Battey Edmund, Furrer Regula, Ross Jacob, Handschin Christoph, Ochala Julien, Stroud Matthew J
Centre of Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
J Cell Physiol. 2022 Jan;237(1):696-705. doi: 10.1002/jcp.30539. Epub 2021 Jul 28.
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-γ coactivator-1α (PGC-1α). Previous work has shown that overexpression of PGC-1α in skeletal muscle regulates mitochondrial biogenesis, myonuclear accretion and MND volume. However, whether PGC-1α 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-1α in skeletal muscle (PGC-1α mKO). Here, we show a differential myonuclear accretion response to endurance training that is governed by PGC-1α 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-1α mKO. However, in larger fibres, the relationship between MND and CSA was significantly altered in trained versus sedentary PGC-1α mKO, suggesting that PGC-1α 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-1α 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.
骨骼肌纤维的转录需求很高，需要数百个细胞核（肌细胞核）来沿着其长度生成专门的收缩机制和多个线粒体。每个肌细胞核在有限的细胞质体积（称为肌核域，MND）中对基因表达进行空间调节，该体积与纤维横截面积（CSA）呈正相关。耐力训练会引发骨骼肌的适应性反应，包括肌核增加、MND大小减小以及转录共激活因子过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）的表达增加。先前的研究表明，骨骼肌中PGC-1α的过表达可调节线粒体生物发生、肌核增加和MND体积。然而，PGC-1α在适应耐力训练的这些过程中是否至关重要仍不清楚。为了验证这一点，我们评估了耐力训练的野生型小鼠和骨骼肌中缺乏PGC-1α的小鼠（PGC-1α基因敲除小鼠，PGC-1α mKO）的肌核分布和组织情况。在此，我们展示了对耐力训练的不同肌核增加反应，该反应由PGC-1α控制，并取决于肌纤维大小。耐力训练后，PGC-1α基因敲除小鼠与对照组相比，MND大小与肌纤维CSA的正相关趋势更强，这表明在PGC-1α基因敲除小鼠中，随着纤维CSA增加，肌核增加受到轻微影响。然而，在较大的纤维中，训练组与久坐组的PGC-1α基因敲除小鼠中，MND与CSA之间的关系发生了显著变化，这表明PGC-1α对这些纤维中的肌核增加至关重要。因此，细胞核数量与CSA之间存在负相关，这表明在较大的纤维中，肌核数量未能随CSA成比例增加。我们的研究结果表明，PGC-1α是中等强度耐力训练后肌核增加的重要贡献因素。这可能通过使线粒体生物发生所需基因的转录速率足够，从而有助于对耐力训练的适应性反应。
