upstream activators, and downstream targets.Grant Funding Source: Supported By NSERC.