Origins of interspecies variation in mammalian muscle metabolic enzymes

Kocha KM, Genge CE, Moyes CD. Origins of interspecies variation in mammalian muscle metabolic enzymes. Physiol Genomics 43: 873-883, 2011. First published May 17, 2011; doi:10.1152/physiolgenomics.00025.2011.-Do the transcriptional mechanisms that control an individual's mitochondrial content, PGC1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) and NRF1 (nuclear respiratory factor-1), also cause differences between species? We explored the determinants of cytochrome c oxidase (COX) activities in muscles from 12 rodents differing 1,000-fold in mass. Hindlimb muscles differed in scaling patterns from isometric (soleus, gastrocnemius) to allometric (tibialis anterior, scaling coefficient = -0.16). Consideration of myonuclear domain reduced the differences within species, but interspecies differences remained. For tibialis anterior, there was no significant scaling relationship in mRNA/g for COX4-1, PGC1 alpha, or NRF1, yet COX4-1 mRNA/g was a good predictor of COX activity (r(2) = 0.55), PGC1 alpha and NRF1 mRNA correlated with each other (r(2) = 0.42), and both could predict COX4-1 mRNA (r(2) = 0.48 and 0.52) and COX activity (r(2) = 0.55 and 0.49). This paradox was resolved by multivariate analysis, which explained 90% of interspecies variation, about equally partitioned between mass effects and PGC1 alpha (or NRF1) mRNA levels, independent of mass. To explore the determinants of PGC1 alpha mRNA, we analyzed 52 mammalian PGC1 alpha proximal promoters and found no size dependence in regulatory element distribution. Likewise, the activity of PGC1 alpha promoter reporter genes from 30 mammals showed no significant relationship with body mass. Collectively, these studies suggest that not all muscles scale equivalently, but for those that show allometric scaling, transcriptional regulation of the master regulators, PGC1 alpha and NRF1, does not account for scaling patterns, though it does contribute to interspecies differences in COX activities independent of mass.