PGC-1α regulates myonuclear accretion after moderate endurance training

The transcriptional demands of skeletal muscle fibres are high and require hundreds of nuclei (myonuclei) to produce specialised contractile machinery and multiple mitochondria along their length. Each myonucleus spatially regulates gene expression in a finite volume of cytoplasm, termed the myonuclear domain (MND), which positively correlates with fibre cross-sectional area (CSA). Endurance training triggers adaptive responses in skeletal muscle, including myonuclear accretion, decreased MND sizes and increased expression of the transcription co-activator peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha). Previous work has shown that overexpression of PGC-1 alpha in skeletal muscle regulates mitochondrial biogenesis, myonuclear accretion and MND volume. However, whether PGC-1 alpha is critical for these processes in adaptation to endurance training remained unclear. To test this, we evaluated myonuclear distribution and organisation in endurance-trained wild-type mice and mice lacking PGC-1 alpha in skeletal muscle (PGC-1 alpha mKO). Here, we show a differential myonuclear accretion response to endurance training that is governed by PGC-1 alpha and is dependent on muscle fibre size. The positive relationship of MND size and muscle fibre CSA trended towards a stronger correlation in PGC-1a mKO versus control after endurance training, suggesting that myonuclear accretion was slightly affected with increasing fibre CSA in PGC-1 alpha mKO. However, in larger fibres, the relationship between MND and CSA was significantly altered in trained versus sedentary PGC-1 alpha mKO, suggesting that PGC-1 alpha is critical for myonuclear accretion in these fibres. Accordingly, there was a negative correlation between the nuclear number and CSA, suggesting that in larger fibres myonuclear numbers fail to scale with CSA. Our findings suggest that PGC-1 alpha is an important contributor to myonuclear accretion following moderate-intensity endurance training. This may contribute to the adaptive response to endurance training by enabling a sufficient rate of transcription of genes required for mitochondrial biogenesis.

Automated summary

PGC-1α plays a critical role in myonuclear accretion during adaptation to endurance training, especially in larger muscle fibers. Myonuclear accretion in PGC-1α mKO mice is slightly affected with increasing fiber size, but is significantly altered in trained larger fibers compared to sedentary mice, highlighting the importance of PGC-1α in myonuclear accretion in these fibers.