Transcriptome Analyses of Loss of Pitx2 Gene Function at Fetal/Neonatal Mouse Muscle

Ablation of the homeobox gene Pitx2 in skeletal muscles resulted in abnormally elevated levels of blood glucose and insulin as animals became morbidly obese. Grasping defects, abnormal accumulation of inter-myofiber connective tissue, deformed ultrastructure of the contractile apparatus, vestigial mitochondria accompanied by increased FoxO3-mediated mitophagy, and multiple disrupted metabolic pathways were apparent at the onset of blood-measurable metabolic disease. The respiration rate of mutant muscle cells was reduced, due to problems with both the electron transport chain (complex I, II and IV) and ATP synthase (complex V), and was consistent with the vestigial mitochondria and disruption in fatty acid metabolism observed in mutant muscle. Pitx2 influences expression of components of the contractile apparatus and the molecular machinery that assembles it. Similarly, Pitx2 influences the expression of genes encoding metabolic enzymes and genes encoding the molecular machinery that will be needed after birth for facultative adaptation of muscle energy metabolism. Tibialis mRNA profiles of 30-day old control (Pitx2fl/z) and mutant (MCKcrePitx2fl/z) mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 4000.